International Journal of Molecular Sciences

2024

Jump to: 2023, 2022, 2021

11 pages, 1252 KiB

Open AccessReview

Molecular Mechanism of Action of Endocrine-Disrupting Chemicals on the Respiratory System

by Francesco Molinari, Gianluca Antonio Franco, Nicla Tranchida, Rosanna Di Paola and Marika Cordaro

Int. J. Mol. Sci. 2024, 25(23), 12540; https://doi.org/10.3390/ijms252312540 - 22 Nov 2024

Viewed by 214

Abstract

Endocrine-disrupting chemicals (EDCs) are a growing health hazard for humankind and respiratory health in particular. Such chemical compounds are present in the environment and food and may interfere with physiological processes through interference with functions of the endocrine system, making humans more susceptible [...] Read more.

Endocrine-disrupting chemicals (EDCs) are a growing health hazard for humankind and respiratory health in particular. Such chemical compounds are present in the environment and food and may interfere with physiological processes through interference with functions of the endocrine system, making humans more susceptible to various types of diseases. This review aims to discuss the effects of EDCs on the respiratory system. Exposure to EDCs during fetal development and adulthood increases susceptibility to respiratory diseases such as asthma, COPD, and pulmonary fibrosis. EDCs are both multiple and complex in the ways they can act. Indeed, these chemicals may induce oxidative stress, modify cell proliferation and differentiation, interfere with tissue repair, and modulate the inflammatory response. Moreover, EDCs may also break the integrity of the blood–air barrier, allowing noxious substances to penetrate into the lung and thus enhancing the opportunity for infection. In conclusion, the scientific evidence available tends to indicate that EDCs exposure is strongly linked to the initiation of respiratory disease. Further research will be important in discovering the underlying molecular mechanisms and devising preventive and therapeutic measures. Full article

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14 pages, 1737 KiB

Open AccessArticle

Differential Gene Expression in Late-Onset Friedreich Ataxia: A Comparative Transcriptomic Analysis Between Symptomatic and Asymptomatic Sisters

by Sara Petrillo, Alessia Perna, Andrea Quatrana, Gabriella Silvestri, Enrico Bertini, Fiorella Piemonte and Massimo Santoro

Int. J. Mol. Sci. 2024, 25(21), 11615; https://doi.org/10.3390/ijms252111615 - 29 Oct 2024

Viewed by 560

Abstract

Friedreich ataxia (FRDA) is the most common inherited ataxia, primarily impacting the nervous system and the heart. It is characterized by GAA repeat expansion in the FXN gene, leading to reduced mitochondrial frataxin levels. Previously, we described a family displaying two expanded GAA [...] Read more.

Friedreich ataxia (FRDA) is the most common inherited ataxia, primarily impacting the nervous system and the heart. It is characterized by GAA repeat expansion in the FXN gene, leading to reduced mitochondrial frataxin levels. Previously, we described a family displaying two expanded GAA alleles, not only in the proband affected by late-onset FRDA but also in the younger asymptomatic sister. The molecular characterization of the expanded repeats showed that the affected sister carried two canonical uninterrupted GAA expended repeats, whereas the asymptomatic sister had a compound heterozygous for a canonical GAA repeat and an expanded GAAGGA motif. Therefore, we decided to perform RNA sequencing (RNA-seq) on fibroblasts from both sisters in order to understand whether some genes and/or pathways might be differently involved in the occurrence of FRDA clinical manifestation. The transcriptomic analysis revealed 398 differentially expressed genes. Notably, TLR4, IL20RB, and SLITRK5 were up-regulated, while TCF21 and GRIN2A were down-regulated, as validated by qRT-PCR. Gene ontology (GO) enrichment and network analysis highlighted significant involvement in immune response and neuronal functions. Our results, in particular, suggest that TLR4 may contribute to inflammation in FRDA, while IL20RB, SLITRK5, TCF21, and GRIN2A dysregulation may play roles in the disease pathogenesis. This study introduces new perspectives on the inflammatory and developmental aspects in FRDA, offering potential targets for therapeutic intervention. Full article

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14 pages, 3499 KiB

Open AccessArticle

High Mitophagy and Low Glycolysis Predict Better Clinical Outcomes in Acute Myeloid Leukemias

by Amreen Salwa, Alessandra Ferraresi, Letizia Vallino, Chinmay Maheshwari, Riccardo Moia, Gianluca Gaidano and Ciro Isidoro

Int. J. Mol. Sci. 2024, 25(21), 11527; https://doi.org/10.3390/ijms252111527 - 27 Oct 2024

Viewed by 741

Abstract

Acute myeloid leukemia (AML) emerges as one of the most common and fatal leukemias. Treatment of the disease remains highly challenging owing to profound metabolic rewiring mechanisms that confer plasticity to AML cells, ultimately resulting in therapy resistance. Autophagy, a highly conserved lysosomal-driven [...] Read more.

Acute myeloid leukemia (AML) emerges as one of the most common and fatal leukemias. Treatment of the disease remains highly challenging owing to profound metabolic rewiring mechanisms that confer plasticity to AML cells, ultimately resulting in therapy resistance. Autophagy, a highly conserved lysosomal-driven catabolic process devoted to macromolecular turnover, displays a dichotomous role in AML by suppressing or promoting disease development and progression. Glycolytic metabolism represents a pivotal strategy for AML cells to sustain increasing energy needs related to uncontrolled growth during disease progression. In this study, we tested the hypothesis that a high glycolytic rate and low autophagy flux could represent an advantage for AML cell proliferation and thus be detrimental for patient’s prognosis, and vice versa. TCGA in silico analysis of the AML cohort shows that the high expression of MAP1LC3B (along with that of BECN1 and with low expression of p62/SQSTM1) and the high expression of BNIP3 (along with that of PRKN and of MAP1LC3B), which together are indicative of increased autophagy and mitophagy, correlate with better prognosis. On the other hand, the high expression of glycolytic markers HK2, PFKM, and PKM correlates with poor prognosis. Most importantly, the association of a low expression of glycolytic markers with a high expression of autophagy–mitophagy markers conferred the longest overall survival for AML patients. Transcriptomic analysis showed that this combined signature correlates with the downregulation of a subset of genes required for the differentiation of myeloid cells, lactate/pyruvate transporters, and cell cycle progression, in parallel with the upregulation of genes involved in autophagy/lysosomal trafficking and proteolysis, anti-tumor responses like beta-interferon production, and positive regulation of programmed cell death. Taken together, our data support the view that enhanced autophagy-mitophagy flux together with low glycolytic rate predisposes AML patients to a better clinical outcome, suggesting that autophagy inducers and glucose restrictors may hold potential as adjuvant therapeutics for improving AML management. Full article

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32 pages, 4472 KiB

Open AccessReview

Diagnostic Utility of Copeptin in Pediatric Patients with Polyuria-Polydipsia Syndrome: A Systematic Review and Meta-Analysis

by Diana-Andreea Ciortea, Carmen Loredana Petrea (Cliveți), Laura Bujoreanu Bezman, Iolanda Cristina Vivisenco, Sorin Ion Berbece, Gabriela Gurău, Mădălina Nicoleta Matei and Aurel Nechita

Int. J. Mol. Sci. 2024, 25(19), 10743; https://doi.org/10.3390/ijms251910743 - 5 Oct 2024

Cited by 1 | Viewed by 1036

Abstract

Pediatric patients with polyuria polydipsia syndrome (PPS) represent a diagnostic challenge for clinicians because of the technical difficulties in performing the gold standard water deprivation test (WDT). Copeptin, a stable biomarker representing the C-terminal portion of the polypeptide chain of the antidiuretic hormone, [...] Read more.

Pediatric patients with polyuria polydipsia syndrome (PPS) represent a diagnostic challenge for clinicians because of the technical difficulties in performing the gold standard water deprivation test (WDT). Copeptin, a stable biomarker representing the C-terminal portion of the polypeptide chain of the antidiuretic hormone, is a reliable diagnostic tool. To assess the diagnostic accuracy of baseline copeptin dosing, arginine/hypertonic saline copeptin stimulation tests, and WDT. This study aimed to establish the diagnostic utility of copeptin in pediatric patients by distinguishing between central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia. Comparative and non-comparative primary studies published between January 2018 and August 2024 focusing on children were searched and included in PubMed, Cochrane Library, Web of Science, ScienceDirect, Scopus, and Google Scholar. The QUADAS-2 tool was used to assess the risk of bias and applicability. Meta-analyses used fixed effects models because of low heterogeneity and the HSROC model. Eleven studies were included with an overall low bias and no significant applicability concerns. The mean pooled sensitivity = 0.98 (95% CI: 0.936–1.025), pooled specificity = 0.947 (95% CI: 0.920–0.973), and AUC = 0.972 (95% CI: 0.952–0.992), indicating excellent diagnostic accuracy. Stimulation methods for copeptin dosing represent an effective and less invasive diagnostic test for children with PPS, and future development of standard copeptin testing protocols is needed. Full article

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15 pages, 2904 KiB

Open AccessArticle

Glycoprotein E-Displaying Nanoparticles Induce Robust Neutralizing Antibodies and T-Cell Response against Varicella Zoster Virus

by Hong Wang, Sibo Zhang, Wenhui Xue, Yarong Zeng, Liqin Liu, Lingyan Cui, Hongjing Liu, Yuyun Zhang, Lin Chen, Meifeng Nie, Rongwei Zhang, Zhenqin Chen, Congming Hong, Qingbing Zheng, Tong Cheng, Ying Gu, Tingting Li, Ningshao Xia and Shaowei Li

Int. J. Mol. Sci. 2024, 25(18), 9872; https://doi.org/10.3390/ijms25189872 - 12 Sep 2024

Viewed by 1151

Abstract

The Varicella zoster virus (VZV), responsible for both varicella (chickenpox) and herpes zoster (shingles), presents significant global health challenges. While primary VZV infection primarily affects children, leading to chickenpox, reactivation in later life can result in herpes zoster and associated post-herpetic neuralgia, among [...] Read more.

The Varicella zoster virus (VZV), responsible for both varicella (chickenpox) and herpes zoster (shingles), presents significant global health challenges. While primary VZV infection primarily affects children, leading to chickenpox, reactivation in later life can result in herpes zoster and associated post-herpetic neuralgia, among other complications. Vaccination remains the most effective strategy for VZV prevention, with current vaccines largely based on the attenuated vOka strains. Although these vaccines are generally effective, they can induce varicella-like rashes and have sparked concerns regarding cell virulence. As a safer alternative, subunit vaccines circumvent these issues. In this study, we developed a nanoparticle-based vaccine displaying the glycoprotein E (gE) on ferritin particles using the SpyCatcher/SpyTag system, termed FR-gE. This FR-gE nanoparticle antigen elicited substantial gE-specific binding and VZV-neutralizing antibody responses in BALB/c and C57BL/6 mice—responses that were up to 3.2-fold greater than those elicited by the subunit gE while formulated with FH002C, aluminum hydroxide, or a liposome-based XUA01 adjuvant. Antibody subclass analysis revealed that FR-gE produced comparable levels of IgG1 and significantly higher levels of IgG2a compared to subunit gE, indicating a Th1-biased immune response. Notably, XUA01-adjuvanted FR-gE induced a significant increase in neutralizing antibody response compared to the live attenuated varicella vaccine and recombinant vaccine, Shingrix. Furthermore, ELISPOT assays demonstrated that immunization with FR-gE/XUA01 generated IFN-γ and IL-2 levels comparable to those induced by Shingrix. These findings underscore the potential of FR-gE as a promising immunogen for the development of varicella and herpes zoster vaccines. Full article

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58 pages, 1391 KiB

Open AccessReview

Advancements in Plant-Based Therapeutics for Hepatic Fibrosis: Molecular Mechanisms and Nanoparticulate Drug Delivery Systems

by Alina Ciceu, Ferenc Fenyvesi, Anca Hermenean, Simona Ardelean, Simona Dumitra and Monica Puticiu

Int. J. Mol. Sci. 2024, 25(17), 9346; https://doi.org/10.3390/ijms25179346 - 28 Aug 2024

Viewed by 973

Abstract

Chronic liver injuries often lead to hepatic fibrosis, a condition characterized by excessive extracellular matrix accumulation and abnormal connective tissue hyperplasia. Without effective treatment, hepatic fibrosis can progress to cirrhosis or hepatocellular carcinoma. Current treatments, including liver transplantation, are limited by donor shortages [...] Read more.

Chronic liver injuries often lead to hepatic fibrosis, a condition characterized by excessive extracellular matrix accumulation and abnormal connective tissue hyperplasia. Without effective treatment, hepatic fibrosis can progress to cirrhosis or hepatocellular carcinoma. Current treatments, including liver transplantation, are limited by donor shortages and high costs. As such, there is an urgent need for effective therapeutic strategies. This review focuses on the potential of plant-based therapeutics, particularly polyphenols, phenolic acids, and flavonoids, in treating hepatic fibrosis. These compounds have demonstrated anti-fibrotic activities through various signaling pathways, including TGF-β/Smad, AMPK/mTOR, Wnt/β-catenin, NF-κB, PI3K/AKT/mTOR, and hedgehog pathways. Additionally, this review highlights the advancements in nanoparticulate drug delivery systems that enhance the pharmacokinetics, bioavailability, and therapeutic efficacy of these bioactive compounds. Methodologically, this review synthesizes findings from recent studies, providing a comprehensive analysis of the mechanisms and benefits of these plant-based treatments. The integration of novel drug delivery systems with plant-based therapeutics holds significant promise for developing effective treatments for hepatic fibrosis. Full article

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14 pages, 586 KiB

Open AccessArticle

High Resolution HLA-A, HLA-B, and HLA-C Allele Frequencies in Romanian Hematopoietic Stem Cell Donors

by Andreea Mirela Caragea, Radu-Ioan Ursu, Ion Maruntelu, Maria Tizu, Alexandra-Elena Constantinescu, Adriana Tălăngescu and Ileana Constantinescu

Int. J. Mol. Sci. 2024, 25(16), 8837; https://doi.org/10.3390/ijms25168837 - 14 Aug 2024

Viewed by 736

Abstract

The HLA genes are associated with various autoimmune pathologies, with the control of the immune response also being significant in organs and cells transplantation. The aim of the study is to identify the HLA-A, HLA-B, and HLA-C alleles frequencies in the analyzed Romanian [...] Read more.

The HLA genes are associated with various autoimmune pathologies, with the control of the immune response also being significant in organs and cells transplantation. The aim of the study is to identify the HLA-A, HLA-B, and HLA-C alleles frequencies in the analyzed Romanian cohort. We performed HLA typing using next-generation sequencing (NGS) in a Romanian cohort to estimate class I HLA allele frequencies up to a six-digit resolution. A total of 420 voluntary donors from the National Registry of Voluntary Hematopoietic Stem Cell Donors (RNDVCSH) were included in the study for HLA genotyping. Peripheral blood samples were taken and brought to the Fundeni Clinical Institute during 2020–2021. HLA genotyping was performed using the Immucor Mia Fora NGS MFlex kit. A total of 109 different alleles were detected in 420 analyzed samples, out of which 31 were for HLA-A, 49 for HLA-B, and 29 for HLA-C. The most frequent HLA-A alleles were HLA-A*02:01:01 (26.11%), HLA-A*01:01:01 (12.5%), HLA-A*24:02:01 (11.67%), HLA-A*03:01:01 (9.72%), HLA-A*11:01:01, and HLA-A*32:01:01 (each with 8.6%). For the HLA-B locus, the most frequent allele was HLA-B*18:01:01 (11.25%), followed by HLA-B*51:01:01 (10.83%) and HLA-B*08:01:01 (7.78%). The most common HLA-C alleles were HLA-C*07:01:01 (17.36%), HLA-C*04:01:01 (13.47%), and HLA-C*12:03:01 (10.69%). Follow-up studies are ongoing for confirming the detected results. Full article

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28 pages, 2221 KiB

Open AccessReview

Liquid Biopsy in the Clinical Management of Cancers

by Ho-Yin Ho, Kei-See (Kasey) Chung, Chau-Ming Kan and Sze-Chuen (Cesar) Wong

Int. J. Mol. Sci. 2024, 25(16), 8594; https://doi.org/10.3390/ijms25168594 - 6 Aug 2024

Cited by 2 | Viewed by 2632

Abstract

Liquid biopsy, a noninvasive diagnosis that examines circulating tumor components in body fluids, is increasingly used in cancer management. An overview of relevant literature emphasizes the current state of liquid biopsy applications in cancer care. Biomarkers in liquid biopsy, particularly circulating tumor DNA [...] Read more.

Liquid biopsy, a noninvasive diagnosis that examines circulating tumor components in body fluids, is increasingly used in cancer management. An overview of relevant literature emphasizes the current state of liquid biopsy applications in cancer care. Biomarkers in liquid biopsy, particularly circulating tumor DNA (ctDNA), circulating tumor RNAs (ctRNA), circulating tumor cells (CTCs), extracellular vesicles (EVs), and other components, offer promising opportunities for early cancer diagnosis, treatment selection, monitoring, and disease assessment. The implementation of liquid biopsy in precision medicine has shown significant potential in various cancer types, including lung cancer, colorectal cancer, breast cancer, and prostate cancer. Advances in genomic and molecular technologies such as next-generation sequencing (NGS) and digital polymerase chain reaction (dPCR) have expanded the utility of liquid biopsy, enabling the detection of somatic variants and actionable genomic alterations in tumors. Liquid biopsy has also demonstrated utility in predicting treatment responses, monitoring minimal residual disease (MRD), and assessing tumor heterogeneity. Nevertheless, standardizing liquid biopsy techniques, interpreting results, and integrating them into the clinical routine remain as challenges. Despite these challenges, liquid biopsy has significant clinical implications in cancer management, offering a dynamic and noninvasive approach to understanding tumor biology and guiding personalized treatment strategies. Full article

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13 pages, 1782 KiB

Open AccessArticle

Effects of Atorvastatin and Simvastatin on the Bioenergetic Function of Isolated Rat Brain Mitochondria

by Krzysztof Wojcicki, Adrianna Budzinska and Wieslawa Jarmuszkiewicz

Int. J. Mol. Sci. 2024, 25(15), 8494; https://doi.org/10.3390/ijms25158494 - 3 Aug 2024

Viewed by 1180

Abstract

Little is known about the effects of statins, which are cholesterol-lowering drugs, on the bioenergetic functions of mitochondria in the brain. This study aimed to elucidate the direct effects of atorvastatin and simvastatin on the bioenergetics of isolated rat brain mitochondria by measuring [...] Read more.

Little is known about the effects of statins, which are cholesterol-lowering drugs, on the bioenergetic functions of mitochondria in the brain. This study aimed to elucidate the direct effects of atorvastatin and simvastatin on the bioenergetics of isolated rat brain mitochondria by measuring the statin-induced changes in respiratory chain activity, ATP synthesis efficiency, and the production of reactive oxygen species (ROS). Our results in isolated brain mitochondria are the first to demonstrate that atorvastatin and simvastatin dose-dependently significantly inhibit the activity of the mitochondrial respiratory chain, resulting in a decreased respiratory rate, a decreased membrane potential, and increased ROS formation. Moreover, the tested statins reduced mitochondrial coupling parameters, the ADP/O ratio, the respiratory control ratio, and thus, the oxidative phosphorylation efficiency in brain mitochondria. Among the oxidative phosphorylation complexes, statin-induced mitochondrial impairment concerned complex I, complex III, and ATP synthase activity. The calcium-containing atorvastatin had a significantly more substantial effect on isolated brain mitochondria than simvastatin. The higher inhibitory effect of atorvastatin was dependent on calcium ions, which may lead to the disruption of calcium homeostasis in mitochondria. These findings suggest that while statins are effective in their primary role as cholesterol-lowering agents, their use may impair mitochondrial function, which may have consequences for brain health, particularly when mitochondrial energy efficiency is critical. Full article

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19 pages, 8205 KiB

Open AccessReview

Therapy-Induced Senescence: Novel Approaches for Markers Identification

by Francesco Pacifico, Fulvio Magni, Antonio Leonardi and Elvira Crescenzi

Int. J. Mol. Sci. 2024, 25(15), 8448; https://doi.org/10.3390/ijms25158448 - 2 Aug 2024

Viewed by 1439

Abstract

Therapy-induced senescence (TIS) represents a major cellular response to anticancer treatments. Both malignant and non-malignant cells in the tumor microenvironment undergo TIS and may be harmful for cancer patients since TIS cells develop a senescence-associated secretory phenotype (SASP) that can sustain tumor growth. [...] Read more.

Therapy-induced senescence (TIS) represents a major cellular response to anticancer treatments. Both malignant and non-malignant cells in the tumor microenvironment undergo TIS and may be harmful for cancer patients since TIS cells develop a senescence-associated secretory phenotype (SASP) that can sustain tumor growth. The SASP also modulates anti-tumor immunity, although the immune populations involved and the final results appear to be context-dependent. In addition, senescent cancer cells are able to evade senescence growth arrest and to resume proliferation, likely contributing to relapse. So, research data suggest that TIS induction negatively affects therapy outcomes in cancer patients. In line with this, new interventions aimed at the removal of senescent cells or the reprogramming of their SASP, called senotherapy, have become attractive therapeutic options. To date, the lack of reliable, cost-effective, and easy-to-use TIS biomarkers hinders the application of recent anti-senescence therapeutic approaches in the clinic. Hence, the identification of biomarkers for the detection of TIS tumor cells and TIS non-neoplastic cells is a high priority in cancer research. In this review article, we describe the current knowledge about TIS, outline critical gaps in our knowledge, and address recent advances and novel approaches for the discovery of TIS biomarkers. Full article

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21 pages, 8080 KiB

Open AccessArticle

Assessment of Tie2-Rejuvenated Nucleus Pulposus Cell Transplants from Young and Old Patient Sources Demonstrates That Age Still Matters

by Yuto Otani, Jordy Schol, Daisuke Sakai, Yoshihiko Nakamura, Kosuke Sako, Takayuki Warita, Shota Tamagawa, Luca Ambrosio, Daiki Munesada, Shota Ogasawara, Erika Matsushita, Asami Kawachi, Mitsuru Naiki, Masato Sato and Masahiko Watanabe

Int. J. Mol. Sci. 2024, 25(15), 8335; https://doi.org/10.3390/ijms25158335 - 30 Jul 2024

Viewed by 1370

Abstract

Cell transplantation is being actively explored as a regenerative therapy for discogenic back pain. This study explored the regenerative potential of Tie2⁺ nucleus pulposus progenitor cells (NPPCs) from intervertebral disc (IVD) tissues derived from young (<25 years of age) and old (>60 [...] Read more.

Cell transplantation is being actively explored as a regenerative therapy for discogenic back pain. This study explored the regenerative potential of Tie2⁺ nucleus pulposus progenitor cells (NPPCs) from intervertebral disc (IVD) tissues derived from young (<25 years of age) and old (>60 years of age) patient donors. We employed an optimized culture method to maintain Tie2 expression in NP cells from both donor categories. Our study revealed similar Tie2 positivity rates regardless of donor types following cell culture. Nevertheless, clear differences were also found, such as the emergence of significantly higher (3.6-fold) GD2 positivity and reduced (2.7-fold) proliferation potential for older donors compared to young sources. Our results suggest that, despite obtaining a high fraction of Tie2⁺ NP cells, cells from older donors were already committed to a more mature phenotype. These disparities translated into functional differences, influencing colony formation, extracellular matrix production, and in vivo regenerative potential. This study underscores the importance of considering age-related factors in NPPC-based therapies for disc degeneration. Further investigation into the genetic and epigenetic alterations of Tie2⁺ NP cells from older donors is crucial for refining regenerative strategies. These findings shed light on Tie2⁺ NPPCs as a promising cell source for IVD regeneration while emphasizing the need for comprehensive understanding and scalability considerations in culture methods for broader clinical applicability. Full article

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52 pages, 3749 KiB

Open AccessReview

Comprehensive Review of COVID-19: Epidemiology, Pathogenesis, Advancement in Diagnostic and Detection Techniques, and Post-Pandemic Treatment Strategies

by Yiu-Sing Chung, Ching-Yin Lam, Pak-Hei Tan, Hin-Fung Tsang and Sze-Chuen Cesar Wong

Int. J. Mol. Sci. 2024, 25(15), 8155; https://doi.org/10.3390/ijms25158155 - 26 Jul 2024

Cited by 1 | Viewed by 1843

Abstract

At present, COVID-19 remains a public health concern due to the ongoing evolution of SARS-CoV-2 and its prevalence in particular countries. This paper provides an updated overview of the epidemiology and pathogenesis of COVID-19, with a focus on the emergence of SARS-CoV-2 variants [...] Read more.

At present, COVID-19 remains a public health concern due to the ongoing evolution of SARS-CoV-2 and its prevalence in particular countries. This paper provides an updated overview of the epidemiology and pathogenesis of COVID-19, with a focus on the emergence of SARS-CoV-2 variants and the phenomenon known as ‘long COVID’. Meanwhile, diagnostic and detection advances will be mentioned. Though many inventions have been made to combat the COVID-19 pandemic, some outstanding ones include multiplex RT-PCR, which can be used for accurate diagnosis of SARS-CoV-2 infection. ELISA-based antigen tests also appear to be potential diagnostic tools to be available in the future. This paper also discusses current treatments, vaccination strategies, as well as emerging cell-based therapies for SARS-CoV-2 infection. The ongoing evolution of SARS-CoV-2 underscores the necessity for us to continuously update scientific understanding and treatments for it. Full article

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18 pages, 814 KiB

Open AccessReview

The Purinergic P2X7 Receptor as a Target for Adjunctive Treatment for Drug-Refractory Epilepsy

by Divyeshz Thakku Sivakumar, Krishi Jain, Noura Alfehaid, Yitao Wang, Xinchen Teng, Wolfgang Fischer and Tobias Engel

Int. J. Mol. Sci. 2024, 25(13), 6894; https://doi.org/10.3390/ijms25136894 - 23 Jun 2024

Cited by 2 | Viewed by 1896

Abstract

Epilepsy is one of the most common neurological diseases worldwide. Anti-seizure medications (ASMs) with anticonvulsants remain the mainstay of epilepsy treatment. Currently used ASMs are, however, ineffective to suppress seizures in about one third of all patients. Moreover, ASMs show no significant impact [...] Read more.

Epilepsy is one of the most common neurological diseases worldwide. Anti-seizure medications (ASMs) with anticonvulsants remain the mainstay of epilepsy treatment. Currently used ASMs are, however, ineffective to suppress seizures in about one third of all patients. Moreover, ASMs show no significant impact on the pathogenic mechanisms involved in epilepsy development or disease progression and may cause serious side-effects, highlighting the need for the identification of new drug targets for a more causal therapy. Compelling evidence has demonstrated a role for purinergic signalling, including the nucleotide adenosine 5′-triphosphate (ATP) during the generation of seizures and epilepsy. Consequently, drugs targeting specific ATP-gated purinergic receptors have been suggested as promising treatment options for epilepsy including the cationic P2X7 receptor (P27XR). P2X7R protein levels have been shown to be increased in the brain of experimental models of epilepsy and in the resected brain tissue of patients with epilepsy. Animal studies have provided evidence that P2X7R blocking can reduce the severity of acute seizures and the epileptic phenotype. The current review will provide a brief summary of recent key findings on P2X7R signalling during seizures and epilepsy focusing on the potential clinical use of treatments based on the P2X7R as an adjunctive therapeutic strategy for drug-refractory seizures and epilepsy. Full article

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14 pages, 3511 KiB

Open AccessArticle

Effects of Sapindus mukorossi Seed Oil on Bone Healing Efficiency: An Animal Study

by Po-Jan Kuo, Yu-Hsiang Lin, Yu-Xuan Huang, Sheng-Yang Lee and Haw-Ming Huang

Int. J. Mol. Sci. 2024, 25(12), 6749; https://doi.org/10.3390/ijms25126749 - 19 Jun 2024

Cited by 1 | Viewed by 997

Abstract

Natural products have attracted great interest in the development of tissue engineering. Recent studies have demonstrated that unsaturated fatty acids found in natural plant seed oil may exhibit positive osteogenic effects; however, few in vivo studies have focused on the use of plant [...] Read more.

Natural products have attracted great interest in the development of tissue engineering. Recent studies have demonstrated that unsaturated fatty acids found in natural plant seed oil may exhibit positive osteogenic effects; however, few in vivo studies have focused on the use of plant seed oil for bone regeneration. The aim of this study is to investigate the effects of seed oil found in Sapindus mukorossi (S. mukorossi) on the osteogenic differentiation of mesenchymal stem cells and bone growth in artificial bone defects in vivo. In this study, Wharton-jelly-derived mesenchymal stem cells (WJMSCs) were co-cultured with S. mukorossi seed oil. Cellular osteogenic capacity was assessed using Alizarin Red S staining. Real-time PCR was carried out to evaluate ALP and OCN gene expression. The potential of S. mukorossi seed oil to enhance bone growth was assessed using an animal model. Four 6 mm circular defects were prepared at the parietal bone of New Zealand white rabbits. The defects were filled with hydrogel and hydrogel-S. mukorossi seed oil, respectively. Quantitative analysis of micro-computed tomography (Micro-CT) and histological images was conducted to compare differences in osteogenesis between oil-treated and untreated samples. Although our results showed no significant differences in viability between WJMSCs treated with and without S. mukorossi seed oil, under osteogenic conditions, S. mukorossi seed oil facilitated an increase in mineralized nodule secretion and upregulated the expression of ALP and OCN genes in the cells (p < 0.05). In the animal study, both micro-CT and histological evaluations revealed that new bone formation in artificial bone defects treated with S. mukorossi seed oil were nearly doubled compared to control defects (p < 0.05) after 4 weeks of healing. Based on these findings, it is reasonable to suggest that S. mukorossi seed oil holds promise as a potential candidate for enhancing bone healing efficiency in bone tissue engineering. Full article

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28 pages, 2408 KiB

Open AccessReview

Fibrostenosing Crohn’s Disease: Pathogenetic Mechanisms and New Therapeutic Horizons

by Irene Mignini, Valentina Blasi, Fabrizio Termite, Giorgio Esposto, Raffaele Borriello, Lucrezia Laterza, Franco Scaldaferri, Maria Elena Ainora, Antonio Gasbarrini and Maria Assunta Zocco

Int. J. Mol. Sci. 2024, 25(12), 6326; https://doi.org/10.3390/ijms25126326 - 7 Jun 2024

Cited by 1 | Viewed by 1151

Abstract

Bowel strictures are well recognized as one of the most severe complications in Crohn’s disease, with variable impacts on the prognosis and often needing surgical or endoscopic treatment. Distinguishing inflammatory strictures from fibrotic ones is of primary importance due to the different therapeutic [...] Read more.

Bowel strictures are well recognized as one of the most severe complications in Crohn’s disease, with variable impacts on the prognosis and often needing surgical or endoscopic treatment. Distinguishing inflammatory strictures from fibrotic ones is of primary importance due to the different therapeutic approaches required. Indeed, to better understand the pathogenesis of fibrosis, it is crucial to investigate molecular processes involving genetic factors, cytokines, alteration of the intestinal barrier, and epithelial and endothelial damage, leading to an increase in extracellular matrix synthesis, which ultimately ends in fibrosis. In such a complex mechanism, the gut microbiota also seems to play a role. A better comprehension of molecular processes underlying bowel fibrosis, in addition to radiological and histopathological findings, has led to the identification of high-risk patients for personalized follow-up and testing of new therapies, primarily in preclinical models, targeting specific pathways involving Transforming Growth Factor-β, interleukins, extracellular matrix balance, and gut microbiota. Our review aims to summarize current evidence about molecular factors involved in intestinal fibrosis’ pathogenesis, paving the way for potential diagnostic biomarkers or anti-fibrotic treatments for stricturing Crohn’s disease. Full article

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24 pages, 3174 KiB

Open AccessReview

Decreasing Intracellular Entropy by Increasing Mitochondrial Efficiency and Reducing ROS Formation—The Effect on the Ageing Process and Age-Related Damage

by Borut Poljšak and Irina Milisav

Int. J. Mol. Sci. 2024, 25(12), 6321; https://doi.org/10.3390/ijms25126321 - 7 Jun 2024

Viewed by 1444

Abstract

A hypothesis is presented to explain how the ageing process might be influenced by optimizing mitochondrial efficiency to reduce intracellular entropy. Research-based quantifications of entropy are scarce. Non-equilibrium metabolic reactions and compartmentalization were found to contribute most to lowering entropy in the cells. [...] Read more.

A hypothesis is presented to explain how the ageing process might be influenced by optimizing mitochondrial efficiency to reduce intracellular entropy. Research-based quantifications of entropy are scarce. Non-equilibrium metabolic reactions and compartmentalization were found to contribute most to lowering entropy in the cells. Like the cells, mitochondria are thermodynamically open systems exchanging matter and energy with their surroundings—the rest of the cell. Based on the calculations from cancer cells, glycolysis was reported to produce less entropy than mitochondrial oxidative phosphorylation. However, these estimations depended on the CO₂ concentration so that at slightly increased CO₂, it was oxidative phosphorylation that produced less entropy. Also, the thermodynamic efficiency of mitochondrial respiratory complexes varies depending on the respiratory state and oxidant/antioxidant balance. Therefore, in spite of long-standing theoretical and practical efforts, more measurements, also in isolated mitochondria, with intact and suboptimal respiration, are needed to resolve the issue. Entropy increases in ageing while mitochondrial efficiency of energy conversion, quality control, and turnover mechanisms deteriorate. Optimally functioning mitochondria are necessary to meet energy demands for cellular defence and repair processes to attenuate ageing. The intuitive approach of simply supplying more metabolic fuels (more nutrients) often has the opposite effect, namely a decrease in energy production in the case of nutrient overload. Excessive nutrient intake and obesity accelerate ageing, while calorie restriction without malnutrition can prolong life. Balanced nutrient intake adapted to needs/activity-based high ATP requirement increases mitochondrial respiratory efficiency and leads to multiple alterations in gene expression and metabolic adaptations. Therefore, rather than overfeeding, it is necessary to fine-tune energy production by optimizing mitochondrial function and reducing oxidative stress; the evidence is discussed in this paper. Full article

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16 pages, 5668 KiB

Open AccessArticle

Efficacy of Human Recombinant Growth Hormone in Females of a Non-Obese Hyperglycemic Mouse Model after Birth with Low Birth Weight

by Wataru Tokunaga, Nobuhiko Nagano, Kengo Matsuda, Kimitaka Nakazaki, Shoichi Shimizu, Koh Okuda, Ryoji Aoki, Kazumasa Fuwa, Hitohiko Murakami and Ichiro Morioka

Int. J. Mol. Sci. 2024, 25(12), 6294; https://doi.org/10.3390/ijms25126294 - 7 Jun 2024

Viewed by 806

Abstract

We examined whether the administration of growth hormone (GH) improves insulin resistance in females of a non-obese hyperglycemic mouse model after birth with low birth weight (LBW), given that GH is known to increase muscle mass. The intrauterine Ischemia group underwent uterine artery [...] Read more.

We examined whether the administration of growth hormone (GH) improves insulin resistance in females of a non-obese hyperglycemic mouse model after birth with low birth weight (LBW), given that GH is known to increase muscle mass. The intrauterine Ischemia group underwent uterine artery occlusion for 15 min on day 16.5 of gestation. At 4 weeks of age, female mice in the Ischemia group were divided into the GH-treated (Ischemia-GH) and non-GH-treated (Ischemia) groups. At 8 weeks of age, the glucose metabolism, muscle pathology, and metabolome of liver were assessed. The insulin resistance index improved in the Ischemia-GH group compared with the Ischemia group (p = 0.034). The percentage of type 1 muscle fibers was higher in the Ischemia-GH group than the Ischemia group (p < 0.001); the muscle fiber type was altered by GH. In the liver, oxidative stress factors were reduced, and ATP production was increased in the Ischemia-GH group compared to the Ischemia group (p = 0.014), indicating the improved mitochondrial function of liver. GH administration is effective in improving insulin resistance by increasing the content of type 1 muscle fibers and improving mitochondrial function of liver in our non-obese hyperglycemic mouse model after birth with LBW. Full article

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18 pages, 1025 KiB

Open AccessReview

Substance P’s Impact on Chronic Pain and Psychiatric Conditions—A Narrative Review

by Charles Humes, Aleksandar Sic and Nebojsa Nick Knezevic

Int. J. Mol. Sci. 2024, 25(11), 5905; https://doi.org/10.3390/ijms25115905 - 28 May 2024

Cited by 3 | Viewed by 2030

Abstract

Substance P (SP) plays a crucial role in pain modulation, with significant implications for major depressive disorder (MDD), anxiety disorders, and post-traumatic stress disorder (PTSD). Elevated SP levels are linked to heightened pain sensitivity and various psychiatric conditions, spurring interest in potential therapeutic [...] Read more.

Substance P (SP) plays a crucial role in pain modulation, with significant implications for major depressive disorder (MDD), anxiety disorders, and post-traumatic stress disorder (PTSD). Elevated SP levels are linked to heightened pain sensitivity and various psychiatric conditions, spurring interest in potential therapeutic interventions. In chronic pain, commonly associated with MDD and anxiety disorders, SP emerges as a key mediator in pain and emotional regulation. This review examines SP’s impact on pain perception and its contributions to MDD, anxiety disorders, and PTSD. The association of SP with increased pain sensitivity and chronic pain conditions underscores its importance in pain modulation. Additionally, SP influences the pathophysiology of MDD, anxiety disorders, and PTSD, highlighting its potential as a therapeutic target. Understanding SP’s diverse effects provides valuable insights into the mechanisms underlying these psychiatric disorders and their treatment. Further research is essential to explore SP modulation in psychiatric disorders and develop more effective treatment strategies. Full article

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15 pages, 761 KiB

Open AccessReview

Porocarcinoma: Clinical and Histological Features, Immunohistochemistry and Outcomes: A Systematic Review

by Thomas Bienstman, Canan Güvenç and Marjan Garmyn

Int. J. Mol. Sci. 2024, 25(11), 5760; https://doi.org/10.3390/ijms25115760 - 25 May 2024

Cited by 1 | Viewed by 1037

Abstract

Porocarcinoma (PC) is a rare adnexal tumor, mainly found in the elderly. The tumor arises from the acrosyringium of eccrine sweat glands. The risk of lymph node and distant metastasis is high. Differential diagnosis with squamous cell carcinoma is difficult, although NUT expression [...] Read more.

Porocarcinoma (PC) is a rare adnexal tumor, mainly found in the elderly. The tumor arises from the acrosyringium of eccrine sweat glands. The risk of lymph node and distant metastasis is high. Differential diagnosis with squamous cell carcinoma is difficult, although NUT expression and YAP1 fusion products can be very useful for diagnosis. Currently, wide local excision is the main surgical treatment, although Mohs micrographic surgery is promising. To date, there is no consensus regarding the role of sentinel lymph node biopsy and consequential lymph node dissection. No guidelines exist for radiotherapy, which is mostly performed based on tumor characteristics and excision margins. Only a few studies report systemic treatment for advanced PC, although therapy with pembrolizumab and EGFR inhibitors show promise. In this review, we discuss epidemiology, clinical features, histopathological features, immunohistochemistry and fusion products, surgical management and survival outcomes according to stage, surgical management, radiotherapy and systemic therapy. Full article

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8 pages, 1515 KiB

Open AccessCommunication

Analytical Ultracentrifugation to Assess the Quality of LNP-mRNA Therapeutics

by Giuditta Guerrini, Dora Mehn, Diletta Scaccabarozzi, Sabrina Gioria and Luigi Calzolai

Int. J. Mol. Sci. 2024, 25(11), 5718; https://doi.org/10.3390/ijms25115718 - 24 May 2024

Cited by 1 | Viewed by 1542

Abstract

The approval of safe and effective LNP-mRNA vaccines during the SARS-CoV-2 pandemic is catalyzing the development of the next generation of mRNA therapeutics. Proper characterization methods are crucial for assessing the quality and efficacy of these complex formulations. Here, we show that analytical [...] Read more.

The approval of safe and effective LNP-mRNA vaccines during the SARS-CoV-2 pandemic is catalyzing the development of the next generation of mRNA therapeutics. Proper characterization methods are crucial for assessing the quality and efficacy of these complex formulations. Here, we show that analytical ultracentrifugation (AUC) can measure, simultaneously and without any sample preparation step, the sedimentation coefficients of both the LNP-mRNA formulation and the mRNA molecules. This allows measuring several quality attributes, such as particle size distribution, encapsulation efficiency and density of the formulation. The technique can also be applied to study the stability of the formulation under stress conditions and different buffers. Full article

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14 pages, 1138 KiB

Open AccessArticle

In Vitro Effects of Fentanyl on Aortic Viscoelasticity in a Rat Model of Melatonin Deficiency

by Andreyan Georgiev, Maria Kaneva, Lyudmila Shikova, Polina Mateeva, Jana Tchekalarova and Mariya Antonova

Int. J. Mol. Sci. 2024, 25(11), 5669; https://doi.org/10.3390/ijms25115669 - 23 May 2024

Viewed by 747

Abstract

Melatonin influences arterial biomechanics, and its absence could cause remodeling of the arterial wall, leading to increased stiffness. Direct effects of fentanyl on the aortic wall have also been observed previously. This study aimed to evaluate in vitro the effects of fentanyl on [...] Read more.

Melatonin influences arterial biomechanics, and its absence could cause remodeling of the arterial wall, leading to increased stiffness. Direct effects of fentanyl on the aortic wall have also been observed previously. This study aimed to evaluate in vitro the effects of fentanyl on aortic viscoelasticity in a rat model of melatonin deficiency and to test the hypothesis that melatonin deficiency leads to increased arterial wall stiffness. The viscoelasticity was estimated in strip preparations from pinealectomized (pin, melatonin deficiency) and sham-operated (sham, normal melatonin) adult rats using the forced oscillations method. In the untreated aortic wall pin, the viscoelasticity was not significantly altered. However, combined with 10⁻⁹ M fentanyl, the pin increased the natural frequency (f₀) and modulus of elasticity (E’) compared to the sham-operated. Independently, fentanyl treatment decreased f₀ and E’ compared separately to untreated sham and pin preparations. The effects of fentanyl were neither dose-dependent nor affected by naloxone, suggesting a non-opioid mechanism. Furthermore, an independent effect of naloxone was also detected in the normal rat aortic wall, resulting in reduced E’. Additional studies are needed that may improve the clinical decisions for pain management and anesthesia for certain patients with co-occurring chronic low levels of blood plasma melatonin and some diseases. Full article

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24 pages, 1441 KiB

Open AccessReview

Pathophysiology and Advances in the Therapy of Cardiomyopathy in Patients with Diabetes Mellitus

by Patryk Graczyk, Aleksandra Dach, Kamil Dyrka and Andrzej Pawlik

Int. J. Mol. Sci. 2024, 25(9), 5027; https://doi.org/10.3390/ijms25095027 - 5 May 2024

Cited by 4 | Viewed by 2277

Abstract

Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly diagnosed in less than half of these patients. Despite numerous preventive measures, the number of DM cases [...] Read more.

Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly diagnosed in less than half of these patients. Despite numerous preventive measures, the number of DM cases is steadily increasing. The state of chronic hyperglycaemia in the body leads to numerous complications, including diabetic cardiomyopathy (DCM). A number of pathophysiological mechanisms are behind the development and progression of cardiomyopathy, including increased oxidative stress, chronic inflammation, increased synthesis of advanced glycation products and overexpression of the biosynthetic pathway of certain compounds, such as hexosamine. There is extensive research on the treatment of DCM, and there are a number of therapies that can stop the development of this complication. Among the compounds used to treat DCM are antiglycaemic drugs, hypoglycaemic drugs and drugs used to treat myocardial failure. An important element in combating DCM that should be kept in mind is a healthy lifestyle—a well-balanced diet and physical activity. There is also a group of compounds—including coenzyme Q10, antioxidants and modulators of signalling pathways and inflammatory processes, among others—that are being researched continuously, and their introduction into routine therapies is likely to result in greater control and more effective treatment of DM in the future. This paper summarises the latest recommendations for lifestyle and pharmacological treatment of cardiomyopathy in patients with DM. Full article

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19 pages, 3787 KiB

Open AccessArticle

JMJD6 Autoantibodies as a Potential Biomarker for Inflammation-Related Diseases

by Bo-Shi Zhang, Xiao-Meng Zhang, Masaaki Ito, Satoshi Yajima, Kimihiko Yoshida, Mikiko Ohno, Eiichiro Nishi, Hao Wang, Shu-Yang Li, Masaaki Kubota, Yoichi Yoshida, Tomoo Matsutani, Seiichiro Mine, Toshio Machida, Minoru Takemoto, Hiroki Yamagata, Aiko Hayashi, Koutaro Yokote, Yoshio Kobayashi, Hirotaka Takizawa, Hideyuki Kuroda, Hideaki Shimada, Yasuo Iwadate and Takaki Hiwasa Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(9), 4935; https://doi.org/10.3390/ijms25094935 - 30 Apr 2024

Viewed by 1480

Abstract

Inflammation is closely associated with cerebrovascular diseases, cardiovascular diseases, diabetes, and cancers, and it is accompanied by the development of autoantibodies in the early stage of inflammation-related diseases. Hence, it is meaningful to discover novel antibody biomarkers targeting inflammation-related diseases. In this study, [...] Read more.

Inflammation is closely associated with cerebrovascular diseases, cardiovascular diseases, diabetes, and cancers, and it is accompanied by the development of autoantibodies in the early stage of inflammation-related diseases. Hence, it is meaningful to discover novel antibody biomarkers targeting inflammation-related diseases. In this study, Jumonji C-domain-containing 6 (JMJD6) was identified by the serological identification of antigens through recombinant cDNA expression cloning. In particular, JMJD6 is an antigen recognized in serum IgG from patients with unstable angina pectoris (a cardiovascular disease). Then, the serum antibody levels were examined using an amplified luminescent proximity homogeneous assay-linked immunosorbent assay and a purified recombinant JMJD6 protein as an antigen. We observed elevated levels of serum anti-JMJD6 antibodies (s-JMJD6-Abs) in patients with inflammation-related diseases such as ischemic stroke, acute myocardial infarction (AMI), diabetes mellitus (DM), and cancers (including esophageal cancer, EC; gastric cancer; lung cancer; and mammary cancer), compared with the levels in healthy donors. The s-JMJD6-Ab levels were closely associated with some inflammation indicators, such as C-reactive protein and intima–media thickness (an atherosclerosis index). A better postoperative survival status of patients with EC was observed in the JMJD6-Ab-positive group than in the negative group. An immunohistochemical analysis showed that JMJD6 was highly expressed in the inflamed mucosa of esophageal tissues, esophageal carcinoma tissues, and atherosclerotic plaques. Hence, JMJD6 autoantibodies may reflect inflammation, thereby serving as a potential biomarker for diagnosing specific inflammation-related diseases, including stroke, AMI, DM, and cancers, and for prediction of the prognosis in patients with EC. Full article

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15 pages, 6122 KiB

Open AccessArticle

Exosomes Secreted by Wharton’s Jelly-Derived Mesenchymal Stem Cells Promote the Ability of Cell Proliferation and Migration for Keratinocyte

by Hong-Ren Yu, Hsin-Chun Huang, I-Lun Chen and Sung-Chou Li

Int. J. Mol. Sci. 2024, 25(9), 4758; https://doi.org/10.3390/ijms25094758 - 26 Apr 2024

Cited by 1 | Viewed by 1686

Abstract

Mesenchymal stem cells (MSCs) isolated from Wharton’s jelly (WJ-MSCs) and adipose tissue (AD-MSCs) are alternative sources for bone marrow-derived MSCs. Owing to their multiple functions in angiogenesis, immune modulation, proliferation, migration, and nerve regeneration, MSC-derived exosomes can be applied in “cell-free cell therapy”. [...] Read more.

Mesenchymal stem cells (MSCs) isolated from Wharton’s jelly (WJ-MSCs) and adipose tissue (AD-MSCs) are alternative sources for bone marrow-derived MSCs. Owing to their multiple functions in angiogenesis, immune modulation, proliferation, migration, and nerve regeneration, MSC-derived exosomes can be applied in “cell-free cell therapy”. Here, we investigated the functional protein components between the exosomes from WJ-MSCs and AD-MSCs to explain their distinct functions. Proteins of WJ-MSC and AD-MSC exosomes were collected and compared based on iTRAQ gel-free proteomics data. Results: In total, 1695 proteins were detected in exosomes. Of these, 315 were more abundant (>1.25-fold) in AD-MSC exosomes and 362 kept higher levels in WJ-MSC exosomes, including fibrinogen proteins. Pathway enrichment analysis suggested that WJ-MSC exosomes had higher potential for wound healing than AD-MSC exosomes. Therefore, we treated keratinocyte cells with exosomes and the recombinant protein of fibrinogen beta chain (FGB). It turned out that WJ-MSC exosomes better promoted keratinocyte growth and migration than AD-MSC exosomes. In addition, FGB treatment had similar results to WJ-MSC exosomes. The fact that WJ-MSC exosomes promoted keratinocyte growth and migration better than AD-MSC exosomes can be explained by their higher FGB abundance. Exploring the various components of AD-MSC and WJ-MSC exosomes can aid in their different clinical applications. Full article

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14 pages, 604 KiB

Open AccessReview

Human Cord Blood Endothelial Progenitor Cells and Pregnancy Complications (Preeclampsia, Gestational Diabetes Mellitus, and Fetal Growth Restriction)

by Ja-Young Kwon and Yong-Sun Maeng

Int. J. Mol. Sci. 2024, 25(8), 4444; https://doi.org/10.3390/ijms25084444 - 18 Apr 2024

Cited by 2 | Viewed by 1319

Abstract

Hemangioblasts give rise to endothelial progenitor cells (EPCs), which also express the cell surface markers CD133 and c-kit. They may differentiate into the outgrowth endothelial cells (OECs) that control neovascularization in the developing embryo. According to numerous studies, reduced levels of EPCs in [...] Read more.

Hemangioblasts give rise to endothelial progenitor cells (EPCs), which also express the cell surface markers CD133 and c-kit. They may differentiate into the outgrowth endothelial cells (OECs) that control neovascularization in the developing embryo. According to numerous studies, reduced levels of EPCs in circulation have been linked to human cardiovascular disorders. Furthermore, preeclampsia and senescence have been linked to levels of EPCs produced from cord blood. Uncertainties surround how preeclampsia affects the way EPCs function. It is reasonable to speculate that preeclampsia may have an impact on the function of fetal EPCs during the in utero period; however, the present literature suggests that maternal vasculopathies, including preeclampsia, damage fetal circulation. Additionally, the differentiation potential and general activity of EPCs may serve as an indicator of the health of the fetal vascular system as they promote neovascularization and repair during pregnancy. Thus, the purpose of this review is to compare—through the assessment of their quantity, differentiation potency, angiogenic activity, and senescence—the angiogenic function of fetal EPCs obtained from cord blood for normal and pregnancy problems (preeclampsia, gestational diabetes mellitus, and fetal growth restriction). This will shed light on the relationship between the angiogenic function of fetal EPCs and pregnancy complications, which could have an effect on the management of long-term health issues like metabolic and cardiovascular disorders in offspring with abnormal vasculature development. Full article

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21 pages, 2272 KiB

Open AccessReview

Different Levels of Therapeutic Strategies to Recover the Microbiome to Prevent/Delay Acute Lymphoblastic Leukemia (ALL) or Arrest Its Progression in Children

by Tommaso Silvano Aronica, Miriam Carella and Carmela Rita Balistreri

Int. J. Mol. Sci. 2024, 25(7), 3928; https://doi.org/10.3390/ijms25073928 - 31 Mar 2024

Cited by 2 | Viewed by 1633

Abstract

Changes in the components, variety, metabolism, and products of microbiomes, particularly of the gut microbiome (GM), have been revealed to be closely associated with the onset and progression of numerous human illnesses, including hematological neoplasms. Among the latter pathologies, there is acute lymphoblastic [...] Read more.

Changes in the components, variety, metabolism, and products of microbiomes, particularly of the gut microbiome (GM), have been revealed to be closely associated with the onset and progression of numerous human illnesses, including hematological neoplasms. Among the latter pathologies, there is acute lymphoblastic leukemia (ALL), the most widespread malignant neoplasm in pediatric subjects. Accordingly, ALL cases present a typical dysfunctional GM during all its clinical stages and resulting inflammation, which contributes to its progression, altered response to therapy, and possible relapses. Children with ALL have GM with characteristic variations in composition, variety, and functions, and such alterations may influence and predict the complications and prognosis of ALL after chemotherapy treatment or stem cell hematopoietic transplants. In addition, growing evidence also reports the ability of GM to influence the formation, growth, and roles of the newborn’s hematopoietic system through the process of developmental programming during fetal life as well as its susceptibility to the onset of onco-hematological pathologies, namely ALL. Here, we suggest some therapeutic strategies that can be applied at two levels of intervention to recover the microbiome and consequently prevent/delay ALL or arrest its progression. Full article

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22 pages, 1179 KiB

Open AccessReview

The Heterogeneity of Post-Menopausal Disease Risk: Could the Basis for Why Only Subsets of Females Are Affected Be Due to a Reversible Epigenetic Modification System Associated with Puberty, Menstrual Cycles, Pregnancy and Lactation, and, Ultimately, Menopause?

by David A. Hart

Int. J. Mol. Sci. 2024, 25(7), 3866; https://doi.org/10.3390/ijms25073866 - 30 Mar 2024

Cited by 1 | Viewed by 1704

Abstract

For much of human evolution, the average lifespan was <40 years, due in part to disease, infant mortality, predators, food insecurity, and, for females, complications of childbirth. Thus, for much of evolution, many females did not reach the age of menopause (45–50 years [...] Read more.

For much of human evolution, the average lifespan was <40 years, due in part to disease, infant mortality, predators, food insecurity, and, for females, complications of childbirth. Thus, for much of evolution, many females did not reach the age of menopause (45–50 years of age) and it is mainly in the past several hundred years that the lifespan has been extended to >75 years, primarily due to public health advances, medical interventions, antibiotics, and nutrition. Therefore, the underlying biological mechanisms responsible for disease risk following menopause must have evolved during the complex processes leading to Homo sapiens to serve functions in the pre-menopausal state. Furthermore, as a primary function for the survival of the species is effective reproduction, it is likely that most of the advantages of having such post-menopausal risks relate to reproduction and the ability to address environmental stresses. This opinion/perspective will be discussed in the context of how such post-menopausal risks could enhance reproduction, with improved survival of offspring, and perhaps why such risks are preserved. Not all post-menopausal females exhibit risk for this set of diseases, and those who do develop such diseases do not have all of the conditions. The diseases of the post-menopausal state do not operate as a unified complex, but as independent variables, with the potential for some overlap. The how and why there would be such heterogeneity if the risk factors serve essential functions during the reproductive years is also discussed and the concept of sets of reversible epigenetic changes associated with puberty, pregnancy, and lactation is offered to explain the observations regarding the distribution of post-menopausal conditions and their potential roles in reproduction. While the involvement of an epigenetic system with a dynamic “modification-demodification-remodification” paradigm contributing to disease risk is a hypothesis at this point, validation of it could lead to a better understanding of post-menopausal disease risk in the context of reproduction with commonalities may also lead to future improved interventions to control such risk after menopause. Full article

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15 pages, 4588 KiB

Open AccessArticle

A Multi-Gene Signature of Non-Muscle-Invasive Bladder Cancer Identifies Patients Who Respond to Immunotherapies Including Bacillus Calmette–Guérin and Immune Checkpoint Inhibitors

by Seung-Woo Baek and Sun-Hee Leem

Int. J. Mol. Sci. 2024, 25(7), 3800; https://doi.org/10.3390/ijms25073800 - 28 Mar 2024

Viewed by 1372

Abstract

Approximately 75% of bladder cancer cases originate as non-muscle-invasive bladder cancer (NMIBC). Despite initial diagnosis, NMIBC commonly recurs, with up to 45% advancing to muscle-invasive bladder cancer (MIBC) and metastatic disease. Treatment for high-risk NMIBC typically includes procedures like transurethral resection and, depending [...] Read more.

Approximately 75% of bladder cancer cases originate as non-muscle-invasive bladder cancer (NMIBC). Despite initial diagnosis, NMIBC commonly recurs, with up to 45% advancing to muscle-invasive bladder cancer (MIBC) and metastatic disease. Treatment for high-risk NMIBC typically includes procedures like transurethral resection and, depending on recurrence risk, intravesical chemotherapy or immunotherapy such as Bacillus Calmette–Guérin (BCG). However, persistent shortages of BCG necessitate alternative first-line treatments. We aim to use a multi-gene signature in high-risk NMIBC patients to determine whether patients may benefit from immune checkpoint inhibitors (ICIs) as an alternative to BCG and to evaluate their clinical utility. The multi-gene signature obtained from the three independent NMIBC cohorts was applied to stratify the UROMOL2016 cohort (n = 476) using consensus clustering. Each subtype was distinguished by biological pathway analysis. Validation analysis using a machine learning algorithm was performed in six independent cohorts including the BRS (n = 283) cohort treated with BCG and the IMvigor210 (n = 298) clinical trials treated with PD-L1 inhibitors. Based on consensus cluster analysis, NMIBC patients in the UROMOL2016 cohort were classified into three classes exhibiting distinguished characteristics, including DNA damage repair (DDR). Survival analysis showed that the NMIBC-DDR class had the highest rates of disease progression (progression-free survival, p = 0.002 by log-rank test) in the UROMOL cohort and benefited from BCG and ICIs (respectively, p = 0.02 and p = 0.03 by log-rank test). This study suggests that the multi-gene signature may have a role in identifying high-risk NMIBC patients and improving the responsiveness of ICIs. Additionally, we propose immunotherapy as a new first-line treatment for patients with high-risk NMIBC because of the shortage of BCG supply. It is important to help more patients prioritize cancer immunotherapy. Full article

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13 pages, 1335 KiB

Open AccessArticle

Early Increase in Blood–Brain Barrier Permeability in a Murine Model Exposed to Fifteen Days of Intermittent Hypoxia

by Frederic Roche, Anne Briançon-Marjollet, Maurice Dematteis, Marie Baldazza, Brigitte Gonthier, Frederique Bertholon, Nathalie Perek and Jean-Louis Pépin

Int. J. Mol. Sci. 2024, 25(5), 3065; https://doi.org/10.3390/ijms25053065 - 6 Mar 2024

Cited by 1 | Viewed by 1202

Abstract

Obstructive sleep apnea (OSA) is characterized by intermittent repeated episodes of hypoxia–reoxygenation. OSA is associated with cerebrovascular consequences. An enhanced blood–brain barrier (BBB) permeability has been proposed as a marker of those disorders. We studied in mice the effects of 1 day and [...] Read more.

Obstructive sleep apnea (OSA) is characterized by intermittent repeated episodes of hypoxia–reoxygenation. OSA is associated with cerebrovascular consequences. An enhanced blood–brain barrier (BBB) permeability has been proposed as a marker of those disorders. We studied in mice the effects of 1 day and 15 days intermittent hypoxia (IH) exposure on BBB function. We focused on the dorsal part of the hippocampus and attempted to identify the molecular mechanisms by combining in vivo BBB permeability (Evans blue tests) and mRNA expression of several junction proteins (zona occludens (ZO-1,2,3), VE-cadherin, claudins (1,5,12), cingulin) and of aquaporins (1,4,9) on hippocampal brain tissues. After 15 days of IH exposure we observed an increase in BBB permeability, associated with increased mRNA expressions of claudins 1 and 12, aquaporins 1 and 9. IH seemed to increase early for claudin-1 mRNA expression as it doubled with 1 day of exposure and returned near to its base level after 15 days. Claudin-1 overexpression may represent an immediate response to IH exposure. Then, after 15 days of exposure, an increase in functional BBB permeability was associated with enhanced expression of aquaporin. These BBB alterations are possibly associated with a vasogenic oedema that may affect brain functions and accelerate neurodegenerative processes. Full article

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13 pages, 3740 KiB

Open AccessArticle

Effects of Hemorrhage on Hematopoietic Cell Depletion after a Combined Injury with Radiation: Role of White Blood Cells and Red Blood Cells as Biomarkers

by Juliann G. Kiang, Akeylah K. Woods and Georgetta Cannon

Int. J. Mol. Sci. 2024, 25(5), 2988; https://doi.org/10.3390/ijms25052988 - 4 Mar 2024

Viewed by 1003

Abstract

Combined radiation with hemorrhage (combined injury, CI) exacerbates hematopoietic acute radiation syndrome and mortality compared to radiation alone (RI). We evaluated the effects of RI or CI on blood cell depletion as a biomarker to differentiate the two. Male CD2F1 mice were exposed [...] Read more.

Combined radiation with hemorrhage (combined injury, CI) exacerbates hematopoietic acute radiation syndrome and mortality compared to radiation alone (RI). We evaluated the effects of RI or CI on blood cell depletion as a biomarker to differentiate the two. Male CD2F1 mice were exposed to 8.75 Gy γ-radiation (⁶⁰Co). Within 2 h of RI, animals were bled under anesthesia 0% (RI) or 20% (CI) of total blood volume. Blood samples were collected at 4–5 h and days 1, 2, 3, 7, and 15 after RI. CI decreased WBC at 4–5 h and continued to decrease it until day 3; counts then stayed at the nadir up to day 15. CI decreased neutrophils, lymphocytes, monocytes, eosinophils, and basophils more than RI on day 1 or day 2. CI decreased RBCs, hemoglobin, and hematocrit on days 7 and 15 more than RI, whereas hemorrhage alone returned to the baseline on days 7 and 15. RBCs depleted after CI faster than post-RI. Hemorrhage alone increased platelet counts on days 2, 3, and 7, which returned to the baseline on day 15. Our data suggest that WBC depletion may be a potential biomarker within 2 days post-RI and post-CI and RBC depletion after 3 days post-RI and post-CI. For hemorrhage alone, neutrophil counts at 4–5 h and platelets for day 2 through day 7 can be used as a tool for confirmation. Full article

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17 pages, 16814 KiB

Open AccessArticle

Tetraspanin CD82 Correlates with and May Regulate S100A7 Expression in Oral Cancer

by Kiran Kumar Reddi, Weiqiang Zhang, Shokoufeh Shahrabi-Farahani, Kenneth Mark Anderson, Mingyue Liu, David Kakhniashvili, Xusheng Wang and Yanhui H. Zhang

Int. J. Mol. Sci. 2024, 25(5), 2659; https://doi.org/10.3390/ijms25052659 - 24 Feb 2024

Viewed by 1854

Abstract

Many metastatic cancers with poor prognoses correlate to downregulated CD82, but exceptions exist. Understanding the context of this correlation is essential to CD82 as a prognostic biomarker and therapeutic target. Oral squamous cell carcinoma (OSCC) constitutes over 90% of oral cancer. We aimed [...] Read more.

Many metastatic cancers with poor prognoses correlate to downregulated CD82, but exceptions exist. Understanding the context of this correlation is essential to CD82 as a prognostic biomarker and therapeutic target. Oral squamous cell carcinoma (OSCC) constitutes over 90% of oral cancer. We aimed to uncover the function and mechanism of CD82 in OSCC. We investigated CD82 in human OSCC cell lines, tissues, and healthy controls using the CRISPR-Cas9 gene knockout, transcriptomics, proteomics, etc. CD82 expression is elevated in CAL 27 cells. Knockout CD82 altered over 300 genes and proteins and inhibited cell migration. Furthermore, CD82 expression correlates with S100 proteins in CAL 27, CD82KO, SCC-25, and S-G cells and some OSCC tissues. The 37–50 kDa CD82 protein in CAL 27 cells is upregulated, glycosylated, and truncated. CD82 correlates with S100 proteins and may regulate their expression and cell migration. The truncated CD82 explains the invasive metastasis and poor outcome of the CAL 27 donor. OSCC with upregulated truncated CD82 and S100A7 may represent a distinct subtype with a poor prognosis. Differing alternatives from wild-type CD82 may elucidate the contradictory functions and pave the way for CD82 as a prognostic biomarker and therapeutic target. Full article

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15 pages, 7097 KiB

Open AccessArticle

Myconoside and Calceolarioside E Restrain UV-Induced Skin Photoaging by Activating NRF2-Mediated Defense Mechanisms

by Iva D. Stoykova, Ivanka K. Koycheva, Biser K. Binev, Liliya V. Mihaylova, Maria Y. Benina, Kalina I. Alipieva and Milen I. Georgiev

Int. J. Mol. Sci. 2024, 25(4), 2441; https://doi.org/10.3390/ijms25042441 - 19 Feb 2024

Viewed by 3201

Abstract

Chronic and excessive ultraviolet (UVA/UVB) irradiation exposure is known as a major contributor to premature skin aging, which leads to excessive reactive oxygen species generation, disturbed extracellular matrix homeostasis, DNA damage, and chronic inflammation. Sunscreen products are the major preventive option against UVR-induced [...] Read more.

Chronic and excessive ultraviolet (UVA/UVB) irradiation exposure is known as a major contributor to premature skin aging, which leads to excessive reactive oxygen species generation, disturbed extracellular matrix homeostasis, DNA damage, and chronic inflammation. Sunscreen products are the major preventive option against UVR-induced photodamage, mostly counteracting the acute skin effects and only mildly counteracting accelerated aging. Therefore, novel anti-photoaging and photopreventive compounds are a subject of increased scientific interest. Our previous investigations revealed that the endemic plant Haberlea rhodopensis Friv. (HRE) activates the antioxidant defense through an NRF2-mediated mechanism in neutrophiles. In the present study, we aimed to investigate the photoprotective potential of HRE and two of its specialized compounds—the phenylethanoid glycosides myconoside (MYC) and calceolarioside E (CAL)—in UVA/UVB-stimulated human keratinocytes in an in vitro model of photoaging. The obtained data demonstrated that the application of HRE, MYC, and CAL significantly reduced intracellular ROS formation in UVR-exposed HaCaT cells. The NRF2/PGC-1α and TGF-1β/Smad/Wnt signaling pathways were pointed out as having a critical role in the observed CAL- and MYC-induced photoprotective effect. Collectively, CAL is worth further evaluation as a potent natural NRF2 activator and a promising photoprotective agent that leads to the prevention of UVA/UVB-induced premature skin aging. Full article

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21 pages, 1300 KiB

Open AccessReview

Trained Innate Immunity in Animal Models of Cardiovascular Diseases

by Patricia Kleimann, Lisa-Marie Irschfeld, Maria Grandoch, Ulrich Flögel and Sebastian Temme

Int. J. Mol. Sci. 2024, 25(4), 2312; https://doi.org/10.3390/ijms25042312 - 15 Feb 2024

Cited by 1 | Viewed by 2600

Abstract

Acquisition of immunological memory is an important evolutionary strategy that evolved to protect the host from repetitive challenges from infectious agents. It was believed for a long time that memory formation exclusively occurs in the adaptive part of the immune system with the [...] Read more.

Acquisition of immunological memory is an important evolutionary strategy that evolved to protect the host from repetitive challenges from infectious agents. It was believed for a long time that memory formation exclusively occurs in the adaptive part of the immune system with the formation of highly specific memory T cells and B cells. In the past 10–15 years, it has become clear that innate immune cells, such as monocytes, natural killer cells, or neutrophil granulocytes, also have the ability to generate some kind of memory. After the exposure of innate immune cells to certain stimuli, these cells develop an enhanced secondary response with increased cytokine secretion even after an encounter with an unrelated stimulus. This phenomenon has been termed trained innate immunity (TI) and is associated with epigenetic modifications (histone methylation, acetylation) and metabolic alterations (elevated glycolysis, lactate production). TI has been observed in tissue-resident or circulating immune cells but also in bone marrow progenitors. Risk-factors for cardiovascular diseases (CVDs) which are associated with low-grade inflammation, such as hyperglycemia, obesity, or high salt, can also induce TI with a profound impact on the development and progression of CVDs. In this review, we briefly describe basic mechanisms of TI and summarize animal studies which specifically focus on TI in the context of CVDs. Full article

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14 pages, 7960 KiB

Open AccessArticle

CHST4 Gene as a Potential Predictor of Clinical Outcome in Malignant Pleural Mesothelioma

by Shoji Okado, Taketo Kato, Yuki Hanamatsu, Ryo Emoto, Yoshito Imamura, Hiroki Watanabe, Yuta Kawasumi, Yuka Kadomatsu, Harushi Ueno, Shota Nakamura, Tetsuya Mizuno, Tamotsu Takeuchi, Shigeyuki Matsui and Toyofumi Fengshi Chen-Yoshikawa

Int. J. Mol. Sci. 2024, 25(4), 2270; https://doi.org/10.3390/ijms25042270 - 14 Feb 2024

Viewed by 1811

Abstract

Malignant pleural mesothelioma (MPM) develops primarily from asbestos exposures and has a poor prognosis. In this study, The Cancer Genome Atlas was used to perform a comprehensive survival analysis, which identified the CHST4 gene as a potential predictor of favorable overall survival for [...] Read more.

Malignant pleural mesothelioma (MPM) develops primarily from asbestos exposures and has a poor prognosis. In this study, The Cancer Genome Atlas was used to perform a comprehensive survival analysis, which identified the CHST4 gene as a potential predictor of favorable overall survival for patients with MPM. An enrichment analysis of favorable prognostic genes, including CHST4, showed immune-related ontological terms, whereas an analysis of unfavorable prognostic genes indicated cell-cycle-related terms. CHST4 mRNA expression in MPM was significantly correlated with Bindea immune-gene signatures. To validate the relationship between CHST4 expression and prognosis, we performed an immunohistochemical analysis of CHST4 protein expression in 23 surgical specimens from surgically treated patients with MPM who achieved macroscopic complete resection. The score calculated from the proportion and intensity staining was used to compare the intensity of CHST4 gene expression, which showed that CHST4 expression was stronger in patients with a better postoperative prognosis. The median overall postoperative survival was 107.8 months in the high-expression-score group and 38.0 months in the low-score group (p = 0.044, log-rank test). Survival after recurrence was also significantly improved by CHST4 expression. These results suggest that CHST4 is useful as a prognostic biomarker in MPM. Full article

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44 pages, 2300 KiB

Open AccessReview

Mucus Structure, Viscoelastic Properties, and Composition in Chronic Respiratory Diseases

by Michela Abrami, Alice Biasin, Fabiana Tescione, Domenico Tierno, Barbara Dapas, Annalucia Carbone, Gabriele Grassi, Massimo Conese, Sante Di Gioia, Domenico Larobina and Mario Grassi

Int. J. Mol. Sci. 2024, 25(3), 1933; https://doi.org/10.3390/ijms25031933 - 5 Feb 2024

Cited by 9 | Viewed by 5860

Abstract

The respiratory mucus, a viscoelastic gel, effectuates a primary line of the airway defense when operated by the mucociliary clearance. In chronic respiratory diseases (CRDs), such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), the mucus is overproduced and its [...] Read more.

The respiratory mucus, a viscoelastic gel, effectuates a primary line of the airway defense when operated by the mucociliary clearance. In chronic respiratory diseases (CRDs), such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), the mucus is overproduced and its solid content augments, changing its structure and viscoelastic properties and determining a derangement of essential defense mechanisms against opportunistic microbial (virus and bacteria) pathogens. This ensues in damaging of the airways, leading to a vicious cycle of obstruction and infection responsible for the harsh clinical evolution of these CRDs. Here, we review the essential features of normal and pathological mucus (i.e., sputum in CF, COPD, and asthma), i.e., mucin content, structure (mesh size), micro/macro-rheology, pH, and osmotic pressure, ending with the awareness that sputum biomarkers (mucins, inflammatory proteins and peptides, and metabolites) might serve to indicate acute exacerbation and response to therapies. There are some indications that old and novel treatments may change the structure, viscoelastic properties, and biomarker content of sputum; however, a wealth of work is still needed to embrace these measures as correlates of disease severity in association with (or even as substitutes of) pulmonary functional tests. Full article

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17 pages, 2299 KiB

Open AccessArticle

Beneficial Impact of Eicosapentaenoic Acid on the Adverse Effects Induced by Palmitate and Hyperglycemia on Healthy Rat Chondrocyte

by Chaohua Deng, Nathalie Presle, Anne Pizard, Cécile Guillaume, Arnaud Bianchi and Hervé Kempf

Int. J. Mol. Sci. 2024, 25(3), 1810; https://doi.org/10.3390/ijms25031810 - 2 Feb 2024

Viewed by 1652

Abstract

Osteoarthritis (OA) is the most prevalent form of arthritis and a major cause of pain and disability. The pathology of OA involves the whole joint in an inflammatory and degenerative process, especially in articular cartilage. OA may be divided into distinguishable phenotypes including [...] Read more.

Osteoarthritis (OA) is the most prevalent form of arthritis and a major cause of pain and disability. The pathology of OA involves the whole joint in an inflammatory and degenerative process, especially in articular cartilage. OA may be divided into distinguishable phenotypes including one associated with the metabolic syndrome (MetS) of which dyslipidemia and hyperglycemia have been individually linked to OA. Since their combined role in OA pathogenesis remains to be elucidated, we investigated the chondrocyte response to these metabolic stresses, and determined whether a n-3 polyunsaturated fatty acid (PUFA), i.e., eicosapentaenoic acid (EPA), may preserve chondrocyte functions. Rat chondrocytes were cultured with palmitic acid (PA) and/or EPA in normal or high glucose conditions. The expression of genes encoding proteins found in cartilage matrix (type 2 collagen and aggrecan) or involved in degenerative (metalloproteinases, MMPs) or in inflammatory (cyclooxygenase-2, COX-2 and microsomal prostaglandin E synthase, mPGES) processes was analyzed by qPCR. Prostaglandin E₂ (PGE₂) release was also evaluated by an enzyme-linked immunosorbent assay. Our data indicated that PA dose-dependently up-regulated the mRNA expression of MMP-3 and -13. PA also induced the expression of COX-2 and mPGES and promoted the synthesis of PGE₂. Glucose at high concentrations further increased the chondrocyte response to PA. Interestingly, EPA suppressed the inflammatory effects of PA and glucose, and strongly reduced MMP-13 expression. Among the free fatty acid receptors (FFARs), FFAR4 partly mediated the EPA effects and the activation of FFAR1 markedly reduced the inflammatory effects of PA in high glucose conditions. Our findings demonstrate that dyslipidemia associated with hyperglycemia may contribute to OA pathogenesis and explains why an excess of saturated fatty acids and a low level in n-3 PUFAs may disrupt cartilage homeostasis. Full article

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22 pages, 4675 KiB

Open AccessReview

Antifibrotic Drugs against Idiopathic Pulmonary Fibrosis and Pulmonary Fibrosis Induced by COVID-19: Therapeutic Approaches and Potential Diagnostic Biomarkers

by Aurelio Perez-Favila, Idalia Garza-Veloz, Lucia del Socorro Hernandez-Marquez, Edgar Fernando Gutierrez-Vela, Virginia Flores-Morales and Margarita L. Martinez-Fierro

Int. J. Mol. Sci. 2024, 25(3), 1562; https://doi.org/10.3390/ijms25031562 - 26 Jan 2024

Cited by 1 | Viewed by 2306

Abstract

The COVID-19 pandemic has had a significant impact on the health and economy of the global population. Even after recovery from the disease, post-COVID-19 symptoms, such as pulmonary fibrosis, continue to be a concern. This narrative review aims to address pulmonary fibrosis (PF) [...] Read more.

The COVID-19 pandemic has had a significant impact on the health and economy of the global population. Even after recovery from the disease, post-COVID-19 symptoms, such as pulmonary fibrosis, continue to be a concern. This narrative review aims to address pulmonary fibrosis (PF) from various perspectives, including the fibrotic mechanisms involved in idiopathic and COVID-19-induced pulmonary fibrosis. On the other hand, we also discuss the current therapeutic drugs in use, as well as those undergoing clinical or preclinical evaluation. Additionally, this article will address various biomarkers with usefulness for PF prediction, diagnosis, treatment, prognosis, and severity assessment in order to provide better treatment strategies for patients with this disease. Full article

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14 pages, 3828 KiB

Open AccessArticle

Novel Lipid Nanoparticles Stable and Efficient for mRNA Transfection to Antigen-Presenting Cells

by Kang Chan Choi, Do Hyun Lee, Ji Won Lee, Jin Suk Lee, Yeon Kyung Lee, Moon Jung Choi, Hwa Yeon Jeong, Min Woo Kim, Chang-Gun Lee and Yong Serk Park

Int. J. Mol. Sci. 2024, 25(3), 1388; https://doi.org/10.3390/ijms25031388 - 23 Jan 2024

Cited by 4 | Viewed by 3649

Abstract

mRNA vaccines have emerged as a pivotal tool in combating COVID-19, offering an advanced approach to immunization. A key challenge with these vaccines is their need for extremely-low-temperature storage, which affects their stability and shelf life. Our research addresses this issue by enhancing [...] Read more.

mRNA vaccines have emerged as a pivotal tool in combating COVID-19, offering an advanced approach to immunization. A key challenge with these vaccines is their need for extremely-low-temperature storage, which affects their stability and shelf life. Our research addresses this issue by enhancing the stability of mRNA vaccines through a novel cationic lipid, O,O′-dimyristyl-N-lysyl aspartate (DMKD). DMKD effectively binds with mRNA, improving vaccine stability. We also integrated phosphatidylserine (PS) into the formulation to boost immune response by promoting the uptake of these nanoparticles by immune cells. Our findings reveal that DMKD-PS nanoparticles maintain structural integrity under long-term refrigeration and effectively protect mRNA. When tested, these nanoparticles containing green fluorescent protein (GFP) mRNA outperformed other commercial lipid nanoparticles in protein expression, both in immune cells (RAW 264.7 mouse macrophage) and non-immune cells (CT26 mouse colorectal carcinoma cells). Importantly, in vivo studies show that DMKD-PS nanoparticles are safely eliminated from the body within 48 h. The results suggest that DMKD-PS nanoparticles present a promising alternative for mRNA vaccine delivery, enhancing both the stability and effectiveness of these vaccines. Full article

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37 pages, 4862 KiB

Open AccessReview

The Road towards Gene Therapy for X-Linked Juvenile Retinoschisis: A Systematic Review of Preclinical Gene Therapy in Cell-Based and Rodent Models of XLRS

by Isa van der Veen, Andrea Heredero Berzal, Céline Koster, Anneloor L. M. A. ten Asbroek, Arthur A. Bergen and Camiel J. F. Boon

Int. J. Mol. Sci. 2024, 25(2), 1267; https://doi.org/10.3390/ijms25021267 - 19 Jan 2024

Cited by 2 | Viewed by 2856

Abstract

X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with formation of cystoid retinal cavities, frequently accompanied by splitting of the retinal layers, impaired synaptic transmission of visual signals, and associated loss [...] Read more.

X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with formation of cystoid retinal cavities, frequently accompanied by splitting of the retinal layers, impaired synaptic transmission of visual signals, and associated loss of visual acuity. XLRS is caused by loss-of-function mutations in the retinoschisin gene located on the X chromosome (RS1, MIM 30083). While proof-of-concept studies for gene augmentation therapy have been promising in in vitro and rodent models, clinical trials in XLRS patients have not been successful thus far. We performed a systematic literature investigation using search strings related to XLRS and gene therapy in in vivo and in vitro models. Three rounds of screening (title/abstract, full text and qualitative) were performed by two independent reviewers until consensus was reached. Characteristics related to study design and intervention were extracted from all studies. Results were divided into studies using (1) viral and (2) non-viral therapies. All in vivo rodent studies that used viral vectors were assessed for quality and risk of bias using the SYRCLE’s risk-of-bias tool. Studies using alternative and non-viral delivery techniques, either in vivo or in vitro, were extracted and reviewed qualitatively, given the diverse and dispersed nature of the information. For in-depth analysis of in vivo studies using viral vectors, outcome data for optical coherence tomography (OCT), immunohistopathology and electroretinography (ERG) were extracted. Meta-analyses were performed on the effect of recombinant adeno-associated viral vector (AAV)-mediated gene augmentation therapies on a- and b-wave amplitude as well as the ratio between b- and a-wave amplitudes (b/a-ratio) extracted from ERG data. Subgroup analyses and meta-regression were performed for model, dose, age at injection, follow-up time point and delivery method. Between-study heterogeneity was assessed with a Chi-square test of homogeneity (I²). We identified 25 studies that target RS1 and met our search string. A total of 19 of these studies reported rodent viral methods in vivo. Six of the 25 studies used non-viral or alternative delivery methods, either in vitro or in vivo. Of these, five studies described non-viral methods and one study described an alternative delivery method. The 19 aforementioned in vivo studies were assessed for risk of bias and quality assessments and showed inconsistency in reporting. This resulted in an unclear risk of bias in most included studies. All 19 studies used AAVs to deliver intact human or murine RS1 in rodent models for XLRS. Meta-analyses of a-wave amplitude, b-wave amplitude, and b/a-ratio showed that, overall, AAV-mediated gene augmentation therapy significantly ameliorated the disease phenotype on these parameters. Subgroup analyses and meta-regression showed significant correlations between b-wave amplitude effect size and dose, although between-study heterogeneity was high. This systematic review reiterates the high potential for gene therapy in XLRS, while highlighting the importance of careful preclinical study design and reporting. The establishment of a systematic approach in these studies is essential to effectively translate this knowledge into novel and improved treatment alternatives. Full article

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17 pages, 644 KiB

Open AccessReview

Epigenetic Dysregulation in the Pathogenesis of Systemic Lupus Erythematosus

by Yasuto Araki and Toshihide Mimura

Int. J. Mol. Sci. 2024, 25(2), 1019; https://doi.org/10.3390/ijms25021019 - 13 Jan 2024

Cited by 6 | Viewed by 2586

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease in which immune disorders lead to autoreactive immune responses and cause inflammation and tissue damage. Genetic and environmental factors have been shown to trigger SLE. Recent evidence has also demonstrated that epigenetic factors contribute [...] Read more.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease in which immune disorders lead to autoreactive immune responses and cause inflammation and tissue damage. Genetic and environmental factors have been shown to trigger SLE. Recent evidence has also demonstrated that epigenetic factors contribute to the pathogenesis of SLE. Epigenetic mechanisms play an important role in modulating the chromatin structure and regulating gene transcription. Dysregulated epigenetic changes can alter gene expression and impair cellular functions in immune cells, resulting in autoreactive immune responses. Therefore, elucidating the dysregulated epigenetic mechanisms in the immune system is crucial for understanding the pathogenesis of SLE. In this paper, we review the important roles of epigenetic disorders in the pathogenesis of SLE. Full article

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37 pages, 2476 KiB

Open AccessReview

Harnessing the Stem Cell Niche in Regenerative Medicine: Innovative Avenue to Combat Neurodegenerative Diseases

by Gordana Velikic, Dusan M. Maric, Dusica L. Maric, Gordana Supic, Miljan Puletic, Oliver Dulic and Danilo Vojvodic

Int. J. Mol. Sci. 2024, 25(2), 993; https://doi.org/10.3390/ijms25020993 - 12 Jan 2024

Cited by 6 | Viewed by 4252

Abstract

Regenerative medicine harnesses the body’s innate capacity for self-repair to restore malfunctioning tissues and organs. Stem cell therapies represent a key regenerative strategy, but to effectively harness their potential necessitates a nuanced understanding of the stem cell niche. This specialized microenvironment regulates critical [...] Read more.

Regenerative medicine harnesses the body’s innate capacity for self-repair to restore malfunctioning tissues and organs. Stem cell therapies represent a key regenerative strategy, but to effectively harness their potential necessitates a nuanced understanding of the stem cell niche. This specialized microenvironment regulates critical stem cell behaviors including quiescence, activation, differentiation, and homing. Emerging research reveals that dysfunction within endogenous neural stem cell niches contributes to neurodegenerative pathologies and impedes regeneration. Strategies such as modifying signaling pathways, or epigenetic interventions to restore niche homeostasis and signaling, hold promise for revitalizing neurogenesis and neural repair in diseases like Alzheimer’s and Parkinson’s. Comparative studies of highly regenerative species provide evolutionary clues into niche-mediated renewal mechanisms. Leveraging endogenous bioelectric cues and crosstalk between gut, brain, and vascular niches further illuminates promising therapeutic opportunities. Emerging techniques like single-cell transcriptomics, organoids, microfluidics, artificial intelligence, in silico modeling, and transdifferentiation will continue to unravel niche complexity. By providing a comprehensive synthesis integrating diverse views on niche components, developmental transitions, and dynamics, this review unveils new layers of complexity integral to niche behavior and function, which unveil novel prospects to modulate niche function and provide revolutionary treatments for neurodegenerative diseases. Full article

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14 pages, 3875 KiB

Open AccessArticle

Comparison of Nuclear Medicine Therapeutics Targeting PSMA among Alpha-Emitting Nuclides

by Kazuko Kaneda-Nakashima, Yoshifumi Shirakami, Yuichiro Kadonaga, Tadashi Watabe, Kazuhiro Ooe, Xiaojie Yin, Hiromitsu Haba, Kenji Shirasaki, Hidetoshi Kikunaga, Kazuaki Tsukada, Atsushi Toyoshima, Jens Cardinale, Frederik L. Giesel and Koichi Fukase

Int. J. Mol. Sci. 2024, 25(2), 933; https://doi.org/10.3390/ijms25020933 - 11 Jan 2024

Cited by 3 | Viewed by 2256

Abstract

Currently, targeted alpha therapy (TAT) is a new therapy involving the administration of a therapeutic drug that combines a substance of α-emitting nuclides that kill cancer cells and a drug that selectively accumulates in cancer cells. It is known to be effective against [...] Read more.

Currently, targeted alpha therapy (TAT) is a new therapy involving the administration of a therapeutic drug that combines a substance of α-emitting nuclides that kill cancer cells and a drug that selectively accumulates in cancer cells. It is known to be effective against cancers that are difficult to treat with existing methods, such as cancer cells that are widely spread throughout the whole body, and there are high expectations for its early clinical implementation. The nuclides for TAT, including ¹⁴⁹Tb, ²¹¹At, ^212/213Bi, ²¹²Pb (for ²¹²Bi), ²²³Ra, ²²⁵Ac, ^226/227Th, and ²³⁰U, are known. However, some nuclides encounter problems with labeling methods and lack sufficient preclinical and clinical data. We labeled the compounds targeting prostate specific membrane antigen (PSMA) with ²¹¹At and ²²⁵Ac. PSMA is a molecule that has attracted attention as a theranostic target for prostate cancer, and several targeted radioligands have already shown therapeutic effects in patients. The results showed that ²¹¹At, which has a much shorter half-life, is no less cytotoxic than ²²⁵Ac. In ²¹¹At labeling, our group has also developed an original method (Shirakami Reaction). We have succeeded in obtaining a highly purified labeled product in a short timeframe using this method. Full article

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18 pages, 3741 KiB

Open AccessArticle

Splicing Modulation via Antisense Oligonucleotides in Recessive Dystrophic Epidermolysis Bullosa

by Stefan Hainzl, Lisa Trattner, Bernadette Liemberger, Johannes Bischof, Thomas Kocher, Michael Ablinger, Alexander Nyström, Astrid Obermayer, Alfred Klausegger, Christina Guttmann-Gruber, Verena Wally, Johann W. Bauer, Josefina Piñón Hofbauer and Ulrich Koller

Int. J. Mol. Sci. 2024, 25(2), 761; https://doi.org/10.3390/ijms25020761 - 7 Jan 2024

Cited by 2 | Viewed by 1822

Abstract

Antisense oligonucleotides (ASOs) represent an emerging therapeutic platform for targeting genetic diseases by influencing various aspects of (pre-)mRNA biology, such as splicing, stability, and translation. In this study, we investigated the potential of modulating the splicing pattern in recessive dystrophic epidermolysis bullosa (RDEB) [...] Read more.

Antisense oligonucleotides (ASOs) represent an emerging therapeutic platform for targeting genetic diseases by influencing various aspects of (pre-)mRNA biology, such as splicing, stability, and translation. In this study, we investigated the potential of modulating the splicing pattern in recessive dystrophic epidermolysis bullosa (RDEB) patient cells carrying a frequent genomic variant (c.425A > G) that disrupts splicing in the COL7A1 gene by using short 2′-O-(2-Methoxyethyl) oligoribo-nucleotides (2′-MOE ASOs). COL7A1-encoded type VII collagen (C7) forms the anchoring fibrils within the skin that are essential for the attachment of the epidermis to the underlying dermis. As such, gene variants of COL7A1 leading to functionally impaired or absent C7 manifest in the form of extensive blistering and wounding. The severity of the disease pattern warrants the development of novel therapies for patients. The c.425A > G variant at the COL7A1 exon 3/intron 3 junction lowers the efficiency of splicing at this junction, resulting in non-functional C7 transcripts. However, we found that correct splicing still occurs, albeit at a very low level, highlighting an opportunity for intervention by modulating the splicing reaction. We therefore screened 2′-MOE ASOs that bind along the COL7A1 target region ranging from exon 3 to the intron 3/exon 4 junction for their ability to modulate splicing. We identified ASOs capable of increasing the relative levels of correctly spliced COL7A1 transcripts by RT-PCR, sqRT-PCR, and ddPCR. Furthermore, RDEB-derived skin equivalents treated with one of the most promising ASOs exhibited an increase in full-length C7 expression and its accurate deposition along the basement membrane zone (BMZ). Full article

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2023

Jump to: 2024, 2022, 2021

16 pages, 23275 KiB

Open AccessArticle

Contribution of Signal Transducer and Activator of Transcription 3 (STAT3) to Bone Development and Repair

by Mohamed L. Sobah, Clifford Liongue and Alister C. Ward

Int. J. Mol. Sci. 2024, 25(1), 389; https://doi.org/10.3390/ijms25010389 - 27 Dec 2023

Cited by 1 | Viewed by 1367

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor activated canonically by numerous cytokines and other factors, with significant roles in immunity, immune diseases, and cancer. It has also been implicated in several human skeletal disorders, with loss-of-function (LOF) mutations [...] Read more.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor activated canonically by numerous cytokines and other factors, with significant roles in immunity, immune diseases, and cancer. It has also been implicated in several human skeletal disorders, with loss-of-function (LOF) mutations associated with aberrant skeletal development. To gain further insights, two zebrafish STAT3 lines were investigated: a complete LOF knockout (KO) mutant and a partial LOF mutant with the transactivation domain truncated (ΔTAD). Consistent with other studies, the KO mutants were smaller, with reduced length in early embryos exacerbated by a decreased growth rate from 5 days postfertilization (dpf). They displayed skeletal deformities that approached 80% incidence by 30 dpf, with a significant reduction in early bone but not cartilage formation. Further analysis additionally identified considerable abrogation of caudal fin regeneration, concomitant with a paucity of infiltrating macrophages and neutrophils, which may be responsible for this. Most of these phenotypes were also observed in the ΔTAD mutants, indicating that loss of canonical STAT3 signaling was the likely cause. However, the impacts on early bone formation and regeneration were muted in the ΔTAD mutant, suggesting the potential involvement of noncanonical functions in these processes. Full article

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15 pages, 1520 KiB

Open AccessArticle

Lipidomic Profile of Human Sperm Membrane Identifies a Clustering of Lipids Associated with Semen Quality and Function

by Andrea Di Nisio, Luca De Toni, Iva Sabovic, Alessia Vignoli, Leonardo Tenori, Stefano Dall’Acqua, Stefania Sut, Sandro La Vignera, Rosita Angela Condorelli, Filippo Giacone, Alberto Ferlin, Carlo Foresta and Andrea Garolla

Int. J. Mol. Sci. 2024, 25(1), 297; https://doi.org/10.3390/ijms25010297 - 25 Dec 2023

Cited by 2 | Viewed by 1538

Abstract

Reduced sperm motility and/or count are among the major causes of reduced fertility in men, and sperm membranes play an important role in the spermatogenesis and fertilization processes. However, the impact of sperm lipid composition on male fertility remains under-investigated. The aim of [...] Read more.

Reduced sperm motility and/or count are among the major causes of reduced fertility in men, and sperm membranes play an important role in the spermatogenesis and fertilization processes. However, the impact of sperm lipid composition on male fertility remains under-investigated. The aim of the present study was to perform a lipidomic analysis of human sperm membranes: we performed an untargeted analysis of membrane lipid composition in fertile (N = 33) and infertile subjects (N = 29). In parallel, we evaluated their serum lipid levels. Twenty-one lipids were identified by their mass/charge ratio and post-source decay spectra. Sulfogalactosylglycerolipid (SGG, seminolipid) was the most abundant lipid component in the membranes. In addition, we observed a significant proportion of PUFAs. Important differences have emerged between the fertile and infertile groups, leading to the identification of a lipid cluster that was associated with semen parameters. Among these, cholesterol sulfate, SGG, and PUFAs represented the most important predictors of semen quality. No association was found between the serum and sperm lipids. Dietary PUFAs and SGG have acknowledged antioxidant functions and could, therefore, represent sensitive markers of sperm quality and testicular function. Altogether, these results underline the important role of sperm membrane lipids, which act independently of serum lipids levels and may rather represent an independent marker of reproductive function. Full article

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14 pages, 1561 KiB

Open AccessArticle

The Immune Signature of CSF in Multiple Sclerosis with and without Oligoclonal Bands: A Machine Learning Approach to Proximity Extension Assay Analysis

by Lorenzo Gaetani, Giovanni Bellomo, Elena Di Sabatino, Silvia Sperandei, Andrea Mancini, Kaj Blennow, Henrik Zetterberg, Lucilla Parnetti and Massimiliano Di Filippo

Int. J. Mol. Sci. 2024, 25(1), 139; https://doi.org/10.3390/ijms25010139 - 21 Dec 2023

Cited by 2 | Viewed by 2168

Abstract

Early diagnosis of multiple sclerosis (MS) relies on clinical evaluation, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. Reliable biomarkers are needed to differentiate MS from other neurological conditions and to define the underlying pathogenesis. This study aimed to comprehensively profile immune [...] Read more.

Early diagnosis of multiple sclerosis (MS) relies on clinical evaluation, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. Reliable biomarkers are needed to differentiate MS from other neurological conditions and to define the underlying pathogenesis. This study aimed to comprehensively profile immune activation biomarkers in the CSF of individuals with MS and explore distinct signatures between MS with and without oligoclonal bands (OCB). A total of 118 subjects, including relapsing–remitting MS with OCB (MS OCB+) (n = 58), without OCB (MS OCB−) (n = 24), and controls with other neurological diseases (OND) (n = 36), were included. CSF samples were analyzed by means of proximity extension assay (PEA) for quantifying 92 immune-related proteins. Neurofilament light chain (NfL), a marker of axonal damage, was also measured. Machine learning techniques were employed to identify biomarker panels differentiating MS with and without OCB from controls. Analyses were performed by splitting the cohort into a training and a validation set. CSF CD5 and IL-12B exhibited the highest discriminatory power in differentiating MS from controls. CSF MIP-1-alpha, CD5, CXCL10, CCL23 and CXCL9 were positively correlated with NfL. Multivariate models were developed to distinguish MS OCB+ and MS OCB− from controls. The model for MS OCB+ included IL-12B, CD5, CX3CL1, FGF-19, CST5, MCP-1 (91% sensitivity and 94% specificity in the training set, 81% sensitivity, and 94% specificity in the validation set). The model for MS OCB− included CX3CL1, CD5, NfL, CCL4 and OPG (87% sensitivity and 80% specificity in the training set, 56% sensitivity and 48% specificity in the validation set). Comprehensive immune profiling of CSF biomarkers in MS revealed distinct pathophysiological signatures associated with OCB status. The identified biomarker panels, enriched in T cell activation markers and immune mediators, hold promise for improved diagnostic accuracy and insights into MS pathogenesis. Full article

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14 pages, 680 KiB

Open AccessReview

The Interplay between Helicobacter pylori and Gut Microbiota in Non-Gastrointestinal Disorders: A Special Focus on Atherosclerosis

by Marcello Candelli, Laura Franza, Rossella Cianci, Giulia Pignataro, Giuseppe Merra, Andrea Piccioni, Veronica Ojetti, Antonio Gasbarrini and Francesco Franceschi

Int. J. Mol. Sci. 2023, 24(24), 17520; https://doi.org/10.3390/ijms242417520 - 15 Dec 2023

Cited by 2 | Viewed by 2038

Abstract

The discovery of Helicobacter pylori (H. pylori) in the early 1980s by Nobel Prize winners in medicine Robin Warren and Barry Marshall led to a revolution in physiopathology and consequently in the treatment of peptic ulcer disease. Subsequently, H. pylori has [...] Read more.

The discovery of Helicobacter pylori (H. pylori) in the early 1980s by Nobel Prize winners in medicine Robin Warren and Barry Marshall led to a revolution in physiopathology and consequently in the treatment of peptic ulcer disease. Subsequently, H. pylori has also been linked to non-gastrointestinal diseases, such as autoimmune thrombocytopenia, acne rosacea, and Raynaud’s syndrome. In addition, several studies have shown an association with cardiovascular disease and atherosclerosis. Our narrative review aims to investigate the connection between H. pylori infection, gut microbiota, and extra-gastric diseases, with a particular emphasis on atherosclerosis. We conducted an extensive search on PubMed, Google Scholar, and Scopus, using the keywords “H. pylori”, “dysbiosis”, “microbiota”, “atherosclerosis”, “cardiovascular disease” in the last ten years. Atherosclerosis is a complex condition in which the arteries thicken or harden due to plaque deposits in the inner lining of an artery and is associated with several cardiovascular diseases. Recent research has highlighted the role of the microbiota in the pathogenesis of this group of diseases. H. pylori is able to both directly influence the onset of atherosclerosis and negatively modulate the microbiota. H. pylori is an important factor in promoting atherosclerosis. Progress is being made in understanding the underlying mechanisms, which could open the way to interesting new therapeutic perspectives. Full article

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16 pages, 972 KiB

Open AccessReview

CCL5’s Role in Periodontal Disease: A Narrative Review

by Katarzyna Barczak, Agnieszka Droździk, Mateusz Bosiacki, Ryta Łagocka, Diana Cenariu, Willi Andrei Uriciuc and Irena Baranowska-Bosiacka

Int. J. Mol. Sci. 2023, 24(24), 17332; https://doi.org/10.3390/ijms242417332 - 11 Dec 2023

Cited by 2 | Viewed by 2190

Abstract

Persistent host inflammatory and immune responses to biofilm play a critical role in the mechanisms that govern soft and hard tissue destruction in periodontal disease. Among the less explored facets of these mechanisms are chemokines, including CCL5 (C-C motif chemokine ligand 5), also [...] Read more.

Persistent host inflammatory and immune responses to biofilm play a critical role in the mechanisms that govern soft and hard tissue destruction in periodontal disease. Among the less explored facets of these mechanisms are chemokines, including CCL5 (C-C motif chemokine ligand 5), also known as RANTES (regulated on activation, normal T cell expressed and secreted), a proinflammatory CC subfamily chemokine synthesized by T lymphocytes. Despite its importance, there is currently no comprehensive review of the role of CCL5 in periodontitis in the literature. Therefore, this paper aims to fill this gap by summarizing the existing knowledge on the involvement of CCL5 in the onset and progression of periodontitis. In addition, we aim to stimulate interest in this relatively overlooked factor among periodontitis researchers, potentially accelerating the development of drugs targeting CCL5 or its receptors. The review examines the association of CCL5 with periodontitis risk factors, including aging, cigarette smoking, diabetes, and obesity. It discusses the involvement of CCL5 in pathological processes during periodontitis, such as connective tissue and bone destruction. The data show that CCL5 expression is observed in affected gums and gingival crevicular fluid of periodontitis patients, with bacterial activity contributing significantly to this increase, but the reviewed studies of the association between CCL5 expression and periodontal disease have yielded inconclusive results. Although CCL5 has been implicated in the pathomechanism of periodontitis, a comprehensive understanding of its molecular mechanisms and significance remains elusive, hindering the development of drugs targeting this chemokine or its receptors. Full article

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17 pages, 2424 KiB

Open AccessArticle

Development of an SPRi Test for the Quantitative Detection of Cadherin 12 in Human Plasma and Peritoneal Fluid

by Lukasz Oldak, Zenon Lukaszewski, Anna Leśniewska, Ksawery Goławski, Piotr Laudański and Ewa Gorodkiewicz

Int. J. Mol. Sci. 2023, 24(23), 16894; https://doi.org/10.3390/ijms242316894 - 29 Nov 2023

Viewed by 1114

Abstract

A new method for the determination of cadherin 12 (CDH12)—an adhesive protein that has a significant impact on the development, growth, and movement of cancer cells—was developed and validated. The method is based on a biosensor using surface plasmon resonance imaging (SPRi) detection. [...] Read more.

A new method for the determination of cadherin 12 (CDH12)—an adhesive protein that has a significant impact on the development, growth, and movement of cancer cells—was developed and validated. The method is based on a biosensor using surface plasmon resonance imaging (SPRi) detection. A quartz crystal microbalance was used to analyze the characteristics of the formation of successive layers of the biosensor, from the linker monolayer to the final capture of CDH12 from solution. The association equilibrium constant (K_A = 1.66 × 10¹¹ dm³ mol⁻¹) and the dissociation equilibrium constant (K_D = 7.52 × 10⁻¹² mol dm⁻³) of the anti-CDH12 antibody–CDH12 protein complex were determined. The determined analytical parameters, namely the values determining the accuracy, precision, and repeatability of the method, do not exceed the permissible 20% deviations specified by the aforementioned institutions. The proposed method is also selective with respect to possible potential interferents, occurring in up to 100-fold excess concentration relative to the CDH12 concentration. The determined Limit of Quantification (LOQ = 4.92 pg mL⁻¹) indicates the possibility of performing quantitative analysis in human plasma or peritoneal fluid without the need to concentrate the samples; however, particular attention should be paid to their storage conditions, as the analyte does not exhibit high stability. The Passing–Bablok regression model revealed good agreement between the reference method and the SPRi biosensor, with ρ_Spearman values of 0.961 and 0.925. Full article

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15 pages, 2479 KiB

Open AccessArticle

The Role of Phosphatidylethanolamine N-Methyltransferase (PEMT) and Its Waist-Hip-Ratio-Associated Locus rs4646404 in Obesity-Related Metabolic Traits and Liver Disease

by Chang Sun, David J. F. Holstein, Natalia Garcia-Cubero, Yusef Moulla, Christine Stroh, Arne Dietrich, Michael R. Schön, Daniel Gärtner, Tobias Lohmann, Miriam Dressler, Michael Stumvoll, Matthias Blüher, Peter Kovacs and Esther Guiu-Jurado

Int. J. Mol. Sci. 2023, 24(23), 16850; https://doi.org/10.3390/ijms242316850 - 28 Nov 2023

Cited by 2 | Viewed by 1584

Abstract

In previous genome-wide association studies (GWAS), genetic loci associated with obesity and impaired fat distribution (FD) have been identified. In the present study, we elucidated the role of the PEMT gene, including the waist–hip-ratio-associated single nucleotide polymorphism rs4646404, and its influence on obesity-related [...] Read more.

In previous genome-wide association studies (GWAS), genetic loci associated with obesity and impaired fat distribution (FD) have been identified. In the present study, we elucidated the role of the PEMT gene, including the waist–hip-ratio-associated single nucleotide polymorphism rs4646404, and its influence on obesity-related metabolic traits. DNA from 2926 metabolically well-characterized subjects was used for genotyping. PEMT expression was analyzed in paired visceral (vis) and subcutaneous (sc) adipose tissue (AT) from a subset of 574 individuals. Additionally, PEMT expression was examined in vis, sc AT and liver tissue in a separate cohort of 64 patients with morbid obesity and liver disease. An in vitro Pemt knockdown was conducted in murine epididymal and inguinal adipocytes. Our findings highlight tissue-specific variations in PEMT mRNA expression across the three studied tissues. Specifically, vis PEMT mRNA levels correlated significantly with T2D and were implicated in the progression of non-alcoholic steatohepatitis (NASH), in contrast to liver tissue, where no significant associations were found. Moreover, sc PEMT expression showed significant correlations with several anthropometric- and metabolic-related parameters. The rs4646404 was associated with vis AT PEMT expression and also with diabetes-related traits. Our in vitro experiments supported the influence of PEMT on adipogenesis, emphasizing its role in AT biology. In summary, our data suggest that PEMT plays a role in regulating FD and has implications in metabolic diseases. Full article

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18 pages, 3441 KiB

Open AccessArticle

Allergenic Activity of Individual Cat Allergen Molecules

by Daria Trifonova, Mirela Curin, Ksenja Riabova, Antonina Karsonova, Walter Keller, Hans Grönlund, Ulrika Käck, Jon R. Konradsen, Marianne van Hage, Alexander Karaulov and Rudolf Valenta

Int. J. Mol. Sci. 2023, 24(23), 16729; https://doi.org/10.3390/ijms242316729 - 24 Nov 2023

Cited by 5 | Viewed by 1820

Abstract

More than 10% of the world’s population suffers from an immunoglobulin E (IgE)-mediated allergy to cats which is accompanied mainly by respiratory symptoms such as rhinitis and asthma. Several cat allergen molecules have been identified, but their allergenic activity has not been investigated [...] Read more.

More than 10% of the world’s population suffers from an immunoglobulin E (IgE)-mediated allergy to cats which is accompanied mainly by respiratory symptoms such as rhinitis and asthma. Several cat allergen molecules have been identified, but their allergenic activity has not been investigated in depth. Purified cat allergen molecules (Fel d 1, Fel d 2, Fel d 3, Fel d 4, Fel d 6, Fel d 7 and Fel d 8) were characterized via mass spectrometry and circular dichroism spectroscopy regarding their molecular mass and fold, respectively. Cat-allergen-specific IgE levels were quantified via ImmunoCAP measurements in IgE-sensitized subjects with (n = 37) and without (n = 20) respiratory symptoms related to cat exposure. The allergenic activity of the cat allergens was investigated by loading patients’ IgE onto rat basophils expressing the human FcεRI receptor and studying the ability of different allergen concentrations to induce β-hexosaminidase release. Purified and folded cat allergens with correct masses were obtained. Cat-allergen-specific IgE levels were much higher in patients with a respiratory allergy than in patients without a respiratory allergy. Fel d 1, Fel d 2, Fel d 4 and Fel d 7 bound the highest levels of specific IgE and already-induced basophil degranulation at hundred-fold-lower concentrations than the other allergens. Fel d 1, Fel d 4 and Fel d 7 were recognized by more than 65% of patients with a respiratory allergy, whereas Fel d 2 was recognized by only 30%. Therefore, in addition to the major cat allergen Fel d 1, Fel d 4 and Fel d 7 should also be considered to be important allergens for the diagnosis and specific immunotherapy of cat allergy. Full article

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17 pages, 3491 KiB

Open AccessArticle

Sex Drives Functional Changes in the Progression and Regression of Liver Fibrosis

by Katia Sayaf, Ilaria Zanotto, Daniela Gabbia, Dafne Alberti, Giulia Pasqual, Alice Zaramella, Alberto Fantin, Sara De Martin and Francesco Paolo Russo

Int. J. Mol. Sci. 2023, 24(22), 16452; https://doi.org/10.3390/ijms242216452 - 17 Nov 2023

Cited by 4 | Viewed by 1531

Abstract

Liver fibrosis is a common and reversible feature of liver damage associated with many chronic liver diseases, and its onset is influenced by sex. In this study, we investigated the mechanisms of liver fibrosis and regeneration, focusing on understanding the mechanistic gaps between [...] Read more.

Liver fibrosis is a common and reversible feature of liver damage associated with many chronic liver diseases, and its onset is influenced by sex. In this study, we investigated the mechanisms of liver fibrosis and regeneration, focusing on understanding the mechanistic gaps between females and males. We injected increasing doses of carbon tetrachloride into female and male mice and maintained them for a washout period of eight weeks to allow for liver regeneration. We found that male mice were more prone to developing severe liver fibrosis as a consequence of early chronic liver damage, supported by the recruitment of a large number of Ly6C^high MoMφs and neutrophils. Although prolonged liver damage exacerbated the fibrosis in mice of both sexes, activated HSCs and Ly6C^high MoMφs were more numerous and active in the livers of female mice than those of male mice. After eight weeks of washout, only fibrotic females reported no activated HSCs, and a phenotype switching of Ly6C^high MoMφs to anti-fibrogenic Ly6C^low MoMφs. The early stages of liver fibrosis mostly affected males rather than females, while long-term chronic liver damage was not influenced by sex, at least for liver fibrosis. Liver repair and regeneration were more efficient in females than in males. Full article

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59 pages, 2702 KiB

Open AccessReview

An Overview of Recent Developments in the Management of Burn Injuries

by Elżbieta Radzikowska-Büchner, Inga Łopuszyńska, Wojciech Flieger, Michał Tobiasz, Ryszard Maciejewski and Jolanta Flieger

Int. J. Mol. Sci. 2023, 24(22), 16357; https://doi.org/10.3390/ijms242216357 - 15 Nov 2023

Cited by 16 | Viewed by 21343

Abstract

According to the World Health Organization (WHO), around 11 million people suffer from burns every year, and 180,000 die from them. A burn is a condition in which heat, chemical substances, an electrical current or other factors cause tissue damage. Burns mainly affect [...] Read more.

According to the World Health Organization (WHO), around 11 million people suffer from burns every year, and 180,000 die from them. A burn is a condition in which heat, chemical substances, an electrical current or other factors cause tissue damage. Burns mainly affect the skin, but can also affect deeper tissues such as bones or muscles. When burned, the skin loses its main functions, such as protection from the external environment, pathogens, evaporation and heat loss. Depending on the stage of the burn, the patient’s condition and the cause of the burn, we need to choose the most appropriate treatment. Personalization and multidisciplinary collaboration are key to the successful management of burn patients. In this comprehensive review, we have collected and discussed the available treatment options, focusing on recent advances in topical treatments, wound cleansing, dressings, skin grafting, nutrition, pain and scar tissue management. Full article

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11 pages, 929 KiB

Open AccessCommunication

Pre-Emptive Use of Rituximab in Epstein–Barr Virus Reactivation: Incidence, Predictive Factors, Monitoring, and Outcomes

by Apostolia Papalexandri, Eleni Gavriilaki, Anna Vardi, Nikolaos Kotsiou, Christos Demosthenous, Natassa Constantinou, Tasoula Touloumenidou, Panagiota Zerva, Fotini Kika, Michalis Iskas, Ioannis Batsis, Despina Mallouri, Evangelia Yannaki, Achilles Anagnostopoulos and Ioanna Sakellari

Int. J. Mol. Sci. 2023, 24(22), 16029; https://doi.org/10.3390/ijms242216029 - 7 Nov 2023

Cited by 2 | Viewed by 2541

Abstract

Post-transplant lymphoproliferative disease (PTLD) is a fatal complication of hematopoietic cell transplantation (HCT) associated with the Epstein–Barr virus (EBV). Multiple factors such as transplant type, graft-versus-host disease (GVHD), human leukocyte antigens (HLA) mismatch, patient age, and T-lymphocyte-depleting treatments increase the risk of PTLD. [...] Read more.

Post-transplant lymphoproliferative disease (PTLD) is a fatal complication of hematopoietic cell transplantation (HCT) associated with the Epstein–Barr virus (EBV). Multiple factors such as transplant type, graft-versus-host disease (GVHD), human leukocyte antigens (HLA) mismatch, patient age, and T-lymphocyte-depleting treatments increase the risk of PTLD. EBV reactivation in hematopoietic cell transplant recipients is monitored through periodic quantitative polymerase chain reaction (Q-PCR) tests. However, substantial uncertainty persists regarding the clinically significant EBV levels for these patients. Guidelines recommend initiating EBV monitoring no later than four weeks post-HCT and conducting it weekly. Pre-emptive therapies, such as the reduction of immunosuppressive therapy and the administration of rituximab to treat EBV viral loads are also suggested. In this study, we investigated the occurrence of EBV-PTLD in 546 HCT recipients, focusing on the clinical manifestations and risk factors associated with the disease. We managed to identify 67,150 viral genomic copies/mL as the cutoff point for predicting PTLD, with 80% sensitivity and specificity. Among our cohort, only 1% of the patients presented PTLD. Anti-thymocyte globulin (ATG) and GVHD were independently associated with lower survival rates and higher treatment-related mortality. According to our findings, prophylactic measures including regular monitoring, pre-emptive therapy, and supportive treatment against infections can be effective in preventing EBV-related complications. This study also recommends conducting EBV monitoring at regular intervals, initiating pre-emptive therapy when viral load increases, and identifying factors that increase the risk of PTLD. Our study stresses the importance of frequent and careful follow-ups of post-transplant complications and early intervention in order to improve survival rates and reduce mortality. Full article

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24 pages, 1002 KiB

Open AccessReview

AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

by Szymon Milnerowicz, Julia Maszewska, Paulina Skowera, Magdalena Stelmach and Monika Lejman

Int. J. Mol. Sci. 2023, 24(21), 15849; https://doi.org/10.3390/ijms242115849 - 31 Oct 2023

Cited by 3 | Viewed by 2955

Abstract

Acute myeloid leukemia (AML) is a disease that mainly affects elderly patients who are more often unfit for intensive chemotherapy (median age of diagnosis is 68). The regimens, including venetoclax, a highly specific BCL-2 (B-cell lymphoma-2) inhibitor, are a common alternative because of [...] Read more.

Acute myeloid leukemia (AML) is a disease that mainly affects elderly patients who are more often unfit for intensive chemotherapy (median age of diagnosis is 68). The regimens, including venetoclax, a highly specific BCL-2 (B-cell lymphoma-2) inhibitor, are a common alternative because of their safer profile and fewer side effects. However, the resistance phenomenon of leukemic cells necessitates the search for drugs that would help to overcome the resistance and improve treatment outcomes. One of the resistance mechanisms takes place through the upregulation of MCL-1 and BCL-XL, preventing BAX/BAK-driven MOMP (mitochondrial outer membrane permeabilization), thus stopping the apoptosis process. Possible partners for BCL-2 inhibitors may include inhibitors from the FLT3i (FMS-like tyrosine kinase-3 inhibitor) group. They resensitize cancer cells through the downregulation of MCL-1 expression in the FLT3 mutated cells, resulting in the stronger efficacy of BCL-2 inhibitors. Also, they provide an additional pathway for targeting the clonal cell. Both preclinical and clinical data suggest that the combination might show a synergistic effect and improve patients’ outcomes. The aim of this review is to determine whether the combination of venetoclax and FLT3 inhibitors can impact the therapeutic approaches and what other agents they can be combined with. Full article

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18 pages, 2296 KiB

Open AccessArticle

Comparison and Validation of Rapid Molecular Testing Methods for Theranostic Epidermal Growth Factor Receptor Alterations in Lung Cancer: Idylla versus Digital Droplet PCR

by Camille Léonce, Clémence Guerriau, Lara Chalabreysse, Michaël Duruisseaux, Sébastien Couraud, Marie Brevet, Pierre-Paul Bringuier and Delphine Aude Poncet

Int. J. Mol. Sci. 2023, 24(21), 15684; https://doi.org/10.3390/ijms242115684 - 27 Oct 2023

Cited by 1 | Viewed by 1273

Abstract

Targeting EGFR alterations, particularly the L858R (Exon 21) mutation and Exon 19 deletion (del19), has significantly improved the survival of lung cancer patients. From now on, the issue is to shorten the time to treatment. Here, we challenge two well-known rapid strategies for [...] Read more.

Targeting EGFR alterations, particularly the L858R (Exon 21) mutation and Exon 19 deletion (del19), has significantly improved the survival of lung cancer patients. From now on, the issue is to shorten the time to treatment. Here, we challenge two well-known rapid strategies for EGFR testing: the cartridge-based platform Idylla™ (Biocartis) and a digital droplet PCR (ddPCR) approach (ID_Solution). To thoroughly investigate each testing performance, we selected a highly comprehensive cohort of 39 unique del19 (in comparison, the cbioportal contains 40 unique del19), and 9 samples bearing unique polymorphisms in exon 19. Additional L858R (N = 24), L861Q (N = 1), del19 (N = 63), and WT samples (N = 34) were used to determine clear technical and biological cutoffs. A total of 122 DNA samples extracted from formaldehyde-fixed samples was used as input. No false positive results were reported for either of the technologies, as long as careful droplet selection (ddPCR) was ensured for two polymorphisms. ddPCR demonstrated higher sensitivity in detecting unique del19 (92.3%, 36/39) compared to Idylla (67.7%, 21/31). However, considering the prevalence of del19 and L858R in the lung cancer population, the adjusted theranostic values were similar (96.51% and 95.26%, respectively). ddPCR performs better for small specimens and low tumoral content, but in other situations, Idylla is an alternative (especially if a molecular platform is absent). Full article

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25 pages, 2158 KiB

Open AccessReview

The Role of Genetics in the Management of Heart Failure Patients

by Gianpaolo Palmieri, Maria Francesca D’Ambrosio, Michele Correale, Natale Daniele Brunetti, Rosa Santacroce, Massimo Iacoviello and Maurizio Margaglione

Int. J. Mol. Sci. 2023, 24(20), 15221; https://doi.org/10.3390/ijms242015221 - 16 Oct 2023

Viewed by 2038

Abstract

Over the last decades, the relevance of genetics in cardiovascular diseases has expanded, especially in the context of cardiomyopathies. Its relevance extends to the management of patients diagnosed with heart failure (HF), given its capacity to provide invaluable insights into the etiology of [...] Read more.

Over the last decades, the relevance of genetics in cardiovascular diseases has expanded, especially in the context of cardiomyopathies. Its relevance extends to the management of patients diagnosed with heart failure (HF), given its capacity to provide invaluable insights into the etiology of cardiomyopathies and identify individuals at a heightened risk of poor outcomes. Notably, the identification of an etiological genetic variant necessitates a comprehensive evaluation of the family lineage of the affected patients. In the future, these genetic variants hold potential as therapeutic targets with the capability to modify gene expression. In this complex setting, collaboration among cardiologists, specifically those specializing in cardiomyopathies and HF, and geneticists becomes paramount to improving individual and family health outcomes, as well as therapeutic clinical results. This review is intended to offer geneticists and cardiologists an updated perspective on the value of genetic research in HF and its implications in clinical practice. Full article

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17 pages, 316 KiB

Open AccessArticle

Cytokine Dynamics in Autism: Analysis of BMAC Therapy Outcomes

by Dusan M. Maric, Danilo Vojvodic, Dusica L. Maric, Gordana Velikic, Mihajlo Radomir, Ivana Sokolovac, Debora Stefik, Nemanja Ivkovic, Sonja Susnjevic, Miljan Puletic, Oliver Dulic and Dzihan Abazovic

Int. J. Mol. Sci. 2023, 24(20), 15080; https://doi.org/10.3390/ijms242015080 - 11 Oct 2023

Cited by 1 | Viewed by 1484

Abstract

Autism spectrum disorder (ASD) has recently been linked to neuroinflammation and an aberrant immune response within the central nervous system. The intricate relationship between immune response and ASD remains elusive, with a gap in understanding the connection between specific immune mechanisms and neural [...] Read more.

Autism spectrum disorder (ASD) has recently been linked to neuroinflammation and an aberrant immune response within the central nervous system. The intricate relationship between immune response and ASD remains elusive, with a gap in understanding the connection between specific immune mechanisms and neural manifestations in autism. In this study, we employed a comprehensive statistical approach, fusing both overarching and granular methods to examine the concentration of 16 cytokines in the cerebrospinal fluid (CSF) across each autologous bone marrow aspirate concentrate (BMAC) intrathecal administration in 63 male and 17 female autism patients. Following a six-month period post the third administration, patients were stratified into three categories based on clinical improvement: Group 1- no/mild (28 subjects), Group 2—moderate (16 subjects), and Group 3—major improvement (15 subjects). Our integrated analysis revealed pronounced disparities in CSF cytokine patterns and clinical outcomes in autism subjects pre- and post-BMAC transplantation. Crucially, our results suggest that these cytokine profiles hold promise as predictive markers, pinpointing ASD individuals who might not exhibit notable clinical amelioration post-BMAC therapy. Full article

14 pages, 3647 KiB

Open AccessArticle

The Determination of Mitochondrial Mass Is a Prerequisite for Accurate Assessment of Peripheral Blood Mononuclear Cells’ Oxidative Metabolism

by Belay Tessema, Janine Haag, Ulrich Sack and Brigitte König

Int. J. Mol. Sci. 2023, 24(19), 14824; https://doi.org/10.3390/ijms241914824 - 2 Oct 2023

Cited by 2 | Viewed by 3193

Abstract

Mitochondria are responsible for ATP synthesis through oxidative phosphorylation in cells. However, there are limited data on the influence of mitochondrial mass (MM) in the adequate assessment of cellular stress assay (CSA) results in human peripheral blood mononuclear cells (PBMCs). Therefore, the aim [...] Read more.

Mitochondria are responsible for ATP synthesis through oxidative phosphorylation in cells. However, there are limited data on the influence of mitochondrial mass (MM) in the adequate assessment of cellular stress assay (CSA) results in human peripheral blood mononuclear cells (PBMCs). Therefore, the aim of this study was to determine MM in PBMCS and assess its influence on the results of CSA measurements. Blood samples were collected and sent to the laboratory for MM and CSA measurements during different seasons of the year. The mitochondrial mass was determined based on the mtDNA:nDNA ratio in PBMCs using quantitative real-time PCR (qRT-PCR). CSA was measured using Seahorse technology. The MM was significantly lower during summer and autumn compared to winter and spring (p < 0.0001). On the contrary, we found that the maximal respiration per mitochondrion (MP) was significantly higher in summer and autumn compared to winter and spring (p < 0.0001). The estimated effect of MM on mitochondrial performance was −0.002 pmol/min/mitochondrion (p < 0.0001) and a correlation coefficient (r) of −0.612. Similarly, MM was negatively correlated with maximal respiration (r = −0.12) and spare capacity (in % r = −0.05, in pmol/min r = −0.11). In conclusion, this study reveals that MM changes significantly with seasons and is negatively correlated with CSA parameters and MP. Our findings indicate that the mitochondrial mass is a key parameter for determination of mitochondrial fitness. Therefore, we recommend the determination of MM during the measurement of CSA parameters for the correct interpretation and assessment of mitochondrial function. Full article

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15 pages, 9761 KiB

Open AccessArticle

Oryza sativa L. Indica Seed Coat Ameliorated Concanavalin A—Induced Acute Hepatitis in Mice via MDM2/p53 and PKCα/MAPK1 Signaling Pathways

by Zhiye Zhao, Ye Li, Shancheng Guo, Yuxu Chen, Haiaolong Yin, Yaxian Li, Guiguang Cheng and Lei Tian

Int. J. Mol. Sci. 2023, 24(19), 14503; https://doi.org/10.3390/ijms241914503 - 25 Sep 2023

Cited by 2 | Viewed by 1356

Abstract

Acute hepatitis (AH) is a common liver disease with an increasing number of patients each year, requiring the development of new treatments. Hence, our work aimed to evaluate the therapeutic effect of Oryza sativa L. indica (purple rice) seed coat on concanavalin A [...] Read more.

Acute hepatitis (AH) is a common liver disease with an increasing number of patients each year, requiring the development of new treatments. Hence, our work aimed to evaluate the therapeutic effect of Oryza sativa L. indica (purple rice) seed coat on concanavalin A (ConA)-induced AH and further reveal its potential mechanisms. Purple rice seed coat extract (PRE) was extracted with hydrochloric acid ethanol and analyzed through a widely targeted components method. We evaluated the effects of PRE on AH through histopathological examination, liver function, gut microbiota composition, and the intestinal barrier. The potential targets of PRE on AH were predicted by bioinformatics. Western blotting, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining, and corresponding kits were used to investigate PRE effects on predicting targets and associated signaling pathways in AH mice. In AH model mice, PRE treatment increased transformed mouse 3T3 cell double minute 2 (MDM2) expression to inhibit apoptosis; it also markedly downregulated protein kinase C alpha (PKCα), prostaglandin-endoperoxide synthase 1 (PTGS1), and mitogen-activated protein kinase 1 (MAPK1) activity to alleviate inflammation. Thus, PRE treatment also recovered the intestinal barrier, decreased the lipopolysaccharide (LPS) levels of plasma and the liver, enhanced liver function, and improved the composition of intestinal microbiota. In general, PRE targeting MDM2, PKCα, MAPK1, and PTGS1 ameliorated ConA-induced AH by attenuating inflammation and apoptosis, restoring the intestinal barrier, enhancing the liver function, and improving the gut microbiota, which revealed that the purple rice seed coat might hold possibilities as a therapeutic option for AH. Full article

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18 pages, 1021 KiB

Open AccessReview

Microplastics and Kidneys: An Update on the Evidence for Deposition of Plastic Microparticles in Human Organs, Tissues and Fluids and Renal Toxicity Concern

by Edoardo La Porta, Ottavia Exacoustos, Francesca Lugani, Andrea Angeletti, Decimo Silvio Chiarenza, Carolina Bigatti, Sonia Spinelli, Xhuliana Kajana, Andrea Garbarino, Maurizio Bruschi, Giovanni Candiano, Gianluca Caridi, Nicoletta Mancianti, Marta Calatroni, Daniela Verzola, Pasquale Esposito, Francesca Viazzi, Enrico Verrina and Gian Marco Ghiggeri

Int. J. Mol. Sci. 2023, 24(18), 14391; https://doi.org/10.3390/ijms241814391 - 21 Sep 2023

Cited by 13 | Viewed by 4545

Abstract

Plastic pollution became a main challenge for human beings as demonstrated by the increasing dispersion of plastic waste into the environment. Microplastics (MPs) have become ubiquitous and humans are exposed daily to inhalation or ingestion of plastic microparticles. Recent studies performed using mainly [...] Read more.

Plastic pollution became a main challenge for human beings as demonstrated by the increasing dispersion of plastic waste into the environment. Microplastics (MPs) have become ubiquitous and humans are exposed daily to inhalation or ingestion of plastic microparticles. Recent studies performed using mainly spectroscopy or spectrometry-based techniques have shown astounding evidence for the presence of MPs in human tissues, organs and fluids. The placenta, meconium, breast milk, lung, intestine, liver, heart and cardiovascular system, blood, urine and cerebrovascular liquid are afflicted by MPs’ presence and deposition. On the whole, obtained data underline a great heterogeneity among different tissue and organs of the polymers characterized and the microparticles’ dimension, even if most of them seem to be below 50–100 µm. Evidence for the possible contribution of MPs in human diseases is still limited and this field of study in medicine is in an initial state. However, increasing studies on their toxicity in vitro and in vivo suggest worrying effects on human cells mainly mediated by oxidative stress, inflammation and fibrosis. Nephrological studies are insufficient and evidence for the presence of MPs in human kidneys is still lacking, but the little evidence present in the literature has demonstrated histological and functional alteration of kidneys in animal models and cytotoxicity through apoptosis, autophagy, oxidative stress and inflammation in kidney cells. Overall, the manuscript we report in this review recommends urgent further study to analyze potential correlations between kidney disease and MPs’ exposure in human. Full article

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28 pages, 23130 KiB

Open AccessArticle

Correlations between Immune Response and Etiopathogenic Factors of Medication-Related Osteonecrosis of the Jaw in Cancer Patients Treated with Zoledronic Acid

by George Adrian Ciobanu, Laurențiu Mogoantă, Sanda Mihaela Popescu, Mihaela Ionescu, Cristina Maria Munteanu, Ionela Elisabeta Staicu, Răzvan Mercuț, Cristian Corneliu Georgescu, Monica Scrieciu, Daniel Vlad and Adrian Camen

Int. J. Mol. Sci. 2023, 24(18), 14345; https://doi.org/10.3390/ijms241814345 - 20 Sep 2023

Cited by 2 | Viewed by 1788

Abstract

Impairment of the immune response in MRONJ (medication-related osteonecrosis of the jaws) is one of the still unclear etiopathogenic mechanisms of this condition encountered in cancer patients treated with bisphosphonates, with negative effects on the patient’s quality of life. The aim of the [...] Read more.

Impairment of the immune response in MRONJ (medication-related osteonecrosis of the jaws) is one of the still unclear etiopathogenic mechanisms of this condition encountered in cancer patients treated with bisphosphonates, with negative effects on the patient’s quality of life. The aim of the present study was to correlate the immune response with etiopathogenic factors via immunohistochemical evaluation of the maxillary tissues in zoledronic acid osteonecrosis. The retrospective study included a group of 51 patients with various types of cancers, diagnosed with stage 2 or 3 MRONJ at zoledronic acid and treated surgically. Immunohistochemical expressions of αSMA, CD3, CD4, CD8, CD20, CD79α, CD68, CD204, and tryptase were evaluated. Immunohistochemical markers expressions were statistically analyzed according to the duration of the treatment, the trigger factor, the location of the MRONJ, and the healing status. Analysis of the immune response included T lymphocytes, B lymphocytes, plasma cells, macrophages, and mast cells. The duration of treatment significantly influenced the immunohistochemical expression of most markers (p < 0.05). For an increasing trend in treatment duration, a decreasing trend in marker score was observed, suggesting an inverse correlation. The expression of the markers was different depending on the trigger factor, on MRONJ localization (maxilla/mandible), and the healing status, being more intense in patients cured per primam compared to those who had relapses. The patient’s immune response was negatively influenced by the duration of the treatment, the trigger factor, the location of the lesion in the mandible, and the recurrence of MRONJ. Full article

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13 pages, 3512 KiB

Open AccessArticle

The Impact of Abnormal Lipid Metabolism on the Occurrence Risk of Idiopathic Pulmonary Arterial Hypertension

by Yaqin Wei, Hui Zhao, Bill Kalionis, Xu Huai, Xiaoyi Hu, Wenhui Wu, Rong Jiang, Sugang Gong, Lan Wang, Jinming Liu, Shijin Xia, Ping Yuan and Qinhua Zhao

Int. J. Mol. Sci. 2023, 24(18), 14280; https://doi.org/10.3390/ijms241814280 - 19 Sep 2023

Cited by 1 | Viewed by 1487

Abstract

The aim was to determine whether lipid molecules can be used as potential biomarkers for idiopathic pulmonary arterial hypertension (IPAH), providing important reference value for early diagnosis and treatment. Liquid chromatography–mass spectrometry-based lipidomic assays allow for the simultaneous detection of a large number [...] Read more.

The aim was to determine whether lipid molecules can be used as potential biomarkers for idiopathic pulmonary arterial hypertension (IPAH), providing important reference value for early diagnosis and treatment. Liquid chromatography–mass spectrometry-based lipidomic assays allow for the simultaneous detection of a large number of lipids. In this study, lipid profiling was performed on plasma samples from 69 IPAH patients and 30 healthy controls to compare the levels of lipid molecules in the 2 groups of patients, and Cox regression analysis was used to identify meaningful metrics, along with receiver operator characteristic curves to assess the ability of the lipid molecules to predict the risk of disease in patients. Among the 14 lipid subclasses tested, 12 lipid levels were significantly higher in IPAH patients than in healthy controls. Free fatty acids (FFA) and monoacylglycerol (MAG) were significantly different between IPAH patients and healthy controls. Logistic regression analysis showed that FFA (OR: 1.239, 95%CI: 1.101, 1.394, p < 0.0001) and MAG (OR: 3.711, 95%CI: 2.214, 6.221, p < 0.001) were independent predictors of IPAH development. Among the lipid subclasses, FFA and MAG have potential as biomarkers for predicting the pathogenesis of IPAH, which may improve the early diagnosis of IPAH. Full article

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18 pages, 1121 KiB

Open AccessReview

by Donatella Coradduzza, Stefania Sedda, Sara Cruciani, Maria Rosaria De Miglio, Carlo Ventura, Alessandra Nivoli and Margherita Maioli

Int. J. Mol. Sci. 2023, 24(18), 13680; https://doi.org/10.3390/ijms241813680 - 5 Sep 2023

Cited by 7 | Viewed by 3303

Abstract

Aging is a complex process influenced by genetics and the environment, leading to physiological decline and increased susceptibility to diseases. Cognitive decline is a prominent feature of aging, with implications for different neurodegenerative disorders. The gut microbiome has gained attention for its potential [...] Read more.

Aging is a complex process influenced by genetics and the environment, leading to physiological decline and increased susceptibility to diseases. Cognitive decline is a prominent feature of aging, with implications for different neurodegenerative disorders. The gut microbiome has gained attention for its potential impact on health and disease, including cognitive function. This systematic review and meta-analysis aimed to investigate the relationship between the gut microbiome and cognitive function in the context of aging. Following PRISMA guidelines, a comprehensive search strategy was employed in PubMed, Scopus, and Web of Science databases. Studies exploring the role of the microbiome in cognition and neurodegenerative disorders, published between 2013 and 2023, were included. Data extraction and quality assessment were performed. Quantitative synthesis using statistical analyses was performed to examine microbial diversity and relative abundance in various cognitive conditions. Sixteen studies involving a total of 1303 participants were included in the analysis. The gut microbiota’s relative abundance was different in individuals with cognitive impairments such as Alzheimer’s disease, Parkinson’s disease, and dementia, compared to the healthy controls. The most prevalent phyla affected were Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Meta-analyses indicated substantial heterogeneity among studies focusing on Alzheimer’s disease. The overall quality of evidence related to microbial analysis was moderate. The gut microbiome’s role in cognitive decline and neurodegenerative disorders warrants investigation. Altered microbial abundance, particularly in specific phyla, is associated with cognitive impairments. However, variations in study findings and methodologies highlight the complexity of the relationship between the gut microbiome and cognitive function. Further studies are needed to better understand the mechanisms underlying this connection and its potential implications for aging and cognitive health. Full article

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17 pages, 2766 KiB

Open AccessArticle

The Effect of Skeletal Muscle-Specific Creatine Treatment on ALS NMJ Integrity and Function

by Agnes Badu-Mensah, Xiufang Guo, Roxana Mendez, Hemant Parsaud and James J. Hickman

Int. J. Mol. Sci. 2023, 24(17), 13519; https://doi.org/10.3390/ijms241713519 - 31 Aug 2023

Cited by 2 | Viewed by 2221

Abstract

Although skeletal muscle (hSKM) has been proven to be actively involved in Amyotrophic Lateral Sclerosis (ALS) neuromuscular junction (NMJ) dysfunction, it is rarely considered as a pharmacological target in preclinical drug discovery. This project investigated how improving ALS hSKM viability and function effects [...] Read more.

Although skeletal muscle (hSKM) has been proven to be actively involved in Amyotrophic Lateral Sclerosis (ALS) neuromuscular junction (NMJ) dysfunction, it is rarely considered as a pharmacological target in preclinical drug discovery. This project investigated how improving ALS hSKM viability and function effects NMJ integrity. Phenotypic ALS NMJ human-on-a-chip models developed from patient-derived induced pluripotent stem cells (iPSCs) were used to study the effect of hSKM-specific creatine treatment on clinically relevant functional ALS NMJ parameters, such as NMJ numbers, fidelity, stability, and fatigue index. Results indicated comparatively enhanced NMJ numbers, fidelity, and stability, as well as reduced fatigue index, across all hSKM-specific creatine-treated systems. Immunocytochemical analysis of the NMJs also revealed improved post-synaptic nicotinic Acetylcholine receptor (AChR) clustering and cluster size in systems supplemented with creatine relative to the un-dosed control. This work strongly suggests hSKM as a therapeutic target in ALS drug discovery. It also demonstrates the need to consider all tissues involved in multi-systemic diseases, such as ALS, in drug discovery efforts. Finally, this work further establishes the BioMEMs NMJ platform as an effective means of performing mutation-specific drug screening, which is a step towards personalized medicine for rare diseases. Full article

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25 pages, 10387 KiB

Open AccessArticle

The Influence of Race/Ethnicity on the Transcriptomic Landscape of Uterine Fibroids

by Tsai-Der Chuang, Nhu Ton, Shawn Rysling, Derek Quintanilla, Drake Boos, Jianjun Gao, Hayden McSwiggin, Wei Yan and Omid Khorram

Int. J. Mol. Sci. 2023, 24(17), 13441; https://doi.org/10.3390/ijms241713441 - 30 Aug 2023

Cited by 5 | Viewed by 1796

Abstract

The objective of this study was to determine if the aberrant expression of select genes could form the basis for the racial disparity in fibroid characteristics. The next-generation RNA sequencing results were analyzed as fold change [leiomyomas/paired myometrium, also known as differential expression [...] Read more.

The objective of this study was to determine if the aberrant expression of select genes could form the basis for the racial disparity in fibroid characteristics. The next-generation RNA sequencing results were analyzed as fold change [leiomyomas/paired myometrium, also known as differential expression (DF)], comparing specimens from White (n = 7) and Black (n = 12) patients. The analysis indicated that 95 genes were minimally changed in tumors from White (DF ≈ 1) but were significantly altered by more than 1.5-fold (up or down) in Black patients. Twenty-one novel genes were selected for confirmation in 69 paired fibroids by qRT-PCR. Among these 21, coding of transcripts for the differential expression of FRAT2, SOX4, TNFRSF19, ACP7, GRIP1, IRS4, PLEKHG4B, PGR, COL24A1, KRT17, MMP17, SLN, CCDC177, FUT2, MYO5B, MYOG, ZNF703, CDC25A, and CDCA7 was significantly higher, while the expression of DAB2 and CAV2 was significantly lower in tumors from Black or Hispanic patients compared with tumors from White patients. Western blot analysis revealed a greater differential expression of PGR-A and total progesterone (PGR-A and PGR-B) in tumors from Black compared with tumors from White patients. Collectively, we identified a set of genes uniquely expressed in a race/ethnicity-dependent manner, which could form the underlying mechanisms for the racial disparity in fibroids and their associated symptoms. Full article

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17 pages, 28530 KiB

Open AccessArticle

Targeting Melanoma-Associated Fibroblasts (MAFs) with Activated γδ (Vδ2) T Cells: An In Vitro Cytotoxicity Model

by Anna Hajdara, Uğur Çakır, Barbara Érsek, Pálma Silló, Balázs Széky, Gábor Barna, Shaaban Faqi, Miklós Gyöngy, Sarolta Kárpáti, Krisztián Németh and Balázs Mayer

Int. J. Mol. Sci. 2023, 24(16), 12893; https://doi.org/10.3390/ijms241612893 - 17 Aug 2023

Cited by 3 | Viewed by 1691

Abstract

The tumor microenvironment (TME) has gained considerable scientific attention by playing a role in immunosuppression and tumorigenesis. Besides tumor cells, TME is composed of various other cell types, including cancer-associated fibroblasts (CAFs or MAFs when referring to melanoma-derived CAFs) and tumor-infiltrating lymphocytes (TILs), [...] Read more.

The tumor microenvironment (TME) has gained considerable scientific attention by playing a role in immunosuppression and tumorigenesis. Besides tumor cells, TME is composed of various other cell types, including cancer-associated fibroblasts (CAFs or MAFs when referring to melanoma-derived CAFs) and tumor-infiltrating lymphocytes (TILs), a subpopulation of which is labeled as γδ T cells. Since the current anti-cancer therapies using γδ T cells in various cancers have exhibited mixed treatment responses, to better understand the γδ T cell biology in melanoma, our research group aimed to investigate whether activated γδ T cells are capable of killing MAFs. To answer this question, we set up an in vitro platform using freshly isolated Vδ2-type γδ T cells and cultured MAFs that were biobanked from our melanoma patients. This study proved that the addition of zoledronic acid (1–2.5 µM) to the γδ T cells was necessary to drive MAFs into apoptosis. The MAF cytotoxicity of γδ T cells was further enhanced by using the stimulatory clone 20.1 of anti-BTN3A1 antibody but was reduced when anti-TCR γδ or anti-BTN2A1 antibodies were used. Since the administration of zoledronic acid is safe and tolerable in humans, our results provide further data for future clinical studies on the treatment of melanoma. Full article

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15 pages, 4999 KiB

Open AccessReview

Epigenetic Regulation in Lean Nonalcoholic Fatty Liver Disease

by Ioanna Aggeletopoulou, Maria Kalafateli, Efthymios P. Tsounis and Christos Triantos

Int. J. Mol. Sci. 2023, 24(16), 12864; https://doi.org/10.3390/ijms241612864 - 16 Aug 2023

Cited by 7 | Viewed by 2494

Abstract

Nonalcoholic fatty liver disease (NAFLD), the most prominent cause of chronic liver disease worldwide, is a rapidly growing epidemic. It consists of a wide range of liver diseases, from steatosis to nonalcoholic steatohepatitis, and predisposes patients to liver fibrosis, cirrhosis, and even hepatocellular [...] Read more.

Nonalcoholic fatty liver disease (NAFLD), the most prominent cause of chronic liver disease worldwide, is a rapidly growing epidemic. It consists of a wide range of liver diseases, from steatosis to nonalcoholic steatohepatitis, and predisposes patients to liver fibrosis, cirrhosis, and even hepatocellular carcinoma. NAFLD is strongly correlated with obesity; however, it has been extensively reported among lean/nonobese individuals in recent years. Although lean patients demonstrate a lower prevalence of diabetes mellitus, central obesity, dyslipidemia, hypertension, and metabolic syndrome, a percentage of these patients may develop steatohepatitis, advanced liver fibrosis, and cardiovascular disease, and have increased all-cause mortality. The pathophysiological mechanisms of lean NAFLD remain vague. Studies have reported that lean NAFLD demonstrates a close association with environmental factors, genetic predisposition, and epigenetic modifications. In this review, we aim to discuss and summarize the epigenetic mechanisms involved in lean NAFLD and to introduce the interaction between epigenetic patterns and genetic or non genetic factors. Several epigenetic mechanisms have been implicated in the regulation of lean NAFLD. These include DNA methylation, histone modifications, and noncoding-RNA-mediated gene regulation. Epigenetics is an area of special interest in the setting of lean NAFLD as it could provide new insights into the therapeutic options and noninvasive biomarkers that target this under-recognized and challenging disorder. Full article

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9 pages, 3303 KiB

Open AccessCommunication

Further Developments towards a Minimal Potent Derivative of Human Relaxin-2

by Thomas N. G. Handley, Praveen Praveen, Julien Tailhades, Hongkang Wu, Ross A. D. Bathgate and Mohammed Akhter Hossain

Int. J. Mol. Sci. 2023, 24(16), 12670; https://doi.org/10.3390/ijms241612670 - 11 Aug 2023

Cited by 2 | Viewed by 1629

Abstract

Human relaxin-2 (H2 relaxin) is a peptide hormone with potent vasodilatory and anti-fibrotic effects, which is of interest for the treatment of heart failure and fibrosis. H2 relaxin binds to the Relaxin Family Peptide Receptor 1 (RXFP1). Native H2 relaxin is a two-chain, [...] Read more.

Human relaxin-2 (H2 relaxin) is a peptide hormone with potent vasodilatory and anti-fibrotic effects, which is of interest for the treatment of heart failure and fibrosis. H2 relaxin binds to the Relaxin Family Peptide Receptor 1 (RXFP1). Native H2 relaxin is a two-chain, three-disulfide-bond-containing peptide, which is unstable in human serum and difficult to synthesize efficiently. In 2016, our group developed B7-33, a single-chain peptide derived from the B-chain of H2 relaxin. B7-33 demonstrated poor affinity and potency in HEK cells overexpressing RXFP1; however, it displayed equivalent potency to H2 relaxin in fibroblasts natively expressing RXFP1, where it also demonstrated the anti-fibrotic effects of the native hormone. B7-33 reversed organ fibrosis in numerous pre-clinical animal studies. Here, we detail our efforts towards a minimal H2 relaxin scaffold and attempts to improve scaffold activity through Aib substitution and hydrocarbon stapling to re-create the peptide helicity present in the native H2 relaxin. Full article

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26 pages, 1301 KiB

Open AccessReview

Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy

by Flavia Urbano, Ilaria Farella, Giacomina Brunetti and Maria Felicia Faienza

Int. J. Mol. Sci. 2023, 24(15), 11980; https://doi.org/10.3390/ijms241511980 - 26 Jul 2023

Cited by 5 | Viewed by 3999

Abstract

Type 1 diabetes (T1D) is one of the most common chronic diseases in childhood, with a progressively increasing incidence. T1D management requires lifelong insulin treatment and ongoing health care support. The main goal of treatment is to maintain blood glucose levels as close [...] Read more.

Type 1 diabetes (T1D) is one of the most common chronic diseases in childhood, with a progressively increasing incidence. T1D management requires lifelong insulin treatment and ongoing health care support. The main goal of treatment is to maintain blood glucose levels as close to the physiological range as possible, particularly to avoid blood glucose fluctuations, which have been linked to morbidity and mortality in patients with T1D. Indeed, the guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend a glycated hemoglobin (HbA1c) level < 53 mmol/mol (<7.0%) for young people with T1D to avoid comorbidities. Moreover, diabetic disease strongly influences the quality of life of young patients who must undergo continuous monitoring of glycemic values and the administration of subcutaneous insulin. In recent decades, the development of automated insulin delivery (AID) systems improved the metabolic control and the quality of life of T1D patients. Continuous subcutaneous insulin infusion (CSII) combined with continuous glucose monitoring (CGM) devices connected to smartphones represent a good therapeutic option, especially in young children. In this literature review, we revised the mechanisms of the currently available technologies for T1D in pediatric age and explored their effect on short- and long-term diabetes-related comorbidities, quality of life, and life expectation. Full article

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18 pages, 1801 KiB

Open AccessReview

Extracellular Succinate: A Physiological Messenger and a Pathological Trigger

by Kenneth K. Wu

Int. J. Mol. Sci. 2023, 24(13), 11165; https://doi.org/10.3390/ijms241311165 - 6 Jul 2023

Cited by 8 | Viewed by 3055

Abstract

When tissues are under physiological stresses, such as vigorous exercise and cold exposure, skeletal muscle cells secrete succinate into the extracellular space for adaptation and survival. By contrast, environmental toxins and injurious agents induce cellular secretion of succinate to damage tissues, trigger inflammation, [...] Read more.

When tissues are under physiological stresses, such as vigorous exercise and cold exposure, skeletal muscle cells secrete succinate into the extracellular space for adaptation and survival. By contrast, environmental toxins and injurious agents induce cellular secretion of succinate to damage tissues, trigger inflammation, and induce tissue fibrosis. Extracellular succinate induces cellular changes and tissue adaptation or damage by ligating cell surface succinate receptor-1 (SUCNR-1) and activating downstream signaling pathways and transcriptional programs. Since SUCNR-1 mediates not only pathological processes but also physiological functions, targeting it for drug development is hampered by incomplete knowledge about the characteristics of its physiological vs. pathological actions. This review summarizes the current status of extracellular succinate in health and disease and discusses the underlying mechanisms and therapeutic implications. Full article

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15 pages, 298 KiB

Open AccessArticle

FTO Gene Polymorphisms and Their Roles in Acromegaly

by Aleksandra Jawiarczyk-Przybyłowska, Justyna Kuliczkowska-Płaksej, Katarzyna Kolačkov, Agnieszka Zembska, Jowita Halupczok-Żyła, Małgorzata Rolla, Michał Miner, Marcin Kałużny and Marek Bolanowski

Int. J. Mol. Sci. 2023, 24(13), 10974; https://doi.org/10.3390/ijms241310974 - 30 Jun 2023

Viewed by 1705

Abstract

The major causes of both morbidity and mortality in patients with acromegaly are cardiovascular diseases (CVDs). The polymorphisms of the fat mass and obesity-associated gene (FTO) are associated with obesity, as well as with an increased risk of CVDs. The aim of [...] Read more.

The major causes of both morbidity and mortality in patients with acromegaly are cardiovascular diseases (CVDs). The polymorphisms of the fat mass and obesity-associated gene (FTO) are associated with obesity, as well as with an increased risk of CVDs. The aim of the study was to determine the relationship of risk alleles of four FTO gene polymorphisms with selected parameters of lipid and glucose metabolism as well as with IGF-1 and GH levels in the group of patients with acromegaly compared to the control group. The study group consisted of 104 patients with acromegaly and 64 healthy subjects constituting the control group. In the whole acromegaly group, the data reveal that the homozygous for risk allele carriers (rs1421085, rs9930506, rs9939609) as well as carriers of only one risk allele have lower IGF-1 concentrations. In the well-controlled acromegaly group, the homozygous for three risk allele carriers of FTO gene polymorphisms have lower HDL cholesterol concentration (rs1121980, rs1421085, rs993609). In the cured acromegaly group, homozygous risk allele carriers rs9930506 tend to have higher levels of total cholesterol and LDL cholesterol. These associations are not observed in the control group. Conclusion: there is an association between FTO gene polymorphisms and the metabolism of lipids, suggesting that the FTO gene may be associated with higher CVD risk in patients with acromegaly. In addition, there is an association between FTO gene polymorphisms and IGF-1, implying that FTO gene may influence/modify IGF-1 synthesis. Further investigation on a larger scale is required to provide more precise evidence. Full article

29 pages, 1622 KiB

Open AccessReview

The Role of Activation of PI3K/AKT/mTOR and RAF/MEK/ERK Pathways in Aggressive Pituitary Adenomas—New Potential Therapeutic Approach—A Systematic Review

by Aleksandra Derwich, Monika Sykutera, Barbara Bromińska, Błażej Rubiś, Marek Ruchała and Nadia Sawicka-Gutaj

Int. J. Mol. Sci. 2023, 24(13), 10952; https://doi.org/10.3390/ijms241310952 - 30 Jun 2023

Cited by 5 | Viewed by 2458

Abstract

Pituitary tumors (PT) are mostly benign, although occasionally they demonstrate aggressive behavior, invasion of surrounding tissues, rapid growth, resistance to conventional treatments, and multiple recurrences. The pathogenesis of PT is still not fully understood, and the factors responsible for its invasiveness, aggressiveness, and [...] Read more.

Pituitary tumors (PT) are mostly benign, although occasionally they demonstrate aggressive behavior, invasion of surrounding tissues, rapid growth, resistance to conventional treatments, and multiple recurrences. The pathogenesis of PT is still not fully understood, and the factors responsible for its invasiveness, aggressiveness, and potential for metastasis are unknown. RAF/MEK/ERK and mTOR signaling are significant pathways in the regulation of cell growth, proliferation, and survival, its importance in tumorigenesis has been highlighted. The aim of our review is to determine the role of the activation of PI3K/AKT/mTOR and RAF/MEK/ERK pathways in the pathogenesis of pituitary tumors. Additionally, we evaluate their potential in a new therapeutic approach to provide alternative therapies and improved outcomes for patients with aggressive pituitary tumors that do not respond to standard treatment. We perform a systematic literature search using the PubMed, Embase, and Scopus databases (search date was 2012–2023). Out of the 529 screened studies, 13 met the inclusion criteria, 7 related to the PI3K/AKT/mTOR pathway, and 7 to the RAF/MEK/ERK pathway (one study was used in both analyses). Understanding the specific factors involved in PT tumorigenesis provides opportunities for targeted therapies. We also review the possible new targeted therapies and the use of mTOR inhibitors and TKI in PT management. Although the RAF/MEK/ERK and PI3K/AKT/mTOR pathways play a pivotal role in the complex signaling network along with many interactions, further research is urgently needed to clarify the exact functions and the underlying mechanisms of these signaling pathways in the pathogenesis of pituitary adenomas and their role in its invasiveness and aggressive clinical outcome. Full article

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13 pages, 2394 KiB

Open AccessArticle

TRIM21 Promotes Rabies Virus Production by Degrading IRF7 through Ubiquitination

by Boyue Zhang, Ting Cai, Hongling He, Xuezhe Huang, Guie Chen, Yanqin Lai, Yongwen Luo, Shile Huang, Jun Luo and Xiaofeng Guo

Int. J. Mol. Sci. 2023, 24(13), 10892; https://doi.org/10.3390/ijms241310892 - 30 Jun 2023

Cited by 3 | Viewed by 2492

Abstract

Rabies, a highly fatal zoonotic disease, is a significant global public health threat. Currently, the pathogenic mechanism of rabies has not been fully elucidated, and no effective treatment for rabies is available. Increasing evidence shows that the tripartite-motif protein (TRIM) family of proteins [...] Read more.

Rabies, a highly fatal zoonotic disease, is a significant global public health threat. Currently, the pathogenic mechanism of rabies has not been fully elucidated, and no effective treatment for rabies is available. Increasing evidence shows that the tripartite-motif protein (TRIM) family of proteins participates in the host’s regulation of viral replication. Studies have demonstrated the upregulated expression of tripartite-motif protein 21 (TRIM21) in the brain tissue of mice infected with the rabies virus. Related studies have shown that TRIM21 knockdown inhibits RABV replication, while overexpression of TRIM21 exerted the opposite effect. Knockdown of interferon-alpha and interferon-beta modulates the inhibition of RABV replication caused by TRIM21 knockdown and promotes the replication of the virus. Furthermore, our previous study revealed that TRIM21 regulates the secretion of type I interferon during RABV infection by targeting interferon regulatory factor 7 (IRF7). IRF7 knockdown reduced the inhibition of RABV replication caused by the knockdown of TRIM21 and promoted viral replication. TRIM21 regulates RABV replication via the IRF7-IFN axis. Our study identified TRIM21 as a novel host factor required by RABV for replication. Thus, TRIM21 is a potential target for rabies treatment or management. Full article

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16 pages, 2790 KiB

Open AccessArticle

Comparative Analysis of Cell Mixtures Deconvolution and Gene Signatures Generated for Blood, Immune and Cancer Cells

by Natalia Alonso-Moreda, Alberto Berral-González, Enrique De La Rosa, Oscar González-Velasco, José Manuel Sánchez-Santos and Javier De Las Rivas

Int. J. Mol. Sci. 2023, 24(13), 10765; https://doi.org/10.3390/ijms241310765 - 28 Jun 2023

Cited by 4 | Viewed by 2672

Abstract

In the last two decades, many detailed full transcriptomic studies on complex biological samples have been published and included in large gene expression repositories. These studies primarily provide a bulk expression signal for each sample, including multiple cell-types mixed within the global signal. [...] Read more.

In the last two decades, many detailed full transcriptomic studies on complex biological samples have been published and included in large gene expression repositories. These studies primarily provide a bulk expression signal for each sample, including multiple cell-types mixed within the global signal. The cellular heterogeneity in these mixtures does not allow the activity of specific genes in specific cell types to be identified. Therefore, inferring relative cellular composition is a very powerful tool to achieve a more accurate molecular profiling of complex biological samples. In recent decades, computational techniques have been developed to solve this problem by applying deconvolution methods, designed to decompose cell mixtures into their cellular components and calculate the relative proportions of these elements. Some of them only calculate the cell proportions (supervised methods), while other deconvolution algorithms can also identify the gene signatures specific for each cell type (unsupervised methods). In these work, five deconvolution methods (CIBERSORT, FARDEEP, DECONICA, LINSEED and ABIS) were implemented and used to analyze blood and immune cells, and also cancer cells, in complex mixture samples (using three bulk expression datasets). Our study provides three analytical tools (corrplots, cell-signature plots and bar-mixture plots) that allow a thorough comparative analysis of the cell mixture data. The work indicates that CIBERSORT is a robust method optimized for the identification of immune cell-types, but not as efficient in the identification of cancer cells. We also found that LINSEED is a very powerful unsupervised method that provides precise and specific gene signatures for each of the main immune cell types tested: neutrophils and monocytes (of the myeloid lineage), B-cells, NK cells and T-cells (of the lymphoid lineage), and also for cancer cells. Full article

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18 pages, 2841 KiB

Open AccessArticle

Dual-Warhead Conjugate Based on Fibroblast Growth Factor 2 Dimer Loaded with α-Amanitin and Monomethyl Auristatin E Exhibits Superior Cytotoxicity towards Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1

by Daria Nawrocka, Mateusz Adam Krzyscik, Katarzyna Dominika Sluzalska and Jacek Otlewski

Int. J. Mol. Sci. 2023, 24(12), 10143; https://doi.org/10.3390/ijms241210143 - 14 Jun 2023

Cited by 3 | Viewed by 2193

Abstract

Targeting fibroblast growth factor receptor 1 (FGFR1) is a promising therapeutic strategy for various cancers associated with alterations in the FGFR1 gene. In this study, we developed a highly cytotoxic bioconjugate based on fibroblast growth factor 2 (FGF2), which is a natural ligand [...] Read more.

Targeting fibroblast growth factor receptor 1 (FGFR1) is a promising therapeutic strategy for various cancers associated with alterations in the FGFR1 gene. In this study, we developed a highly cytotoxic bioconjugate based on fibroblast growth factor 2 (FGF2), which is a natural ligand of this receptor, and two potent cytotoxic drugs—α-amanitin and monomethyl auristatin E—with completely independent mechanistic modes of action. Utilizing recombinant DNA technology, we produced an FGF2 N- to C-end dimer that exhibited superior internalization capacity in FGFR1-positive cells. The drugs were site-specifically attached to the targeting protein using SnoopLigase- and evolved sortase A-mediated ligations. The resulting dimeric dual-warhead conjugate selectively binds to the FGFR1 and utilizes receptor-mediated endocytosis to enter the cells. Moreover, our results demonstrate that the developed conjugate exhibits about 10-fold higher cytotoxic potency against FGFR1-positive cell lines than an equimolar mixture of single-warhead conjugates. The diversified mode of action of the dual-warhead conjugate may help to overcome the potential acquired resistance of FGFR1-overproducing cancer cells to single cytotoxic drugs. Full article

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20 pages, 595 KiB

Open AccessReview

Primary Undifferentiated/Dedifferentiated Cutaneous Melanomas—A Review on Histological, Immunohistochemical, and Molecular Features with Emphasis on Prognosis and Treatment

by Dana Antonia Țăpoi, Ancuța-Augustina Gheorghișan-Gălățeanu, Adrian Vasile Dumitru, Ana Maria Ciongariu, Andreea Roxana Furtunescu, Andrei Marin and Mariana Costache

Int. J. Mol. Sci. 2023, 24(12), 9985; https://doi.org/10.3390/ijms24129985 - 10 Jun 2023

Cited by 6 | Viewed by 2182

Abstract

Diagnosing cutaneous melanoma is usually straightforward based on these malignancies’ histopathological and immunohistochemical features. Nevertheless, melanomas can imitate various other neoplasms, sometimes lacking the expression of conventional melanocytic markers and expressing non-melanocytic ones. Furthermore, divergent differentiation is more often encountered in metastatic melanomas [...] Read more.

Diagnosing cutaneous melanoma is usually straightforward based on these malignancies’ histopathological and immunohistochemical features. Nevertheless, melanomas can imitate various other neoplasms, sometimes lacking the expression of conventional melanocytic markers and expressing non-melanocytic ones. Furthermore, divergent differentiation is more often encountered in metastatic melanomas and is still poorly described in primary cutaneous melanomas, and little is known about these patients’ prognosis and therapeutic approach. Therefore, we reviewed the literature on undifferentiated/dedifferentiated cutaneous melanomas, and we discuss the histological, immunohistochemical, and molecular profiles of undifferentiated/dedifferentiated cutaneous melanomas to understand these peculiar lesions better and improve their diagnostic algorithm. In addition to this, we also discuss how different genetic mutations may influence prognosis and become potential therapeutic targets. Full article

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15 pages, 4363 KiB

Open AccessArticle

Vitamin E Analog Trolox Attenuates MPTP-Induced Parkinson’s Disease in Mice, Mitigating Oxidative Stress, Neuroinflammation, and Motor Impairment

by Abubakar Atiq, Hyeon Jin Lee, Amjad Khan, Min Hwa Kang, Inayat Ur Rehman, Riaz Ahmad, Muhammad Tahir, Jawad Ali, Kyonghwan Choe, Jun Sung Park and Myeong Ok Kim

Int. J. Mol. Sci. 2023, 24(12), 9942; https://doi.org/10.3390/ijms24129942 - 9 Jun 2023

Cited by 11 | Viewed by 3659

Abstract

Trolox is a potent antioxidant and a water-soluble analog of vitamin E. It has been used in scientific studies to examine oxidative stress and its impact on biological systems. Trolox has been shown to have a neuroprotective effect against ischemia and IL-1β-mediated neurodegeneration. [...] Read more.

Trolox is a potent antioxidant and a water-soluble analog of vitamin E. It has been used in scientific studies to examine oxidative stress and its impact on biological systems. Trolox has been shown to have a neuroprotective effect against ischemia and IL-1β-mediated neurodegeneration. In this study, we investigated the potential protective mechanisms of Trolox against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease mouse model. Western blotting, immunofluorescence staining, and ROS/LPO assays were performed to investigate the role of trolox against neuroinflammation, the oxidative stress mediated by MPTP in the Parkinson’s disease (PD) mouse model (wild-type mice (C57BL/6N), eight weeks old, average body weight 25–30 g). Our study showed that MPTP increased the expression of α-synuclein, decreased tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels in the striatum and substantia nigra pars compacta (SNpc), and impaired motor function. However, Trolox treatment significantly reversed these PD-like pathologies. Furthermore, Trolox treatment reduced oxidative stress by increasing the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Lastly, Trolox treatment inhibited the activated astrocytes (GFAP) and microglia (Iba-1), also reducing phosphorylated nuclear factor-κB, (p-NF-κB) and tumor necrosis factor-alpha (TNF-α) in the PD mouse brain. Overall, our study demonstrated that Trolox may exert neuroprotection on dopaminergic neurons against MPTP-induced oxidative stress, neuroinflammation, motor dysfunction, and neurodegeneration. Full article

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12 pages, 6199 KiB

Open AccessCase Report

Discordant Eosinophilic/T-Cell Chorionic Vasculitis in a Dichorionic Diamniotic Placenta

by Evelina Silvestri, Francesca Servadei, Ione Tamagnini, Laura Moretti and Maria Paola Bonasoni

Int. J. Mol. Sci. 2023, 24(11), 9207; https://doi.org/10.3390/ijms24119207 - 24 May 2023

Viewed by 1710

Abstract

Eosinophilic/T-cell chorionic vasculitis (ETCV) is an idiopathic lesion composed of eosinophils, CD3+ T lymphocytes, and histiocytes. In twins, ETCV may affect only one chorionic plate, a feature defined as “discordant”. We present a case of ETCV discordance in a diamniotic dichorionic placenta at [...] Read more.

Eosinophilic/T-cell chorionic vasculitis (ETCV) is an idiopathic lesion composed of eosinophils, CD3+ T lymphocytes, and histiocytes. In twins, ETCV may affect only one chorionic plate, a feature defined as “discordant”. We present a case of ETCV discordance in a diamniotic dichorionic placenta at 38 weeks of gestation, in which the female twin was small for gestational age, weighing 2670 g (25th percentile). The corresponding placental territory presented ETCV in two close chorionic vessels with concordance of the fetal inflammatory response. Immunohistochemistry showed an abundance of CD3+/CD4+/CD25+T lymphocytes, CD68 PG M1+ macrophages, and scattered CD8+ T cells with focal TIA-1 positivity. Granzyme B, CD20 B lymphocytes, and CD56 natural killer cells were negative. High-grade villitis of unknown etiology (VUE) was additionally found and displayed comparable ETCV findings, except for an equivalent ratio of CD4+/CD8+ T cells, but TIA-1 was focally expressed. VUE was associated with chronic histiocytic intervillositis (CHI). The combination of ETCV, VUE, and CHI may have been responsible for reduced fetal growth. Concordance was observed in the ETCV and TIA-1 expression, both in ETCV and in VUE, which is a maternal response. These findings may suggest a common antigen or chemokine pathway to which both mother and fetus accordingly responded. Full article

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9 pages, 611 KiB

Open AccessCommunication

The Prognostic Value of Anti-PLA2R Antibodies Levels in Primary Membranous Nephropathy

by Olga Lesya Kukuy, Ron Cohen, Boris Gilburd, Eleanor Zeruya, Talia Weinstein, Timna Agur, Dganit Dinour, Pazit Beckerman, Alexander Volkov, Johnatan Nissan, Tima Davidson, Howard Amital, Yehuda Shoenfeld and Ora Shovman

Int. J. Mol. Sci. 2023, 24(10), 9051; https://doi.org/10.3390/ijms24109051 - 21 May 2023

Cited by 5 | Viewed by 2356

Abstract

Anti-PLA2R antibodies (Ab) are a diagnostic and prognostic biomarker in primary membranous nephropathy (PMN). We assessed the relationship between the levels of anti-PLA2R Ab at diagnosis and different variables related to disease activity and prognosis in a western population of PMN patients. Forty-one [...] Read more.

Anti-PLA2R antibodies (Ab) are a diagnostic and prognostic biomarker in primary membranous nephropathy (PMN). We assessed the relationship between the levels of anti-PLA2R Ab at diagnosis and different variables related to disease activity and prognosis in a western population of PMN patients. Forty-one patients with positive anti-PLA2R Ab from three nephrology departments in Israel were enrolled. Clinical and laboratory data were collected at diagnosis and after one year of follow-up, including serum anti-PLA2R Ab levels (ELISA) and glomerular PLA2R deposits on biopsy. Univariable statistical analysis and permutation-based ANOVA and ANCOVA tests were performed. The median [(interquartile range (IQR)) age of the patients was 63 [50–71], with 28 (68%) males. At the time of diagnosis, 38 (93%) of the patients had nephrotic range proteinuria, and 19 (46%) had heavy proteinuria (≥8 gr/24 h). The median [IQR] level of anti-PLA2R at diagnosis was 78 [35–183] RU/mL. Anti-PLA2R levels at diagnosis were correlated with 24 h proteinuria, hypoalbuminemia and remission after one year (p = 0.017, p = 0.003 and p = 0.034, respectively). The correlations for 24 h proteinuria and hypoalbuminemia remained significant after adjustment for immunosuppressive treatment (p = 0.003 and p = 0.034, respectively). Higher levels of anti-PLA2R Ab at diagnosis in patients with active PMN from a western population are associated with higher proteinuria, lower serum albumin and remission one year after the diagnosis. This finding supports the prognostic value of anti-PLA2R Ab levels and their possible use in stratifying PMN patients. Full article

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17 pages, 3689 KiB

Open AccessArticle

Potential Function of Testicular MicroRNAs in Heat-Stress-Induced Spermatogenesis Disorders

by Mailin Gan, Yunhong Jing, Zhongwei Xie, Jianfeng Ma, Lei Chen, Shunhua Zhang, Ye Zhao, Lili Niu, Yan Wang, Xuewei Li, Li Zhu and Linyuan Shen

Int. J. Mol. Sci. 2023, 24(10), 8809; https://doi.org/10.3390/ijms24108809 - 16 May 2023

Cited by 13 | Viewed by 2856

Abstract

Spermatogenesis is temperature-dependent, and the increase in testicular temperature seriously affects mammalian spermatogenesis and semen quality. In this study, the testicular heat stress model of mice was made with a 43 °C water bath for 25 min, and the effects of heat stress [...] Read more.

Spermatogenesis is temperature-dependent, and the increase in testicular temperature seriously affects mammalian spermatogenesis and semen quality. In this study, the testicular heat stress model of mice was made with a 43 °C water bath for 25 min, and the effects of heat stress on semen quality and spermatogenesis-related regulators were analyzed. On the 7th day after heat stress, testis weight shrank to 68.45% and sperm density dropped to 33.20%. High-throughput sequencing analysis showed that 98 microRNAs (miRNAs) and 369 mRNAs were down-regulated, while 77 miRNAs and 1424 mRNAs were up-regulated after heat stress. Through gene ontology (GO) analysis of differentially expressed genes and miRNA–mRNA co-expression networks, it was found that heat stress may be involved in the regulation of testicular atrophy and spermatogenesis disorders by affecting cell meiosis process and cell cycle. In addition, through functional enrichment analysis, co-expression regulatory network, correlation analysis and in vitro experiment, it was found that miR-143-3p may be a representative potential key regulatory factor affecting spermatogenesis under heat stress. In summary, our results enrich the understanding of miRNAs in testicular heat stress and provide a reference for the prevention and treatment of heat-stress-induced spermatogenesis disorders. Full article

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24 pages, 1677 KiB

Open AccessReview

Compartmental Cerebrospinal Fluid Events Occurring after Subarachnoid Hemorrhage: An “Heparin Oriented” Systematic Review

by Fulvio Tartara, Andrea Montalbetti, Emanuela Crobeddu, Daniele Armocida, Eleonora Tavazzi, Andrea Cardia, Marco Cenzato, Davide Boeris, Diego Garbossa and Fabio Cofano

Int. J. Mol. Sci. 2023, 24(9), 7832; https://doi.org/10.3390/ijms24097832 - 25 Apr 2023

Cited by 1 | Viewed by 2256

Abstract

Subarachnoid hemorrhage (SAH) represents a severe acute event with high morbidity and mortality due to the development of early brain injury (EBI), secondary delayed cerebral ischemia (DCI), and shunt-related hydrocephalus. Secondary events (SSE) such as neuroinflammation, vasospasm, excitotoxicity, blood-brain barrier disruption, oxidative cascade, [...] Read more.

Subarachnoid hemorrhage (SAH) represents a severe acute event with high morbidity and mortality due to the development of early brain injury (EBI), secondary delayed cerebral ischemia (DCI), and shunt-related hydrocephalus. Secondary events (SSE) such as neuroinflammation, vasospasm, excitotoxicity, blood-brain barrier disruption, oxidative cascade, and neuronal apoptosis are related to DCI. Despite improvement in management strategies and therapeutic protocols, surviving patients frequently present neurological deficits with neurocognitive impairment. The aim of this paper is to offer to clinicians a practical review of the actually documented pathophysiological events following subarachnoid hemorrhage. To reach our goal we performed a literature review analyzing reported studies regarding the mediators involved in the pathophysiological events following SAH occurring in the cerebrospinal fluid (CSF) (hemoglobin degradation products, platelets, complement, cytokines, chemokines, leucocytes, endothelin-1, NO-synthase, osteopontin, matricellular proteins, blood-brain barrier disruption, microglia polarization). The cascade of pathophysiological events secondary to SAH is very complex and involves several interconnected, but also distinct pathways. The identification of single therapeutical targets or specific pharmacological agents may be a limited strategy able to block only selective pathophysiological paths, but not the global evolution of SAH-related events. We report furthermore on the role of heparin in SAH management and discuss the rationale for use of intrathecal heparin as a pleiotropic therapeutical agent. The combination of the anticoagulant effect and the ability to interfere with SSE theoretically make heparin a very interesting molecule for SAH management. Full article

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17 pages, 3607 KiB

Open AccessArticle

Immunopathological Alterations after Blast Injury and Hemorrhage in a Swine Model of Prolonged Damage Control Resuscitation

by Milomir O. Simovic, Zhangsheng Yang, Bryan S. Jordan, Tamara L. Fraker, Tomas S. Cancio, Michael L. Lucas, Leopoldo C. Cancio and Yansong Li

Int. J. Mol. Sci. 2023, 24(8), 7494; https://doi.org/10.3390/ijms24087494 - 19 Apr 2023

Cited by 3 | Viewed by 1708

Abstract

Trauma-related hemorrhagic shock (HS) remains a leading cause of death among military and civilian trauma patients. We have previously shown that administration of complement and HMGB1 inhibitors attenuate morbidity and mortality 24 h after injury in a rat model of blast injury (BI) [...] Read more.

Trauma-related hemorrhagic shock (HS) remains a leading cause of death among military and civilian trauma patients. We have previously shown that administration of complement and HMGB1 inhibitors attenuate morbidity and mortality 24 h after injury in a rat model of blast injury (BI) and HS. To further validate these results, this study aimed to develop a swine model and evaluate BI+HS-induced pathophysiology. Anesthetized Yucatan minipigs underwent combined BI and volume-controlled hemorrhage. After 30 min of shock, animals received an intravenous bolus of PlasmaLyte A and a continuous PlasmaLyte A infusion. The survival rate was 80% (4/5), and the non-survivor expired 72 min post-BI. Circulating organ-functional biomarkers, inflammatory biomarkers, histopathological evaluation, and CT scans indicated evidence of multiple-organ damage, systemic innate immunological activation, and local tissue inflammation in the injured animals. Interestingly, a rapid and dramatic increase in plasma levels of HMGB1 and C3a and markedly early myocarditis and encephalitis were associated with early death post-BI+HS. This study suggests that this model reflects the immunopathological alterations of polytrauma in humans during shock and prolonged damage control resuscitation. This experimental protocol could be helpful in the assessment of immunological damage control resuscitation approaches during the prolonged care of warfighters. Full article

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26 pages, 59995 KiB

Open AccessArticle

Potential Benefits of Dietary Plant Compounds on Normal and Tumor Brain Cells in Humans: In Silico and In Vitro Approaches

by Lucia Camelia Pirvu, Georgeta Neagu, Adrian Albulescu, Amalia Stefaniu and Lucia Pintilie

Int. J. Mol. Sci. 2023, 24(8), 7404; https://doi.org/10.3390/ijms24087404 - 17 Apr 2023

Cited by 2 | Viewed by 1681

Abstract

Neuroblastoma can be accessed with compounds of larger sizes and wider polarities, which do not usually cross the blood–brain barrier. Clinical data indicate cases of spontaneous regression of neuroblastoma, suggesting a reversible point in the course of cell brain tumorigenesis. Dual specificity tyrosine-phosphorylation-regulated [...] Read more.

Neuroblastoma can be accessed with compounds of larger sizes and wider polarities, which do not usually cross the blood–brain barrier. Clinical data indicate cases of spontaneous regression of neuroblastoma, suggesting a reversible point in the course of cell brain tumorigenesis. Dual specificity tyrosine-phosphorylation-regulated kinase2 (DYRK2) is a major molecular target in tumorigenesis, while curcumin was revealed to be a strong inhibitor of DYRK2 (PBD ID: 5ZTN). Methods: in silico studies by CLC Drug Discovery Workbench (CLC) and Molegro Virtual Docker (MVD) Software on 20 vegetal compounds from the human diet tested on 5ZTN against the native ligand curcumin, in comparison with anemonin. In vitro studies were conducted on two ethanolic extracts from Anemone nemorosa tested on normal and tumor human brain cell lines NHA and U87, compared with four phenolic acids (caffeic, ferulic, gentisic, and para-aminobenzoic/PABA). Conclusions: in silico studies revealed five dietary compounds (verbascoside, lariciresinol, pinoresinol, medioresinol, matairesinol) acting as stronger inhibitors of 5ZTN compared to the native ligand curcumin. In vitro studies indicated that caffeic acid has certain anti-proliferative effects on U87 and small benefits on NHA viability. A. nemorosa extracts indicated potential benefits on NHA viability, and likely dangerous effects on U87. Full article

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22 pages, 3455 KiB

Open AccessArticle

In Response to a Punctual Stress Male and Female Tyrosine Hydroxylase Haploinsufficient Mice Show a Deteriorated Behavior, Immunity, and Redox State

by Judith Félix, Antonio Garrido and Mónica De la Fuente

Int. J. Mol. Sci. 2023, 24(8), 7335; https://doi.org/10.3390/ijms24087335 - 15 Apr 2023

Cited by 1 | Viewed by 1781

Abstract

An inadequate stress response is associated with impaired neuroimmunoendocrine communication, increasing morbidity and mortality. Since catecholamines (CA) constitute one of the acute stress response pathways, female mice with an haploinsufficiency of the tyrosine hydroxylase gene (TH-HZ), the main limiting enzyme in CA synthesis, [...] Read more.

An inadequate stress response is associated with impaired neuroimmunoendocrine communication, increasing morbidity and mortality. Since catecholamines (CA) constitute one of the acute stress response pathways, female mice with an haploinsufficiency of the tyrosine hydroxylase gene (TH-HZ), the main limiting enzyme in CA synthesis, show low CA amounts, exhibiting an impairment of homeostatic systems. The aim of this study was to investigate the effect of a punctual stress in TH-HZ mice, determining the differences with wild-type (WT) mice and those due to sex by restraint with a clamp for 10 min. After restraint, a behavioral battery was performed, and several immune functions, redox state parameters, and CA amounts were evaluated in peritoneal leukocytes. Results show that this punctual stress impaired WT behavior and improved female WT immunity and oxidative stress, whereas in TH-HZ mice, all parameters were impaired. In addition, different responses to stress due to sex were observed, with males having a worse response. In conclusion, this study confirms that a correct CA synthesis is necessary to deal with stress, and that when a positive stress (eustress) occurs, individuals may improve their immune function and oxidative state. Furthermore, it shows that the response to the same stressor is different according to sex. Full article

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18 pages, 2667 KiB

Open AccessArticle

Differential Cytokine Responses and the Clinical Severity of Adult and Pediatric Nephropathia Epidemica

by Ekaterina Martynova, Robert J. Stott-Marshall, Venera Shakirova, Albina Saubanova, Asiya Bulatova, Yuriy N. Davidyuk, Emmanuel Kabwe, Maria Markelova, Ilseyar Khaertynova, Toshana L. Foster and Svetlana Khaiboullina

Int. J. Mol. Sci. 2023, 24(8), 7016; https://doi.org/10.3390/ijms24087016 - 10 Apr 2023

Cited by 2 | Viewed by 1699

Abstract

Nephropathia epidemica (NE), caused by the hantavirus infection, is endemic in Tatarstan Russia. The majority of patients are adults, with infection rarely diagnosed in children. This limited number of pediatric NE cases means there is an inadequate understanding of disease pathogenesis in this [...] Read more.

Nephropathia epidemica (NE), caused by the hantavirus infection, is endemic in Tatarstan Russia. The majority of patients are adults, with infection rarely diagnosed in children. This limited number of pediatric NE cases means there is an inadequate understanding of disease pathogenesis in this age category. Here, we have analyzed clinical and laboratory data in adults and children with NE to establish whether and how the disease severity differs between the two age groups. Serum cytokines were analyzed in samples collected from 11 children and 129 adult NE patients during an outbreak in 2019. A kidney toxicity panel was also used to analyze urine samples from these patients. Additionally, serum and urine samples were analyzed from 11 control children and 26 control adults. Analysis of clinical and laboratory data revealed that NE was milder in children than in adults. A variation in serum cytokine activation could explain the differences in clinical presentation. Cytokines associated with activation of Th1 lymphocytes were prominent in adults, while they were obscured in sera from pediatric NE patients. In addition, a prolonged activation of kidney injury markers was found in adults with NE, whilst only a short-lasting activation of these markers was observed in children with NE. These findings support previous observations of age differences in NE severity, which should be considered when diagnosing the disease in children. Full article

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9 pages, 233 KiB

Open AccessCommunication

A Method and Formula for the Quantitative Analysis of the Total Bioactivity of Natural Products

by Shintu Mathew, Ritesh Raju, Xian Zhou, Francis Bodkin, Suresh Govindaraghavan and Gerald Münch

Int. J. Mol. Sci. 2023, 24(7), 6850; https://doi.org/10.3390/ijms24076850 - 6 Apr 2023

Cited by 4 | Viewed by 2567

Abstract

Identification of bioactive natural products from plants starts with the screening of extracts for a desired bioactivity such as antimicrobial, antifungal, anti-cancer, anti-inflammatory, or neuroprotective. When the bioactivity shows sufficient potency, the plant material is subjected to bio-activity-guided fractionation, which involves, e.g., sequential [...] Read more.

Identification of bioactive natural products from plants starts with the screening of extracts for a desired bioactivity such as antimicrobial, antifungal, anti-cancer, anti-inflammatory, or neuroprotective. When the bioactivity shows sufficient potency, the plant material is subjected to bio-activity-guided fractionation, which involves, e.g., sequential extraction followed by chromatographic separation, including HPLC. The bioactive compounds are then structurally identified by high-resolution mass spectrometry and nuclear magnetic resonance (NMR). One of the questions that come up during the purification process is how much of the bioactivity originally present in the crude extract is preserved during the purification process. If this is the case, it is interesting to investigate if the loss of total bioactivity is caused by the loss of material during purification or by the degradation or evaporation of potent compounds. A further possibility would be the loss of synergy between compounds present in the mixture, which disappears when the compounds are separated. In this publication, a novel formula is introduced that allows researchers to calculate total bioactivity in biological samples using experimental data from our research into the discovery of anti-inflammatory compounds from Backhousia myrtifolia (Grey Myrtle). The results presented show that a raw ethanolic extract retains slightly more bioactivity than the sum of all sequential extracts per gram of starting material and that—despite a large loss of material during HPLC purification—the total bioactivity in all purified fractions is retained, which is indicative of rather an additive than a synergistic principle. Full article

15 pages, 883 KiB

Open AccessReview

Checkpoint Kinase 1 Is a Key Signal Transducer of DNA Damage in the Early Mammalian Cleavage Embryo

by Vladimír Baran and Alexandra Mayer

Int. J. Mol. Sci. 2023, 24(7), 6778; https://doi.org/10.3390/ijms24076778 - 5 Apr 2023

Cited by 2 | Viewed by 2301

Abstract

After fertilization, remodeling of the oocyte and sperm genome is essential for the successful initiation of mitotic activity in the fertilized oocyte and subsequent proliferative activity of the early embryo. Despite the fact that the molecular mechanisms of cell cycle control in early [...] Read more.

After fertilization, remodeling of the oocyte and sperm genome is essential for the successful initiation of mitotic activity in the fertilized oocyte and subsequent proliferative activity of the early embryo. Despite the fact that the molecular mechanisms of cell cycle control in early mammalian embryos are in principle comparable to those in somatic cells, there are differences resulting from the specific nature of the gene totipotency of the blastomeres of early cleavage embryos. In this review, we focus on the Chk1 kinase as a key transduction factor in monitoring the integrity of DNA molecules during early embryogenesis. Full article

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18 pages, 8822 KiB

Open AccessArticle

Different Alterations of Hippocampal and Reticulo-Thalamic GABAergic Parvalbumin-Expressing Interneurons Underlie Different States of Unconsciousness

by Ljiljana Radovanovic, Andrea Novakovic, Jelena Petrovic and Jasna Saponjic

Int. J. Mol. Sci. 2023, 24(7), 6769; https://doi.org/10.3390/ijms24076769 - 5 Apr 2023

Viewed by 1993

Abstract

We traced the changes in GABAergic parvalbumin (PV)-expressing interneurons of the hippocampus and reticulo-thalamic nucleus (RT) as possible underlying mechanisms of the different local cortical and hippocampal electroencephalographic (EEG) microstructures during the non-rapid-eye movement (NREM) sleep compared with anesthesia-induced unconsciousness by two anesthetics [...] Read more.

We traced the changes in GABAergic parvalbumin (PV)-expressing interneurons of the hippocampus and reticulo-thalamic nucleus (RT) as possible underlying mechanisms of the different local cortical and hippocampal electroencephalographic (EEG) microstructures during the non-rapid-eye movement (NREM) sleep compared with anesthesia-induced unconsciousness by two anesthetics with different main mechanisms of action (ketamine/diazepam versus propofol). After 3 h of recording their sleep, the rats were divided into two experimental groups: one half received ketamine/diazepam anesthesia and the other half received propofol anesthesia. We simultaneously recorded the EEG of the motor cortex and hippocampus during sleep and during 1 h of surgical anesthesia. We performed immunohistochemistry and analyzed the PV and postsynaptic density protein 95 (PSD-95) expression. PV suppression in the hippocampus and at RT underlies the global theta amplitude attenuation and hippocampal gamma augmentation that is a unique feature of ketamine-induced versus propofol-induced unconsciousness and NREM sleep. While PV suppression resulted in an increase in hippocampal PSD-95 expression, there was no imbalance between inhibition and excitation during ketamine/diazepam anesthesia compared with propofol anesthesia in RT. This increased excitation could be a consequence of a lower GABA interneuronal activity and an additional mechanism underlying the unique local EEG microstructure in the hippocampus during ketamine/diazepam anesthesia. Full article

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14 pages, 3832 KiB

Open AccessArticle

Clinicopathological Features and Survival Analysis in Molecular Subtypes of Muscle-Invasive Bladder Cancer

by Francesca Sanguedolce, Ugo Giovanni Falagario, Magda Zanelli, Andrea Palicelli, Maurizio Zizzo, Stefano Ascani, Simona Tortorella, Vito Mancini, Angelo Cormio, Giuseppe Carrieri and Luigi Cormio

Int. J. Mol. Sci. 2023, 24(7), 6610; https://doi.org/10.3390/ijms24076610 - 1 Apr 2023

Viewed by 1925

Abstract

Molecular subtyping of bladder cancer (BC) aims to capture the biological heterogeneity of this complex disease in order to provide better patient risk stratification. Immunohistochemical (IHC) markers are regarded as promising surrogates to classify BCs into luminal and basal subtypes in routine practice. [...] Read more.

Molecular subtyping of bladder cancer (BC) aims to capture the biological heterogeneity of this complex disease in order to provide better patient risk stratification. Immunohistochemical (IHC) markers are regarded as promising surrogates to classify BCs into luminal and basal subtypes in routine practice. We investigated the correlation between the molecular subclassification, assessed through IHC, and the conventional prognostic variables of a cohort of 93 muscle-invasive BCs (MIBCs), with a focus on the pattern of muscularis propria (MP) invasion, and evaluated their association with outcome. Basal, luminal, double-positive (DP), and double-negative (DN) phenotypes were identified according to the coordinate expression of 1 basal (CK5/6) and 2 luminal (CK20, GATA3) markers, and accounted for 33.3%, 32.3%, 3.2%, and 31.2% (Scheme #1) and 9.7%, 60.2%, 26.9%, and 3.2% (Scheme #2). There was a significant association between the pattern of MP invasion and the molecular subtypes according to Scheme #2, in that all 8 basal and DN cases, as well as 83% of DP cases, had a non-infiltrative invasion pattern. No consistent differences were observed in terms of OS and CSS between the molecular subtypes obtained through surrogate IHC markers. In keeping with previous studies, we report the correlation between the identification of BC subtypes and the presence of morphological prognostic factors, supporting the need for a comprehensive pathological evaluation, including clinicopathological and molecular parameters, in order to improve the diagnosis and management of MIBC. Full article

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18 pages, 5339 KiB

Open AccessArticle

Non-Ceruloplasmin Copper Identifies a Subtype of Alzheimer’s Disease (CuAD): Characterization of the Cognitive Profile and Case of a CuAD Patient Carrying an RGS7 Stop-Loss Variant

by Rosanna Squitti, Claudio Catalli, Laura Gigante, Massimo Marianetti, Mattia Rosari, Stefania Mariani, Serena Bucossi, Gioia Mastromoro, Mariacarla Ventriglia, Ilaria Simonelli, Vincenzo Tondolo, Parminder Singh, Ashok Kumar, Amit Pal and Mauro Rongioletti

Int. J. Mol. Sci. 2023, 24(7), 6377; https://doi.org/10.3390/ijms24076377 - 28 Mar 2023

Cited by 11 | Viewed by 2154

Abstract

Alzheimer’s disease (AD) is a type of dementia whose cause is incompletely defined. Copper (Cu) involvement in AD etiology was confirmed by a meta-analysis on about 6000 participants, showing that Cu levels were decreased in AD brain specimens, while Cu and non-bound ceruloplasmin [...] Read more.

Alzheimer’s disease (AD) is a type of dementia whose cause is incompletely defined. Copper (Cu) involvement in AD etiology was confirmed by a meta-analysis on about 6000 participants, showing that Cu levels were decreased in AD brain specimens, while Cu and non-bound ceruloplasmin Cu (non-Cp Cu) levels were increased in serum/plasma samples. Non-Cp Cu was advocated as a stratification add-on biomarker of a Cu subtype of AD (CuAD subtype). To further circumstantiate this concept, we evaluated non-Cp Cu reliability in classifying subtypes of AD based on the characterization of the cognitive profile. The stratification of the AD patients into normal AD (non-Cp Cu ≤ 1.6 µmol/L) and CuAD (non-Cp Cu > 1.6 µmol/L) showed a significant difference in executive function outcomes, even though patients did not differ in disease duration and severity. Among the Cu-AD patients, a 76-year-old woman showed significantly abnormal levels in the Cu panel and underwent whole exome sequencing. The CuAD patient was detected with possessing the homozygous (c.1486T > C; p.(Ter496Argext*19) stop-loss variant in the RGS7 gene (MIM*602517), which encodes for Regulator of G Protein Signaling 7. Non-Cp Cu as an add-on test in the AD diagnostic pathway can provide relevant information about the underlying pathological processes in subtypes of AD and suggest specific therapeutic options. Full article

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16 pages, 4458 KiB

Open AccessArticle

Inhibitory Effects of 3-Cyclopropylmethoxy-4-(difluoromethoxy) Benzoic Acid on TGF-β1-Induced Epithelial–Mesenchymal Transformation of In Vitro and Bleomycin-Induced Pulmonary Fibrosis In Vivo

by Tianxiao Sun, Haihua Li, Yan Zhang, Guixin Xiong, Yuerun Liang, Fang Lu, Rong Zheng, Qi Zou and Jiejie Hao

Int. J. Mol. Sci. 2023, 24(7), 6172; https://doi.org/10.3390/ijms24076172 - 24 Mar 2023

Cited by 8 | Viewed by 2037

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by lung inflammation and excessive deposition of extracellular matrix components. Transforming growth factor-β1 (TGF-β1) induced epithelial–mesenchymal transformation of type 2 lung epithelial cells leads to excessive extracellular matrix deposition, which plays an important [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by lung inflammation and excessive deposition of extracellular matrix components. Transforming growth factor-β1 (TGF-β1) induced epithelial–mesenchymal transformation of type 2 lung epithelial cells leads to excessive extracellular matrix deposition, which plays an important role in fibrosis. Our objective was to evaluate the effects of 3-cyclopropylmethoxy-4-(difluoromethoxy) benzoic acid (DGM) on pulmonary fibrosis and aimed to determine whether EMT plays a key role in the pathogenesis of pulmonary fibrosis and whether EMT can be used as a therapeutic target for DGM therapy to reduce IPF. Firstly, stimulation of in vitro cultured A549 cells to construct EMTs with TGF-β1. DGM treatment inhibited the expression of proteins such as α-SMA, vimentin, and collagen Ⅰ and increased the expression of E-cadherin. Accordingly, Smad2/3 phosphorylation levels were significantly reduced by DGM treatment. Secondly, models of tracheal instillation of bleomycin and DGM were used to treat rats to demonstrate their therapeutic effects, such as improving lung function, reducing lung inflammation and fibrosis, reducing collagen deposition, and reducing the expression of E-cadherin. In conclusion, DGM attenuates TGF-β1-induced EMT in A549 cells and bleomycin-induced pulmonary fibrosis in rats. Full article

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15 pages, 8127 KiB

Open AccessArticle

Deciphering the Polyglucosan Accumulation Present in Lafora Disease Using an Astrocytic Cellular Model

by Mireia Moreno-Estellés, Ángela Campos-Rodríguez, Carla Rubio-Villena, Lorena Kumarasinghe, Maria Adelaida Garcia-Gimeno and Pascual Sanz

Int. J. Mol. Sci. 2023, 24(7), 6020; https://doi.org/10.3390/ijms24076020 - 23 Mar 2023

Cited by 2 | Viewed by 2634

Abstract

Lafora disease (LD) is a neurological disorder characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of insoluble forms of glycogen (polyglucosan bodies, or PGBs) in the brain. The accumulation of PGBs is causative of the pathophysiological features of [...] Read more.

Lafora disease (LD) is a neurological disorder characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of insoluble forms of glycogen (polyglucosan bodies, or PGBs) in the brain. The accumulation of PGBs is causative of the pathophysiological features of LD. However, despite the efforts made by different groups, the question of why PGBs accumulate in the brain is still unanswered. We have recently demonstrated that, in vivo, astrocytes accumulate most of the PGBs present in the brain, and this could lead to astrocyte dysfunction. To develop a deeper understanding of the defects present in LD astrocytes that lead to LD pathophysiology, we obtained pure primary cultures of astrocytes from LD mice from the postnatal stage under conditions that accumulate PGBs, the hallmark of LD. These cells serve as novel in vitro models for studying PGBs accumulation and related LD dysfunctions. In this sense, the metabolomics of LD astrocytes indicate that they accumulate metabolic intermediates of the upper part of the glycolytic pathway, probably as a consequence of enhanced glucose uptake. In addition, we also demonstrate the feasibility of using the model in the identification of different compounds that may reduce the accumulation of polyglucosan inclusions. Full article

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13 pages, 570 KiB

Open AccessArticle

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway and Their Relationship with High Blood Pressure Risk

by Susana Rojo-Tolosa, Noelia Márquez-Pete, José María Gálvez-Navas, Laura Elena Pineda-Lancheros, Andrea Fernández-Alonso, Cristina Membrive-Jiménez, María Carmen Ramírez-Tortosa, Cristina Pérez-Ramírez and Alberto Jiménez-Morales

Int. J. Mol. Sci. 2023, 24(6), 5974; https://doi.org/10.3390/ijms24065974 - 22 Mar 2023

Cited by 3 | Viewed by 2776

Abstract

High blood pressure (HBP) is the leading risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide. The progression of the disease leads to structural and/or functional alterations in various organs and increases cardiovascular risk. Currently, there are significant deficiencies in its diagnosis, [...] Read more.

High blood pressure (HBP) is the leading risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide. The progression of the disease leads to structural and/or functional alterations in various organs and increases cardiovascular risk. Currently, there are significant deficiencies in its diagnosis, treatment, and control. Vitamin D is characterized by its functional versatility and its involvement in countless physiological processes. This has led to the association of vitamin D with many chronic diseases, including HBP and CVD, due to its involvement in the regulation of the renin–angiotensin–aldosterone system. The aim of this study was to evaluate the effect of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolic pathway on the risk of developing HBP. An observational case-control study was performed, including 250 patients diagnosed with HBP and 500 controls from the south of Spain (Caucasians). Genetic polymorphisms in CYP27B1 (rs4646536, rs3782130, rs703842, and rs10877012), CYP2R1 rs10741657, GC rs7041, CYP24A1 (rs6068816, and rs4809957), and VDR (BsmI, Cdx2, FokI, ApaI, and TaqI) were analyzed by real-time PCR using TaqMan probes. Logistic regression analysis, adjusted for body mass index (BMI), dyslipidemia, and diabetes, showed that in the genotypic model, carriers of the GC rs7041 TT genotype were associated with a lower risk of developing HBP than the GG genotype (odds ratio (OR) = 0.44, 95% confidence interval (CI): 0.41–0.77, p = 0.005, TT vs. GG). In the dominant model, this association was maintained; carriers of the T allele showed a lower risk of developing HBP than carriers of the GG genotype (OR = 0.69, 95% CI: 0.47–1.03; TT + TG vs. GG, p = 0.010). Finally, in the additive model, consistent with previous models, the T allele was associated with a lower risk of developing HBP than the G allele (OR = 0.65, 95% CI: 0.40–0.87, p = 0.003, T vs. G). Haplotype analysis revealed that GACATG haplotypes for SNPs rs1544410, rs7975232, rs731236, rs4646536, rs703842, and rs10877012 were associated with a marginally significant lower risk of developing HBP (OR = 0.35, 95% CI: 0.12–1.02, p = 0.054). Several studies suggest that GC 7041 is associated with a lower active isoform of the vitamin D binding protein. In conclusion, the rs7041 polymorphism located in the GC gene was significantly associated with a lower risk of developing HBP. This polymorphism could therefore act as a substantial predictive biomarker of the disease. Full article

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16 pages, 2463 KiB

Open AccessArticle

Differences in Whole-Blood Transcriptional Profiles in Inflammatory Bowel Disease Patients Responding to Vedolizumab Compared with Non-Responders

by Sofie Haglund, Jan Söderman and Sven Almer

Int. J. Mol. Sci. 2023, 24(6), 5820; https://doi.org/10.3390/ijms24065820 - 18 Mar 2023

Cited by 4 | Viewed by 2019

Abstract

Vedolizumab is efficacious in the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). However, a significant proportion of patients present with a non-response. To investigate whether differences in the clinical response to vedolizumab is reflected in changes in gene expression levels in [...] Read more.

Vedolizumab is efficacious in the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). However, a significant proportion of patients present with a non-response. To investigate whether differences in the clinical response to vedolizumab is reflected in changes in gene expression levels in whole blood, samples were collected at baseline before treatment, and at follow-up after 10–12 weeks. Whole genome transcriptional profiles were established by RNA sequencing. Before treatment, no differentially expressed genes were noted between responders (n = 9, UC 4, CD 5) and non-responders (n = 11, UC 3, CD 8). At follow-up, compared with baseline, responders displayed 201 differentially expressed genes, and 51 upregulated (e.g., translation initiation, mitochondrial translation, and peroxisomal membrane protein import) and 221 downregulated (e.g., Toll-like receptor activating cascades, and phagocytosis related) pathways. Twenty-two of the upregulated pathways in responders were instead downregulated in non-responders. The results correspond with a dampening of inflammatory activity in responders. Although considered a gut-specific drug, our study shows a considerable gene regulation in the blood of patients responding to vedolizumab. It also suggests that whole blood is not optimal for identifying predictive pre-treatment biomarkers based on individual genes. However, treatment outcomes may depend on several interacting genes, and our results indicate a possible potential of pathway analysis in predicting response to treatment, which merits further investigation. Full article

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25 pages, 1576 KiB

Open AccessReview

Molecular Markers of Blood Cell Populations Can Help Estimate Aging of the Immune System

by Natalia Rybtsova, Tatiana N. Berezina and Stanislav Rybtsov

Int. J. Mol. Sci. 2023, 24(6), 5708; https://doi.org/10.3390/ijms24065708 - 16 Mar 2023

Cited by 6 | Viewed by 3371

Abstract

Aging of the immune system involves functional changes in individual cell populations, in hematopoietic tissues and at the systemic level. They are mediated by factors produced by circulating cells, niche cells, and at the systemic level. Age-related alterations in the microenvironment of the [...] Read more.

Aging of the immune system involves functional changes in individual cell populations, in hematopoietic tissues and at the systemic level. They are mediated by factors produced by circulating cells, niche cells, and at the systemic level. Age-related alterations in the microenvironment of the bone marrow and thymus cause a decrease in the production of naive immune cells and functional immunodeficiencies. Another result of aging and reduced tissue immune surveillance is the accumulation of senescent cells. Some viral infections deplete adaptive immune cells, increasing the risk of autoimmune and immunodeficiency conditions, leading to a general degradation in the specificity and effectiveness of the immune system in old age. During the COVID-19 pandemic, the state-of-the-art application of mass spectrometry, multichannel flow cytometry, and single-cell genetic analysis have provided vast data on the mechanisms of aging of the immune system. These data require systematic analysis and functional verification. In addition, the prediction of age-related complications is a priority task of modern medicine in the context of the increase in the aged population and the risk of premature death during epidemics. In this review, based on the latest data, we discuss the mechanisms of immune aging and highlight some cellular markers as indicators of age-related immune disbalance that increase the risk of senile diseases and infectious complications. Full article

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21 pages, 2502 KiB

Open AccessArticle

The Association of the Polymorphisms in the FUT8-Related Locus with the Plasma Glycosylation in Post-Traumatic Stress Disorder

by Lucija Tudor, Gordana Nedic Erjavec, Matea Nikolac Perkovic, Marcela Konjevod, Suzana Uzun, Oliver Kozumplik, Ninoslav Mimica, Gordan Lauc, Dubravka Svob Strac and Nela Pivac

Int. J. Mol. Sci. 2023, 24(6), 5706; https://doi.org/10.3390/ijms24065706 - 16 Mar 2023

Cited by 2 | Viewed by 1762

Abstract

The molecular underpinnings of post-traumatic stress disorder (PTSD) are still unclear due to the complex interactions of genetic, psychological, and environmental factors. Glycosylation is a common post-translational modification of proteins, and different pathophysiological states, such as inflammation, autoimmune diseases, and mental disorders including [...] Read more.

The molecular underpinnings of post-traumatic stress disorder (PTSD) are still unclear due to the complex interactions of genetic, psychological, and environmental factors. Glycosylation is a common post-translational modification of proteins, and different pathophysiological states, such as inflammation, autoimmune diseases, and mental disorders including PTSD, show altered N-glycome. Fucosyltransferase 8 (FUT8) is the enzyme that catalyzes the addition of core fucose on glycoproteins, and mutations in the FUT8 gene are associated with defects in glycosylation and functional abnormalities. This is the first study that investigated the associations of plasma N-glycan levels with FUT8-related rs6573604, rs11621121, rs10483776, and rs4073416 polymorphisms and their haplotypes in 541 PTSD patients and control participants. The results demonstrated that the rs6573604 T allele was more frequent in the PTSD than in the control participants. Significant associations of plasma N-glycan levels with PTSD and FUT8-related polymorphisms were observed. We also detected associations of rs11621121 and rs10483776 polymorphisms and their haplotypes with plasma levels of specific N-glycan species in both the control and PTSD groups. In carriers of different rs6573604 and rs4073416 genotypes and alleles, differences in plasma N-glycan levels were only found in the control group. These molecular findings suggest a possible regulatory role of FUT8-related polymorphisms in glycosylation, the alternations of which could partially explain the development and clinical manifestation of PTSD. Full article

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13 pages, 2839 KiB

Open AccessArticle

Leucocyte Abnormalities in Synovial Fluid of Degenerative and Inflammatory Arthropathies

by Chiara Baggio, Roberto Luisetto, Carlotta Boscaro, Anna Scanu, Roberta Ramonda, Mattia Albiero, Paolo Sfriso and Francesca Oliviero

Int. J. Mol. Sci. 2023, 24(6), 5450; https://doi.org/10.3390/ijms24065450 - 13 Mar 2023

Cited by 3 | Viewed by 4531

Abstract

Genome damage has been related to the induction of autoimmune processes, chronic inflammation, and apoptosis. Recent studies suggest that some rheumatological diseases are associated with overall genomic instability in the T cell compartment. However, no data regarding leucocyte abnormalities in synovial fluid (SF) [...] Read more.

Genome damage has been related to the induction of autoimmune processes, chronic inflammation, and apoptosis. Recent studies suggest that some rheumatological diseases are associated with overall genomic instability in the T cell compartment. However, no data regarding leucocyte abnormalities in synovial fluid (SF) and their relationship with inflammation are available. The aim of this study was to investigate cellular phenotypes in SF collected from patients with different inflammatory arthropathies, including rhematoid arthritis (RA), psoriatic arthritis (PsA), crystal-induced arthritis (CIA), and non-inflammatory arthropathies, such as osteoarthritis (OA). We found high percentage of micronuclei in SF from CIA compared to the other groups and a high frequency of pyknotic cell in RA and CIA patients. A correlation between pyknosis and immature polymorphonuclear cells with local inflammatory indices was observed. The study of the apoptosis process revealed an increased BAX expression in CIA and RA compared to OA and PsA, while Bcl-2 was higher in CIA. Caspase-3 activity was increased in SF from RA patients and correlates with inflammatory and anti-inflammatory cytokines. In conclusion, our results showed that inflammatory SF is associated with genomic instability and abnormal cell subsets. Full article

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12 pages, 3938 KiB

Open AccessArticle

A Novel Fluorescence-Based Screen of Gene Editing Molecules for Junctional Epidermolysis Bullosa

by Janine Zwicklhuber, Thomas Kocher, Bernadette Liemberger, Stefan Hainzl, Johannes Bischof, Dirk Strunk, Anna M. Raninger, Iris Gratz, Verena Wally, Christina Guttmann-Gruber, Josefina Piñón Hofbauer, Johann W. Bauer and Ulrich Koller

Int. J. Mol. Sci. 2023, 24(6), 5197; https://doi.org/10.3390/ijms24065197 - 8 Mar 2023

Cited by 1 | Viewed by 2500

Abstract

Junctional epidermolysis bullosa (JEB) is a severe blistering skin disease caused by mutations in genes encoding structural proteins essential for skin integrity. In this study, we developed a cell line suitable for gene expression studies of the JEB-associated COL17A1 encoding type XVII collagen [...] Read more.

Junctional epidermolysis bullosa (JEB) is a severe blistering skin disease caused by mutations in genes encoding structural proteins essential for skin integrity. In this study, we developed a cell line suitable for gene expression studies of the JEB-associated COL17A1 encoding type XVII collagen (C17), a transmembrane protein involved in connecting basal keratinocytes to the underlying dermis of the skin. Using the CRISPR/Cas9 system of Streptococcus pyogenes we fused the coding sequence of GFP to COL17A1 leading to the constitutive expression of GFP-C17 fusion proteins under the control of the endogenous promoter in human wild-type and JEB keratinocytes. We confirmed the accurate full-length expression and localization of GFP-C17 to the plasma membrane via fluorescence microscopy and Western blot analysis. As expected, the expression of GFP-C17^mut fusion proteins in JEB keratinocytes generated no specific GFP signal. However, the CRISPR/Cas9-mediated repair of a JEB-associated frameshift mutation in GFP-COL17A1^mut-expressing JEB cells led to the restoration of GFP-C17, apparent in the full-length expression of the fusion protein, its accurate localization within the plasma membrane of keratinocyte monolayers as well as within the basement membrane zone of 3D-skin equivalents. Thus, this fluorescence-based JEB cell line provides the potential to serve as a platform to screen for personalized gene editing molecules and applications in vitro and in appropriate animal models in vivo. Full article

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24 pages, 5717 KiB

Open AccessArticle

Anoxia Rapidly Induces Changes in Expression of a Large and Diverse Set of Genes in Endothelial Cells

by Antonella Antonelli, Emanuele Salvatore Scarpa, Santina Bruzzone, Cecilia Astigiano, Francesco Piacente, Michela Bruschi, Alessandra Fraternale, Christian A. Di Buduo, Alessandra Balduini and Mauro Magnani

Int. J. Mol. Sci. 2023, 24(6), 5157; https://doi.org/10.3390/ijms24065157 - 8 Mar 2023

Cited by 2 | Viewed by 1858

Abstract

Sinusoidal endothelial cells are the predominant vascular surface of the bone marrow and constitute the functional hematopoietic niche where hematopoietic stem and progenitor cells receive cues for self-renewal, survival, and differentiation. In the bone marrow hematopoietic niche, the oxygen tension is usually very [...] Read more.

Sinusoidal endothelial cells are the predominant vascular surface of the bone marrow and constitute the functional hematopoietic niche where hematopoietic stem and progenitor cells receive cues for self-renewal, survival, and differentiation. In the bone marrow hematopoietic niche, the oxygen tension is usually very low, and this condition affects stem and progenitor cell proliferation and differentiation and other important functions of this region. Here, we have investigated in vitro the response of endothelial cells to a marked decrease in O₂ partial pressure to understand how the basal gene expression of some relevant biological factors (i.e., chemokines and interleukins) that are fundamental for the intercellular communication could change in anoxic conditions. Interestingly, mRNA levels of CXCL3, CXCL5, and IL-34 genes are upregulated after anoxia exposure but become downmodulated by sirtuin 6 (SIRT6) overexpression. Indeed, the expression levels of some other genes (such as Leukemia Inhibitory Factor (LIF)) that were not significantly affected by 8 h anoxia exposure become upregulated in the presence of SIRT6. Therefore, SIRT6 mediates also the endothelial cellular response through the modulation of selected genes in an extreme hypoxic condition. Full article

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23 pages, 2939 KiB

Open AccessArticle

Respiratory Health Effects of In Vivo Sub-Chronic Diesel and Biodiesel Exhaust Exposure

by Katherine R. Landwehr, Ryan Mead-Hunter, Rebecca A. O’Leary, Anthony Kicic, Benjamin J. Mullins and Alexander N. Larcombe

Int. J. Mol. Sci. 2023, 24(6), 5130; https://doi.org/10.3390/ijms24065130 - 7 Mar 2023

Cited by 2 | Viewed by 1943

Abstract

Biodiesel, which can be made from a variety of natural oils, is currently promoted as a sustainable, healthier replacement for commercial mineral diesel despite little experimental data supporting this. The aim of our research was to investigate the health impacts of exposure to [...] Read more.

Biodiesel, which can be made from a variety of natural oils, is currently promoted as a sustainable, healthier replacement for commercial mineral diesel despite little experimental data supporting this. The aim of our research was to investigate the health impacts of exposure to exhaust generated by the combustion of diesel and two different biodiesels. Male BALB/c mice (n = 24 per group) were exposed for 2 h/day for 8 days to diluted exhaust from a diesel engine running on ultra-low sulfur diesel (ULSD) or Tallow or Canola biodiesel, with room air exposures used as control. A variety of respiratory-related end-point measurements were assessed, including lung function, responsiveness to methacholine, airway inflammation and cytokine response, and airway morphometry. Exposure to Tallow biodiesel exhaust resulted in the most significant health impacts compared to Air controls, including increased airway hyperresponsiveness and airway inflammation. In contrast, exposure to Canola biodiesel exhaust resulted in fewer negative health effects. Exposure to ULSD resulted in health impacts between those of the two biodiesels. The health effects of biodiesel exhaust exposure vary depending on the feedstock used to make the fuel. Full article

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18 pages, 5145 KiB

Open AccessArticle

The Potential Role of MiRs-139-5p and -454-3p in Endoglin-Knockdown-Induced Angiogenic Dysfunction in HUVECs

by Anthony Cannavicci, Qiuwang Zhang and Michael J. B. Kutryk

Int. J. Mol. Sci. 2023, 24(5), 4916; https://doi.org/10.3390/ijms24054916 - 3 Mar 2023

Cited by 1 | Viewed by 2217

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by aberrant angiogenesis and vascular malformations. Mutations in the transforming growth factor beta co-receptor, endoglin (ENG), account for approximately half of known HHT cases and cause abnormal angiogenic activity in endothelial [...] Read more.

Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by aberrant angiogenesis and vascular malformations. Mutations in the transforming growth factor beta co-receptor, endoglin (ENG), account for approximately half of known HHT cases and cause abnormal angiogenic activity in endothelial cells (ECs). To date, how ENG deficiency contributes to EC dysfunction remains to be fully understood. MicroRNAs (miRNAs) regulate virtually every cellular process. We hypothesized that ENG depletion results in miRNA dysregulation that plays an important role in mediating EC dysfunction. Our goal was to test the hypothesis by identifying dysregulated miRNAs in ENG-knockdown human umbilical vein endothelial cells (HUVECs) and characterizing their potential role in EC function. We identified 32 potentially downregulated miRNAs in ENG-knockdown HUVECs with a TaqMan miRNA microarray. MiRs-139-5p and -454-3p were found to be significantly downregulated after RT-qPCR validation. While the inhibition of miR-139-5p or miR-454-3p had no effect on HUVEC viability, proliferation or apoptosis, angiogenic capacity was significantly compromised as determined by a tube formation assay. Most notably, the overexpression of miRs-139-5p and -454-3p rescued impaired tube formation in HUVECs with ENG knockdown. To our knowledge, we are the first to demonstrate miRNA alterations after the knockdown of ENG in HUVECs. Our results indicate a potential role of miRs-139-5p and -454-3p in ENG-deficiency-induced angiogenic dysfunction in ECs. Further study to examine the involvement of miRs-139-5p and -454-3p in HHT pathogenesis is warranted. Full article

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23 pages, 7488 KiB

Open AccessArticle

Impact of Double-Stranded RNA Internalization on Hematopoietic Progenitors and Krebs-2 Cells and Mechanism

by Genrikh S. Ritter, Anastasia S. Proskurina, Maria I. Meschaninova, Ekaterina A. Potter, Daria D. Petrova, Vera S. Ruzanova, Evgeniya V. Dolgova, Svetlana S. Kirikovich, Evgeniy V. Levites, Yaroslav R. Efremov, Valeriy P. Nikolin, Nelly A. Popova, Aliya G. Venyaminova, Oleg S. Taranov, Alexandr A. Ostanin, Elena R. Chernykh, Nikolay A. Kolchanov and Sergey S. Bogachev

Int. J. Mol. Sci. 2023, 24(5), 4858; https://doi.org/10.3390/ijms24054858 - 2 Mar 2023

Viewed by 1854

Abstract

It is well-established that double-stranded RNA (dsRNA) exhibits noticeable radioprotective and radiotherapeutic effects. The experiments conducted in this study directly demonstrated that dsRNA was delivered into the cell in its native form and that it induced hematopoietic progenitor proliferation. The 68 bp synthetic [...] Read more.

It is well-established that double-stranded RNA (dsRNA) exhibits noticeable radioprotective and radiotherapeutic effects. The experiments conducted in this study directly demonstrated that dsRNA was delivered into the cell in its native form and that it induced hematopoietic progenitor proliferation. The 68 bp synthetic dsRNA labeled with 6-carboxyfluorescein (FAM) was internalized into mouse hematopoietic progenitors, c-Kit+ (a marker of long-term hematopoietic stem cells) cells and CD34+ (a marker of short-term hematopoietic stem cells and multipotent progenitors) cells. Treating bone marrow cells with dsRNA stimulated the growth of colonies, mainly cells of the granulocyte–macrophage lineage. A total of 0.8% of Krebs-2 cells internalized FAM-dsRNA and were simultaneously CD34+ cells. dsRNA in its native state was delivered into the cell, where it was present without any signs of processing. dsRNA binding to a cell was independent of cell charge. dsRNA internalization was related to the receptor-mediated process that requires energy from ATP. Synthetic dsRNA did not degrade in the bloodstream for at least 2 h. Hematopoietic precursors that had captured dsRNA reinfused into the bloodstream and populated the bone marrow and spleen. This study, for the first time, directly proved that synthetic dsRNA is internalized into a eukaryotic cell via a natural mechanism. Full article

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15 pages, 5742 KiB

Open AccessArticle

Intrahepatic Cholangiocarcinoma Developing in Patients with Metabolic Syndrome Is Characterized by Osteopontin Overexpression in the Tumor Stroma

by Massimiliano Cadamuro, Samantha Sarcognato, Riccardo Camerotto, Noemi Girardi, Alberto Lasagni, Giacomo Zanus, Umberto Cillo, Enrico Gringeri, Giovanni Morana, Mario Strazzabosco, Elena Campello, Paolo Simioni, Maria Guido and Luca Fabris

Int. J. Mol. Sci. 2023, 24(5), 4748; https://doi.org/10.3390/ijms24054748 - 1 Mar 2023

Cited by 6 | Viewed by 2176

Abstract

Metabolic syndrome (MetS) is a common condition closely associated with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). Recent meta-analyses show that MetS can be prodromal to intrahepatic cholangiocarcinoma (iCCA) development, a liver tumor with features of biliary differentiation characterized by dense extracellular matrix (ECM) [...] Read more.

Metabolic syndrome (MetS) is a common condition closely associated with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). Recent meta-analyses show that MetS can be prodromal to intrahepatic cholangiocarcinoma (iCCA) development, a liver tumor with features of biliary differentiation characterized by dense extracellular matrix (ECM) deposition. Since ECM remodeling is a key event in the vascular complications of MetS, we aimed at evaluating whether MetS patients with iCCA present qualitative and quantitative changes in the ECM able to incite biliary tumorigenesis. In 22 iCCAs with MetS undergoing surgical resection, we found a significantly increased deposition of osteopontin (OPN), tenascin C (TnC), and periostin (POSTN) compared to the matched peritumoral areas. Moreover, OPN deposition in MetS iCCAs was also significantly increased when compared to iCCA samples without MetS (non-MetS iCCAs, n = 44). OPN, TnC, and POSTN significantly stimulated cell motility and the cancer-stem-cell-like phenotype in HuCCT-1 (human iCCA cell line). In MetS iCCAs, fibrosis distribution and components differed quantitatively and qualitatively from non-MetS iCCAs. We therefore propose overexpression of OPN as a distinctive trait of MetS iCCA. Since OPN stimulates malignant properties of iCCA cells, it may provide an interesting predictive biomarker and a putative therapeutic target in MetS patients with iCCA. Full article

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12 pages, 658 KiB

Open AccessReview

Molecular Mechanisms of Hyperoxia-Induced Neonatal Intestinal Injury

by Hsiao-Chin Wang, Hsiu-Chu Chou and Chung-Ming Chen

Int. J. Mol. Sci. 2023, 24(5), 4366; https://doi.org/10.3390/ijms24054366 - 22 Feb 2023

Cited by 8 | Viewed by 2061

Abstract

Oxygen therapy is important for newborns. However, hyperoxia can cause intestinal inflammation and injury. Hyperoxia-induced oxidative stress is mediated by multiple molecular factors and leads to intestinal damage. Histological changes include ileal mucosal thickness, intestinal barrier damage, and fewer Paneth cells, goblet cells, [...] Read more.

Oxygen therapy is important for newborns. However, hyperoxia can cause intestinal inflammation and injury. Hyperoxia-induced oxidative stress is mediated by multiple molecular factors and leads to intestinal damage. Histological changes include ileal mucosal thickness, intestinal barrier damage, and fewer Paneth cells, goblet cells, and villi, effects which decrease the protection from pathogens and increase the risk of necrotizing enterocolitis (NEC). It also causes vascular changes with microbiota influence. Hyperoxia-induced intestinal injuries are influenced by several molecular factors, including excessive nitric oxide, the nuclear factor-κB (NF-κB) pathway, reactive oxygen species, toll-like receptor-4, CXC motif ligand-1, and interleukin-6. Nuclear factor erythroid 2-related factor 2 (Nrf2) pathways and some antioxidant cytokines or molecules including interleukin-17D, n-acetylcysteine, arginyl-glutamine, deoxyribonucleic acid, cathelicidin, and health microbiota play a role in preventing cell apoptosis and tissue inflammation from oxidative stress. NF-κB and Nrf2 pathways are essential to maintain the balance of oxidative stress and antioxidants and prevent cell apoptosis and tissue inflammation. Intestinal inflammation can lead to intestinal damage and death of the intestinal tissue, such as in NEC. This review focuses on histologic changes and molecular pathways of hyperoxia-induced intestinal injuries to establish a framework for potential interventions. Full article

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22 pages, 3155 KiB

Open AccessReview

Outdoor Air Pollution and Childhood Respiratory Disease: The Role of Oxidative Stress

by Arianna Dondi, Claudio Carbone, Elisa Manieri, Daniele Zama, Chiara Del Bono, Ludovica Betti, Carlotta Biagi and Marcello Lanari

Int. J. Mol. Sci. 2023, 24(5), 4345; https://doi.org/10.3390/ijms24054345 - 22 Feb 2023

Cited by 18 | Viewed by 8981

Abstract

The leading mechanisms through which air pollutants exert their damaging effects are the promotion of oxidative stress, the induction of an inflammatory response, and the deregulation of the immune system by reducing its ability to limit infectious agents’ spreading. This influence starts in [...] Read more.

The leading mechanisms through which air pollutants exert their damaging effects are the promotion of oxidative stress, the induction of an inflammatory response, and the deregulation of the immune system by reducing its ability to limit infectious agents’ spreading. This influence starts in the prenatal age and continues during childhood, the most susceptible period of life, due to a lower efficiency of oxidative damage detoxification, a higher metabolic and breathing rate, and enhanced oxygen consumption per unit of body mass. Air pollution is involved in acute disorders like asthma exacerbations and upper and lower respiratory infections, including bronchiolitis, tuberculosis, and pneumoniae. Pollutants can also contribute to the onset of chronic asthma, and they can lead to a deficit in lung function and growth, long-term respiratory damage, and eventually chronic respiratory illness. Air pollution abatement policies, applied in the last decades, are contributing to mitigating air quality issues, but more efforts should be encouraged to improve acute childhood respiratory disease with possible positive long-term effects on lung function. This narrative review aims to summarize the most recent studies on the links between air pollution and childhood respiratory illness. Full article

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22 pages, 6351 KiB

Open AccessArticle

Fatty Acid Sensing in the Gastrointestinal Tract of Rainbow Trout: Different to Mammalian Model?

by Jessica Calo, Sara Comesaña, Ángel L. Alonso-Gómez, José L. Soengas and Ayelén M. Blanco

Int. J. Mol. Sci. 2023, 24(5), 4275; https://doi.org/10.3390/ijms24054275 - 21 Feb 2023

Cited by 6 | Viewed by 2197

Abstract

It is well established in mammals that the gastrointestinal tract (GIT) senses the luminal presence of nutrients and responds to such information by releasing signaling molecules that ultimately regulate feeding. However, gut nutrient sensing mechanisms are poorly known in fish. This research characterized [...] Read more.

It is well established in mammals that the gastrointestinal tract (GIT) senses the luminal presence of nutrients and responds to such information by releasing signaling molecules that ultimately regulate feeding. However, gut nutrient sensing mechanisms are poorly known in fish. This research characterized fatty acid (FA) sensing mechanisms in the GIT of a fish species with great interest in aquaculture: the rainbow trout (Oncorhynchus mykiss). Main results showed that: (i) the trout GIT has mRNAs encoding numerous key FA transporters characterized in mammals (FA transporter CD36 -FAT/CD36-, FA transport protein 4 -FATP4-, and monocarboxylate transporter isoform-1 -MCT-1-) and receptors (several free FA receptor -Ffar- isoforms, and G protein-coupled receptors 84 and 119 -Gpr84 and Gpr119-), and (ii) intragastrically-administered FAs differing in their length and degree of unsaturation (i.e., medium-chain (octanoate), long-chain (oleate), long-chain polyunsaturated (α-linolenate), and short-chain (butyrate) FAs) exert a differential modulation of the gastrointestinal abundance of mRNAs encoding the identified transporters and receptors and intracellular signaling elements, as well as gastrointestinal appetite-regulatory hormone mRNAs and proteins. Together, results from this study offer the first set of evidence supporting the existence of FA sensing mechanisms n the fish GIT. Additionally, we detected several differences in FA sensing mechanisms of rainbow trout vs. mammals, which may suggest evolutionary divergence between fish and mammals. Full article

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10 pages, 886 KiB

Open AccessArticle

Contribution of Glucosylsphingosine (Lyso-Gb1) to Treatment Decisions in Patients with Gaucher Disease

by Tama Dinur, Peter Bauer, Christian Beetz, Claudia Cozma, Michal Becker-Cohen, Majdolen Istaiti, Arndt Rolfs, Volha Skrahina, Ari Zimran and Shoshana Revel-Vilk

Int. J. Mol. Sci. 2023, 24(4), 3945; https://doi.org/10.3390/ijms24043945 - 15 Feb 2023

Cited by 2 | Viewed by 2533

Abstract

Glucosylsphingosine (lyso-Gb1), the deacylated form of glucocerebroside, was shown to be the most specific and sensitive biomarker for diagnosing Gaucher disease (GD). The aim of this study is to assess the contribution of lyso-Gb1 at the time of diagnosis for treatment decisions in [...] Read more.

Glucosylsphingosine (lyso-Gb1), the deacylated form of glucocerebroside, was shown to be the most specific and sensitive biomarker for diagnosing Gaucher disease (GD). The aim of this study is to assess the contribution of lyso-Gb1 at the time of diagnosis for treatment decisions in naïve patients with GD. Newly diagnosed patients from July 2014 to November 2022 were included in this retrospective cohort study. The diagnosis was done by sending a dry blood spot (DBS) sample for GBA1 molecular sequencing and lyso-Gb1 quantification. Treatment decisions were based on symptoms, signs, and routine laboratory tests. We diagnosed 97 patients (41 males), both type 1 (n = 87), and neuronopathic (n = 10). The median (range) age at diagnosis was 22 (1–78), with 36 children. In 65 patients, GD-specific therapy was started with a median (range) lyso-Gb1, 337 (60–1340) ng/mL, significantly higher than in patients who did not go on to treatment, 153.5 (9–442) ng/mL. Using a receiver operating characteristic (ROC) analysis, a cutoff of lyso-Gb1 > 250 ng/mL was associated with treatment with a sensitivity of 71% and specificity of 87.5%. Predictors of treatment were thrombocytopenia, anemia, and elevated lyso-Gb1 (>250 ng/mL). In conclusion, lyso-Gb1 levels contribute to the medical decision related to the initiation of treatment, mainly among mildly affected newly diagnosed patients. For patients with a severe phenotype, as for all patients, the main value of lyso-Gb1 would be to monitor response to therapy. The variable methodology and differences in the units of lyso-Gb1 measurements between laboratories prevent the adaptation of the exact cut-off we found in general practice. However, the concept is that a significant elevation, i.e., a several-fold increase from the diagnostic lyso-Gb1 cutoff, is related to a more severe phenotype and, accordingly, to the decision regarding the initiation of GD-specific therapy. Full article

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15 pages, 2372 KiB

Open AccessArticle

Loss of S1P Lyase Expression in Human Podocytes Causes a Reduction in Nephrin Expression That Involves PKCδ Activation

by Faik Imeri, Bisera Stepanovska Tanturovska, Roxana Manaila, Hermann Pavenstädt, Josef Pfeilschifter and Andrea Huwiler

Int. J. Mol. Sci. 2023, 24(4), 3267; https://doi.org/10.3390/ijms24043267 - 7 Feb 2023

Cited by 4 | Viewed by 1849

Abstract

Sphingosine 1-phosphate (S1P) lyase (SPL, Sgpl1) is an ER-associated enzyme that irreversibly degrades the bioactive lipid, S1P, and thereby regulates multiple cellular functions attributed to S1P. Biallelic mutations in the human Sglp1 gene lead to a severe form of a particular steroid-resistant [...] Read more.

Sphingosine 1-phosphate (S1P) lyase (SPL, Sgpl1) is an ER-associated enzyme that irreversibly degrades the bioactive lipid, S1P, and thereby regulates multiple cellular functions attributed to S1P. Biallelic mutations in the human Sglp1 gene lead to a severe form of a particular steroid-resistant nephrotic syndrome, suggesting that the SPL is critically involved in maintaining the glomerular ultrafiltration barrier, which is mainly built by glomerular podocytes. In this study, we have investigated the molecular effects of SPL knockdown (kd) in human podocytes to better understand the mechanism underlying nephrotic syndrome in patients. A stable SPL-kd cell line of human podocytes was generated by the lentiviral shRNA transduction method and was characterized for reduced SPL mRNA and protein levels and increased S1P levels. This cell line was further studied for changes in those podocyte-specific proteins that are known to regulate the ultrafiltration barrier. We show here that SPL-kd leads to the downregulation of the nephrin protein and mRNA expression, as well as the Wilms tumor suppressor gene 1 (WT1), which is a key transcription factor regulating nephrin expression. Mechanistically, SPL-kd resulted in increased total cellular protein kinase C (PKC) activity, while the stable downregulation of PKCδ revealed increased nephrin expression. Furthermore, the pro-inflammatory cytokine, interleukin 6 (IL-6), also reduced WT1 and nephrin expression. In addition, IL-6 caused increased PKCδ Thr⁵⁰⁵ phosphorylation, suggesting enzyme activation. Altogether, these data demonstrate that nephrin is a critical factor downregulated by the loss of SPL, which may directly cause podocyte foot process effacement as observed in mice and humans, leading to albuminuria, a hallmark of nephrotic syndrome. Furthermore, our in vitro data suggest that PKCδ could represent a new possible pharmacological target for the treatment of a nephrotic syndrome induced by SPL mutations. Full article

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19 pages, 3462 KiB

Open AccessArticle

Study of Effector CD8+ T Cell Interactions with Cortical Neurons in Response to Inflammation in Mouse Brain Slices and Neuronal Cultures

by Ching-Hsin Lin, Anja Scheller, Yang Liu, Elmar Krause and Hsin-Fang Chang

Int. J. Mol. Sci. 2023, 24(4), 3166; https://doi.org/10.3390/ijms24043166 - 6 Feb 2023

Cited by 3 | Viewed by 3477

Abstract

Cytotoxic CD8+ T cells contribute to neuronal damage in inflammatory and degenerative CNS disorders, such as multiple sclerosis (MS). The mechanism of cortical damage associated with CD8+ T cells is not well understood. We developed in vitro cell culture and ex vivo brain [...] Read more.

Cytotoxic CD8+ T cells contribute to neuronal damage in inflammatory and degenerative CNS disorders, such as multiple sclerosis (MS). The mechanism of cortical damage associated with CD8+ T cells is not well understood. We developed in vitro cell culture and ex vivo brain slice co-culture models of brain inflammation to study CD8+ T cell–neuron interactions. To induce inflammation, we applied T cell conditioned media, which contains a variety of cytokines, during CD8+ T cell polyclonal activation. Release of IFNγ and TNFα from co-cultures was verified by ELISA, confirming an inflammatory response. We also visualized the physical interactions between CD8+ T cells and cortical neurons using live-cell confocal imaging. The imaging revealed that T cells reduced their migration velocity and changed their migratory patterns under inflammatory conditions. CD8+ T cells increased their dwell time at neuronal soma and dendrites in response to added cytokines. These changes were seen in both the in vitro and ex vivo models. The results confirm that these in vitro and ex vivo models provide promising platforms for the study of the molecular details of neuron–immune cell interactions under inflammatory conditions, which allow high-resolution live microscopy and are readily amenable to experimental manipulation. Full article

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13 pages, 3260 KiB

Open AccessArticle

Differential Modulation of Human M1 and M2 Macrophage Activity by ICOS-Mediated ICOSL Triggering

by Casimiro Luca Gigliotti, Chiara Dianzani, Ian Stoppa, Chiara Monge, Salvatore Sutti, Daniele Sblattero, Chiara Puricelli, Roberta Rolla, Umberto Dianzani and Elena Boggio

Int. J. Mol. Sci. 2023, 24(3), 2953; https://doi.org/10.3390/ijms24032953 - 2 Feb 2023

Cited by 4 | Viewed by 2468

Abstract

Activated T cells express the inducible T-cell co-stimulator (ICOS) that, upon binding to its ubiquitously expressed ligand (ICOSL), regulates the immune response and tissue repair. We sought to determine the effect of ICOS:ICOSL interaction on human M1 and M2 macrophages. M1 and M2 [...] Read more.

Activated T cells express the inducible T-cell co-stimulator (ICOS) that, upon binding to its ubiquitously expressed ligand (ICOSL), regulates the immune response and tissue repair. We sought to determine the effect of ICOS:ICOSL interaction on human M1 and M2 macrophages. M1 and M2 macrophages were polarized from monocyte-derived macrophages, and the effect of a soluble recombinant form of ICOS (ICOS-CH3) was assessed on cytokine production and cell migration. We show that ICOS-CH3 treatment increased the secretion of CCL3 and CCL4 in resting M1 and M2 cells. In LPS-treated M1 cells, ICOS-CH3 inhibited the secretion of TNF-α, IL-6, IL-10 and CCL4, while it increased that of IL-23. In contrast, M2 cells treated with LPS + IL4 displayed enhanced secretion of IL-6, IL-10, CCL3 and CCL4. In CCL7- or osteopontin-treated M1 cells, ICOS-CH3 boosted the migration rate of M1 cells while it decreased that of M2 cells. Finally, β-Pix expression was upregulated in M1 cells and downregulated in M2 cells by treatment with ICOS-CH3. These findings suggest that ICOSL activation modulates the activity of human M1 and M2 cells, thereby eliciting an overall anti-inflammatory effect consistent with its role in promoting tissue repair. Full article

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24 pages, 470 KiB

Open AccessReview

Molecular and Biologic Effects of Platelet-Rich Plasma (PRP) in Ligament and Tendon Healing and Regeneration: A Systematic Review

by Byron Chalidis, Panagiotis Givissis, Pericles Papadopoulos and Charalampos Pitsilos

Int. J. Mol. Sci. 2023, 24(3), 2744; https://doi.org/10.3390/ijms24032744 - 1 Feb 2023

Cited by 19 | Viewed by 4079

Abstract

Platelet-rich plasma (PRP) has been introduced and applied to a wide spectrum of acute and chronic ligament and tendon pathologic conditions. Although the biological effect of PRP has been studied thoroughly in both animal and human studies, there is no consensus so far [...] Read more.

Platelet-rich plasma (PRP) has been introduced and applied to a wide spectrum of acute and chronic ligament and tendon pathologic conditions. Although the biological effect of PRP has been studied thoroughly in both animal and human studies, there is no consensus so far on the exact mechanism of its action as well as the optimal timing and dosage of its application. Therefore, we conducted a systematic review aiming to evaluate the molecular effect of the administration of PRP in tendoligamentous injuries and degenerative diseases. The literature search revealed 36 in vitro and in vivo studies examining the healing and remodeling response of animal and human ligament or tendon tissues to PRP. Platelet-rich plasma added in the culture media was highly associated with increased cell proliferation, migration, viability and total collagen production of both ligament- and tendon-derived cells in in vitro studies, which was further confirmed by the upregulation of collagen gene expression. In vivo studies correlated the PRP with higher fibroblastic anabolic activity, including increased cellularity, collagen production and vascularity of ligament tissue. Similarly, greater metabolic response of tenocytes along with the acceleration of the healing process in the setting of a tendon tear were noticed after PRP application, particularly between the third and fourth week after treatment. However, some studies demonstrated that PRP had no or even negative effect on tendon and ligament regeneration. This controversy is mainly related to the variable processes and methodologies of preparation of PRP, necessitating standardized protocols for both investigation and ap-plication. Full article

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12 pages, 5180 KiB

Open AccessArticle

Deletion of UCP1 in Tg2576 Mice Increases Body Temperature and Exacerbates Alzheimer’s Disease-Related Pathologies

by Cha-Gyun Jung, Hitoshi Yamashita, Reiko Kato, Chunyu Zhou, Hiroaki Matsushita, Tamaki Takeuchi, Mona Abdelhamid, Yuxin Chen and Makoto Michikawa

Int. J. Mol. Sci. 2023, 24(3), 2741; https://doi.org/10.3390/ijms24032741 - 1 Feb 2023

Cited by 1 | Viewed by 1945

Abstract

We previously demonstrated that the Alzheimer’s disease (AD)-like model mice, Tg2576, housed at a high ambient temperature of 30 °C for 13 months, exhibited increased body temperature, which increased amyloid-β (Aβ) levels and tau stability, leading to tau phosphorylation and ultimately inducing memory [...] Read more.

We previously demonstrated that the Alzheimer’s disease (AD)-like model mice, Tg2576, housed at a high ambient temperature of 30 °C for 13 months, exhibited increased body temperature, which increased amyloid-β (Aβ) levels and tau stability, leading to tau phosphorylation and ultimately inducing memory impairment. Here, we aimed to exclude the possible effect of environmental factors associated with the difference in ambient temperature (23 °C vs. 30 °C) and to further clarify the effects of elevated body temperature on AD-like pathologies. We generated uncoupling protein 1 (UCP1) deletion in Tg2576 mice, Tg2576/UCP1^−/−, because UCP1 deletion mice show a sustained rise in body temperature at normal room temperature. As expected, the body temperature in Tg2576/UCP1^−/− mice was higher than that in Tg2576/ UCP1^+/+ mice at 23 °C, which was accompanied by upregulated Aβ levels due to increased β-secretase (BACE1) and decreased neprilysin (NEP) protein levels in the brains of Tg2576/UCP1^−/− mice compared with those in the Tg2576/ UCP1^+/+ mice. Elevated body temperature also increased total tau levels, leading to enhanced phosphorylation, heat shock protein induction, and activated tau kinases. Furthermore, elevated body temperature enhanced glial activation and decreased synaptic protein levels in the brain. Taken together, these findings demonstrate that elevated body temperatures exacerbate AD-like pathologies. Full article

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15 pages, 3296 KiB

Open AccessArticle

DNA Damage Response Gene Signature as Potential Treatment Markers for Oral Squamous Cell Carcinoma

by Silvia Pomella, Matteo Cassandri, Ombretta Melaiu, Francesco Marampon, Marco Gargari, Vincenzo Campanella, Rossella Rota and Giovanni Barillari

Int. J. Mol. Sci. 2023, 24(3), 2673; https://doi.org/10.3390/ijms24032673 - 31 Jan 2023

Cited by 7 | Viewed by 3159

Abstract

Oral squamous cell carcinoma (OSCC) is a rapidly progressive cancer that often develops resistance against DNA damage inducers, such as radiotherapy and chemotherapy, which are still the standard of care regimens for this tumor. Thus, the identification of biomarkers capable of monitoring the [...] Read more.

Oral squamous cell carcinoma (OSCC) is a rapidly progressive cancer that often develops resistance against DNA damage inducers, such as radiotherapy and chemotherapy, which are still the standard of care regimens for this tumor. Thus, the identification of biomarkers capable of monitoring the clinical progression of OSCC and its responsiveness to therapy is strongly required. To meet this need, here we have employed Whole Genome Sequencing and RNA-seq data from a cohort of 316 patients retrieved from the TCGA Pan-Cancer Atlas to analyze the genomic and transcriptomic status of the DNA damage response (DDR) genes in OSCC. Then, we correlated the transcriptomic data with the clinical parameters of each patient. Finally, we relied on transcriptomic and drug sensitivity data from the CTRP v2 portal, performing Pearson’s correlation analysis to identify putative vulnerabilities of OSCC cell lines correlated with DDR gene expression. Our results indicate that several DDR genes show a high frequency of genomic and transcriptomic alterations and that the expression of some of them correlates with OSCC grading and infection by the human papilloma virus. In addition, we have identified a signature of eight DDR genes (namely CCNB1, CCNB2, CDK2, CDK4, CHECK1, E2F1, FANCD2, and PRKDC) that could be predictive for OSCC response to the novel antitumor compounds sorafenib and tipifarnib-P1. Altogether, our data demonstrate that alterations in DDR genes could have an impact on the biology of OSCC. Moreover, here we propose a DDR gene signature whose expression could be predictive of OSCC responsiveness to therapy. Full article

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15 pages, 4178 KiB

Open AccessArticle

Promotion of Protein Solubility and Reduction in Stiffness in Human Lenses by Aggrelyte-1: Implications for Reversing Presbyopia

by Sudipta Panja, Hanmant Gaikwad, Johanna Rankenberg, Mi-Hyun Nam and Ram H. Nagaraj

Int. J. Mol. Sci. 2023, 24(3), 2196; https://doi.org/10.3390/ijms24032196 - 22 Jan 2023

Cited by 6 | Viewed by 2352

Abstract

With aging, human lenses lose the ability to focus on nearby objects due to decreases in accommodative ability, a condition known as presbyopia. An increase in stiffness or decrease in lens elasticity due to protein aggregation and insolubilization are the primary reasons for [...] Read more.

With aging, human lenses lose the ability to focus on nearby objects due to decreases in accommodative ability, a condition known as presbyopia. An increase in stiffness or decrease in lens elasticity due to protein aggregation and insolubilization are the primary reasons for presbyopia. In this study, we tested aggrelyte-1 (S,N-diacetyl glutathione diethyl ester) for its ability to promote protein solubility and decrease the stiffness of lenses through its dual property of lysine acetylation and disulfide reduction. Treatment of water-insoluble proteins from aged human lenses (58–75 years) with aggrelyte-1 significantly increased the solubility of those proteins. A control compound that did not contain the S-acetyl group (aggrelyte-1C) was substantially less efficient in solubilizing water-insoluble proteins. Aggrelyte-1-treated solubilized protein had significant amounts of acetyllysine, as measured by Western blotting and LC-MS/MS. Aggrelytes increased the protein-free thiol content in the solubilized protein. Aged mouse (7 months) and human (44–66 years) lenses treated with aggrelyte-1 showed reduced stiffness accompanied by higher free thiol and acetyllysine levels compared with those treated with aggrelyte-1C or untreated controls. Our results suggested that aggrelyte-1 reduced lens stiffness through acetylation followed by disulfide reduction. This proof-of-concept study paves the way for developing aggrelyte-1 and related compounds to reverse presbyopia. Full article

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17 pages, 4684 KiB

Open AccessArticle

Functional Characterization of the GNAT Family Histone Acetyltransferase Elp3 and GcnE in Aspergillus fumigatus

by Young-Ho Choi, Sung-Hun Park, Sung-Su Kim, Min-Woo Lee, Jae-Hyuk Yu and Kwang-Soo Shin

Int. J. Mol. Sci. 2023, 24(3), 2179; https://doi.org/10.3390/ijms24032179 - 22 Jan 2023

Cited by 5 | Viewed by 2091

Abstract

Post-translational modifications of chromatin structure by histone acetyltransferase (HATs) play a pivotal role in the regulation of gene expression and diverse biological processes. However, the function of GNAT family HATs, especially Elp3, in the opportunistic human pathogenic fungus Aspergillus fumigatus is largely unknown. [...] Read more.

Post-translational modifications of chromatin structure by histone acetyltransferase (HATs) play a pivotal role in the regulation of gene expression and diverse biological processes. However, the function of GNAT family HATs, especially Elp3, in the opportunistic human pathogenic fungus Aspergillus fumigatus is largely unknown. To investigate the roles of the GNAT family HATs Elp3 and GcnE in the A. fumigatus, we have generated and characterized individual null Δelp3 and ΔgcnE mutants. The radial growth of fungal colonies was significantly decreased by the loss of elp3 or gcnE, and the number of asexual spores (conidia) in the ΔgcnE mutant was significantly reduced. Moreover, the mRNA levels of the key asexual development regulators were also significantly low in the ΔgcnE mutant compared to wild type (WT). Whereas both the Δelp3 and ΔgcnE mutants were markedly impaired in the formation of adherent biofilms, the ΔgcnE mutant showed a complete loss of surface structure and of intercellular matrix. The ΔgcnE mutant responded differently to oxidative stressors and showed significant susceptibility to triazole antifungal agents. Furthermore, Elp3 and GcnE function oppositely in the production of secondary metabolites, and the ΔgcnE mutant showed attenuated virulence. In conclusion, Elp3 and GcnE are associated with diverse biological processes and can be potential targets for controlling the pathogenic fungus. Full article

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15 pages, 4370 KiB

Open AccessArticle

Characterization of IGF2R Molecular Expression in Canine Osteosarcoma as Part of a Novel Comparative Oncology Approach

by Charles Boisclair, Ryan Dickinson, Sabeena Giri, Ekaterina Dadachova and Valerie MacDonald-Dickinson

Int. J. Mol. Sci. 2023, 24(3), 1867; https://doi.org/10.3390/ijms24031867 - 18 Jan 2023

Cited by 5 | Viewed by 2352

Abstract

Progress in prognostic factors, treatments, and outcome for both canine and human osteosarcoma (OS) has been minimal over the last three decades. Surface overexpression of the cation independent mannose-6-phosphate/insulin-like growth factor receptor type 2 (IGF2R) has been proven to occur in human OS [...] Read more.

Progress in prognostic factors, treatments, and outcome for both canine and human osteosarcoma (OS) has been minimal over the last three decades. Surface overexpression of the cation independent mannose-6-phosphate/insulin-like growth factor receptor type 2 (IGF2R) has been proven to occur in human OS cells. Subsequently, radioimmunotherapy (RIT) targeting IGF2R has demonstrated promising preliminary results. The main aims of this study were to investigate the expression of IGF2R in spontaneously occurring canine OS cells using immunohistochemistry (IHC) on archived biopsy samples and to assess its prognostic significance. Thirty-four dogs were included in the study. All cases showed that 80–100% of OS cells stained positive for IGF2R. IGF2R overexpression alone was not shown to have prognostic significance using both visual and quantitative methods of IHC staining intensity. This study has established for the first time the consistent expression of IGF2R in spontaneously occurring canine OS. This comparative oncology approach will allow further investigation into RIT as a novel treatment modality; first in canines and then in humans with OS. In addition, further studies should be performed to assess the true prognostic significance of IGF2R overexpression. Full article

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10 pages, 3052 KiB

Open AccessArticle

Sleeve Gastrectomy-Induced Weight Loss Increases Insulin Clearance in Obese Mice

by Gabriela Moreira Soares, Luana Emanuelly Sinhori Lopes, Sandra Lucinei Balbo, Carine Marmentini, Gabriela Alves Bronczek, Mirian Ayumi Kurauti, Maria Lúcia Bonfleur, Licio Augusto Velloso, Everardo Magalhães Carneiro, Antonio Carlos Boschero and José Maria Costa-Júnior

Int. J. Mol. Sci. 2023, 24(2), 1729; https://doi.org/10.3390/ijms24021729 - 15 Jan 2023

Cited by 1 | Viewed by 2541

Abstract

Sleeve gastrectomy (SG) successfully recovers metabolic homeostasis in obese humans and rodents while also resulting in the normalization of insulin sensitivity and insulinemia. Reduced insulin levels have been attributed to lower insulin secretion and increased insulin clearance in individuals submitted to SG. Insulin [...] Read more.

Sleeve gastrectomy (SG) successfully recovers metabolic homeostasis in obese humans and rodents while also resulting in the normalization of insulin sensitivity and insulinemia. Reduced insulin levels have been attributed to lower insulin secretion and increased insulin clearance in individuals submitted to SG. Insulin degradation mainly occurs in the liver in a process controlled, at least in part, by the insulin-degrading enzyme (IDE). However, research has yet to explore whether liver IDE expression or activity is altered after SG surgery. In this study, C57BL/6 mice were fed a chow (CTL) or high-fat diet (HFD) for 10 weeks. Afterward, the HFD mice were randomly assigned to two groups: sham-surgical (HFD-SHAM) and SG-surgical (HFD-SG). Here, we confirmed that SG improves glucose–insulin homeostasis in obese mice. Additionally, SG reduced insulinemia by reducing insulin secretion, assessed by the analysis of plasmatic C-peptide content, and increasing insulin clearance, which was evaluated through the calculation of the plasmatic C-peptide:insulin ratio. Although no changes in hepatic IDE activity were observed, IDE expression was higher in the liver of HFD-SG compared with HFD-SHAM mice. These results indicate that SG may be helpful to counteract obesity-induced hyperinsulinemia by increasing insulin clearance, likely through enhanced liver IDE expression. Full article

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12 pages, 1551 KiB

Open AccessArticle

Characterization and Seasonal Modulation of Adenosine A₁ Receptors in the Arctic Ground Squirrel Brain

by Zachary Carlson and Kelly Drew

Int. J. Mol. Sci. 2023, 24(2), 1598; https://doi.org/10.3390/ijms24021598 - 13 Jan 2023

Cited by 1 | Viewed by 1730

Abstract

Hibernation is an adaptation that allows animals such as the Arctic ground squirrel (AGS) to survive the absence of food or water during the winter season. Understanding mechanisms of metabolic suppression during hibernation torpor promises new therapies for critical care. The activation of [...] Read more.

Hibernation is an adaptation that allows animals such as the Arctic ground squirrel (AGS) to survive the absence of food or water during the winter season. Understanding mechanisms of metabolic suppression during hibernation torpor promises new therapies for critical care. The activation of the Adenosine A₁ receptor (A₁AR) has been shown to be necessary and sufficient for entrance into hibernation with a winter season sensitization to the agonist, but the role of the A₁AR in seasonal sensitization is unknown. In the current study, we characterize the A₁AR in the forebrain, hippocampus and hypothalamus of summer and torpid AGS. For the first time, we define the pharmacological characteristics of the A₁AR agonist, N⁶-cyclohexyladenosine and the A₁AR antagonist dipropylcyclopentylxanthine (DPCPX) in the AGS brain. In addition, we test the hypothesis that increased A₁AR agonist efficacy is responsible for sensitization of the A₁AR during the torpor season. The resulting ³⁵S-GTPγS binding data indicate an increase in agonist potency during torpor in two out of three brain regions. In addition to ³⁵S-GTPγS binding, [³H]DPCPX saturation and competition assays establish for the first-time pharmacological characteristics for the A₁AR agonist, N⁶-cyclohexyladenosine and the A₁AR antagonist dipropylcyclopentylxanthine (DPCPX) in AGS brain. Full article

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13 pages, 1006 KiB

Open AccessArticle

Endothelial Dysfunction Drives CRTd Outcome at 1-Year Follow-Up: A Novel Role as Biomarker for miR-130a-5p

by Celestino Sardu, Gaetano Santulli, Gianluigi Savarese, Maria Consiglia Trotta, Cosimo Sacra, Matteo Santamaria, Mario Volpicelli, Antonio Ruocco, Ciro Mauro, Giuseppe Signoriello, Lorenza Marfella, Michele D’Amico, Raffaele Marfella and Giuseppe Paolisso

Int. J. Mol. Sci. 2023, 24(2), 1510; https://doi.org/10.3390/ijms24021510 - 12 Jan 2023

Cited by 4 | Viewed by 2095

Abstract

Endothelial dysfunction (ED) causes worse prognoses in heart failure (HF) patients treated with cardiac resynchronization therapy (CRTd). ED triggers the downregulation of microRNA-130 (miR-130a-5p), which targets endothelin-1 (ET-1). Thus, we evaluated ED and the response to CRTd by assessing miR-130a-5p and ET-1 serum [...] Read more.

Endothelial dysfunction (ED) causes worse prognoses in heart failure (HF) patients treated with cardiac resynchronization therapy (CRTd). ED triggers the downregulation of microRNA-130 (miR-130a-5p), which targets endothelin-1 (ET-1). Thus, we evaluated ED and the response to CRTd by assessing miR-130a-5p and ET-1 serum levels. We designed a prospective multi-center study with a 1-year follow-up to evaluate ED, ET-1, and miR-130a-5p in CRTd patients with ED (ED-CRTd) vs. patients without ED (NED-CRTd). Clinical outcomes were CRTd response, HF hospitalization, cardiac death, and all-cause death. At 1-year follow-up, NED-CRTd (n = 541) vs. ED-CRTd (n = 326) patients showed better clinical statuses, lower serum values of B type natriuretic peptide (BNP: 266.25 ± 10.8 vs. 297.43 ± 16.22 pg/mL; p < 0.05) and ET-1 (4.57 ± 0.17 vs. 5.41 ± 0.24 pmol/L; p < 0.05), and higher values of miR-130a-5p (0.51 ± 0.029 vs. 0.41 ± 0.034 A.U; p < 0.05). Compared with NED-CRTd patients, ED-CRTd patients were less likely to be CRTd responders (189 (58%) vs. 380 (70.2%); p < 0.05) and had higher rates of HF hospitalization (115 (35.3%) vs. 154 (28.5%); p < 0.05) and cardiac deaths (30 (9.2%) vs. 21 (3.9%); p < 0.05). Higher miR-130a-5p levels (HR 1.490, CI 95% [1.014–2.188]) significantly predicted CRTd response; the presence of hypertension (HR 0.818, CI 95% [0.669–0.999]), and displaying higher levels of ET-1 (HR 0.859, CI 98% [0.839–0.979]), lymphocytes (HR 0.820, CI 95% [0.758–0.987]), LVEF (HR 0.876, CI 95% [0.760–0.992]), and ED (HR 0.751, CI 95% [0.624–0.905]) predicted CRTd non-response. Higher serum miR-130a-5p levels (HR 0.332, CI 95% [0.347–0.804]) and use of ARNI (HR 0.319, CI 95% [0.310–0.572]) predicted lower risk of HF hospitalization, whereas hypertension (HR 1.818, CI 95% [1.720–2.907]), higher BNP levels (HR 1.210, CI 95% [1.000–1.401]), and presence of ED (HR 1.905, CI 95% [1.238–2.241]) predicted a higher risk of HF hospitalization. Hence, serum miR-130a-5p could identify different stages of ED and independently predict CRTd response, therefore representing a novel prognostic HF biomarker. Full article

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13 pages, 441 KiB

Open AccessReview

Intra-Articular Injection of Botulinum Toxin for the Treatment of Knee Osteoarthritis: A Systematic Review of Randomized Controlled Trials

by Cristiano Sconza, Giulia Leonardi, Carla Carfì, Elizaveta Kon, Stefano Respizzi, Dalila Scaturro, Giulia Letizia Mauro, Giuseppe Massazza and Berardo Di Matteo

Int. J. Mol. Sci. 2023, 24(2), 1486; https://doi.org/10.3390/ijms24021486 - 12 Jan 2023

Cited by 17 | Viewed by 4582

Abstract

The purpose of the present paper was to review the available evidence on intra-articular botulinum toxin (BTX) injection in the treatment of knee osteoarthritis and to compare it to other conservative treatment options. A systematic review of the literature was performed on the [...] Read more.

The purpose of the present paper was to review the available evidence on intra-articular botulinum toxin (BTX) injection in the treatment of knee osteoarthritis and to compare it to other conservative treatment options. A systematic review of the literature was performed on the PubMed, Scopus, Cochrane Library, Web of Science, Pedro and Research Gate databases with the following inclusion criteria: (1) randomized controlled trials (RCTs), (2) written in the English language, and (3) published on indexed journals in the last 20 years (2001–2021) dealing with the use of BTX intra-articular injection for the treatment of knee OA. The risk of bias was assessed using the Cochrane Risk of Bias tool for RCTs. Nine studies involving 811 patients in total were included. Patients in the control groups received different treatments: conventional physiotherapy, hyaluronic acid injection or prolotherapy or a combination thereof in 5 studies, steroid infiltrative therapy (triamcinolone) in 1 study, placebo in 2, and local anesthetic treatment in 1 study. Looking at the quality of the available literature, two of the included studies reached “Good quality” standard, three were ranked as “Fair”, and the rest were considered “Poor”. No major complications or serious adverse events were reported following intra-articular BTX, which provided encouraging pain relief, improved motor function, and quality of life. Based on the available data, no clear indication emerged from the comparison of BTX with other established treatments for knee OA. The analysis of the available RCTs on BTX intra-articular injection for the treatment of knee OA revealed modest methodological quality. However, based on the data retrieved, botulinum toxin has been proven to provide good short-term outcomes, especially in patients with pain sensitization, by modulating neurotransmitter release, peripheral nociceptive transduction, and acting on the control of chronic pain from central sensitization. Full article

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19 pages, 741 KiB

Open AccessReview

The Complex Histopathological and Immunohistochemical Spectrum of Neuroendocrine Tumors—An Overview of the Latest Classifications

by Ancuța-Augustina Gheorghișan-Gălățeanu, Andreea Ilieșiu, Ioana Maria Lambrescu and Dana Antonia Țăpoi

Int. J. Mol. Sci. 2023, 24(2), 1418; https://doi.org/10.3390/ijms24021418 - 11 Jan 2023

Cited by 14 | Viewed by 5518

Abstract

Neuroendocrine neoplasms (NENs) originate from the neuroendocrine cell system, which may either take the shape of organoid cell aggregations or be composed of dispersed cells across various organs. Therefore, these tumors are heterogenous regarding the site of origin, functional status, degree of aggressiveness, [...] Read more.

Neuroendocrine neoplasms (NENs) originate from the neuroendocrine cell system, which may either take the shape of organoid cell aggregations or be composed of dispersed cells across various organs. Therefore, these tumors are heterogenous regarding the site of origin, functional status, degree of aggressiveness, and prognosis. When treating patients with neuroendocrine tumors, one of the most significant challenges for physicians is determining the correct tumor grade and thus classifying patients into risk categories. Over the years, the classification of these tumors has changed significantly, often causing confusion due to clinical, molecular, and immunohistochemical variability. This review aims to outline the latest NENs classifications regardless of their site of origin. Thus, an overview of the key histopathological and immunohistochemical characteristics of NENs could pave the way to validate possible predictive and prognostic markers and also guide the therapeutic conduct. Full article

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14 pages, 2322 KiB

Open AccessArticle

Evaluation of Two Simultaneous Metabolomic and Proteomic Extraction Protocols Assessed by Ultra-High-Performance Liquid Chromatography Tandem Mass Spectrometry

by Ruba A. Zenati, Alexander D. Giddey, Hamza M. Al-Hroub, Yousra A. Hagyousif, Waseem El-Huneidi, Yasser Bustanji, Eman Abu-Gharbieh, Mohammad A. Y. Alqudah, Mohd Shara, Ahmad Y. Abuhelwa, Nelson C. Soares and Mohammad H. Semreen

Int. J. Mol. Sci. 2023, 24(2), 1354; https://doi.org/10.3390/ijms24021354 - 10 Jan 2023

Cited by 9 | Viewed by 2924

Abstract

Untargeted multi-omics analysis of plasma is an emerging tool for the identification of novel biomarkers for evaluating disease prognosis, and for developing a better understanding of molecular mechanisms underlying human disease. The successful application of metabolomic and proteomic approaches relies on reproducibly quantifying [...] Read more.

Untargeted multi-omics analysis of plasma is an emerging tool for the identification of novel biomarkers for evaluating disease prognosis, and for developing a better understanding of molecular mechanisms underlying human disease. The successful application of metabolomic and proteomic approaches relies on reproducibly quantifying a wide range of metabolites and proteins. Herein, we report the results of untargeted metabolomic and proteomic analyses from blood plasma samples following analyte extraction by two frequently-used solvent systems: chloroform/methanol and methanol-only. Whole blood samples were collected from participants (n = 6) at University Hospital Sharjah (UHS) hospital, then plasma was separated and extracted by two methods: (i) methanol precipitation and (ii) 4:3 methanol:chloroform extraction. The coverage and reproducibility of the two methods were assessed by ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS). The study revealed that metabolite extraction by methanol-only showed greater reproducibility for both metabolomic and proteomic quantifications than did methanol/chloroform, while yielding similar peptide coverage. However, coverage of extracted metabolites was higher with the methanol/chloroform precipitation. Full article

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15 pages, 6517 KiB

Open AccessArticle

FISH Diagnostic Assessment of MDM2 Amplification in Liposarcoma: Potential Pitfalls and Troubleshooting Recommendations

by Alessandro Gambella, Luca Bertero, Milena Rondón-Lagos, Ludovica Verdun Di Cantogno, Nelson Rangel, Chiara Pitino, Alessia Andrea Ricci, Luca Mangherini, Isabella Castellano and Paola Cassoni

Int. J. Mol. Sci. 2023, 24(2), 1342; https://doi.org/10.3390/ijms24021342 - 10 Jan 2023

Cited by 7 | Viewed by 6765

Abstract

MDM2 amplification represents the leading oncogenic pathway and diagnostic hallmark of liposarcoma, whose assessment is based on Fluorescence In Situ Hybridization (FISH) analysis. Despite its diagnostic relevance, no univocal interpretation criteria regarding FISH assessments of MDM2 amplification have been established so far, leading [...] Read more.

MDM2 amplification represents the leading oncogenic pathway and diagnostic hallmark of liposarcoma, whose assessment is based on Fluorescence In Situ Hybridization (FISH) analysis. Despite its diagnostic relevance, no univocal interpretation criteria regarding FISH assessments of MDM2 amplification have been established so far, leading to several different approaches and potential diagnostic misinterpretations. This study aims to address the most common issues and proposes troubleshooting guidelines for MDM2 amplification assessments by FISH. We retrospectively retrieved 51 liposarcomas, 25 Lipomas, 5 Spindle Cell Lipoma/Pleomorphic Lipomas, and 2 Atypical Spindle Cell Lipomatous Tumors and the corresponding MDM2 FISH analysis. We observed MDM2 amplification in liposarcomas cases only (43 out of 51 cases) and identified three MDM2-amplified patterns (scattered (50% of cases), clustered (14% of cases), and mixed (36% of cases)) and two nonamplified patterns (low number of signals (82% of cases) and polysomic (18% of cases)). Based on these data and published evidence in the literature, we propose a set of criteria to guide MDM2 amplification analysis in liposarcoma. Kindled by the compelling importance of MDM2 assessments to improve diagnostic and therapeutic liposarcoma management, these suggestions could represent the first step to develop a univocal interpretation model and consensus guidelines. Full article

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19 pages, 1237 KiB

Open AccessReview

S100A6 Protein—Expression and Function in Norm and Pathology

by Wiesława Leśniak and Anna Filipek

Int. J. Mol. Sci. 2023, 24(2), 1341; https://doi.org/10.3390/ijms24021341 - 10 Jan 2023

Cited by 7 | Viewed by 3555

Abstract

S100A6, also known as calcyclin, is a calcium-binding protein belonging to the S100 protein family. It was first identified and purified more than 30 years ago. Initial structural studies, focused mostly on the mode and affinity of Ca²⁺ binding and resolution of [...] Read more.

S100A6, also known as calcyclin, is a calcium-binding protein belonging to the S100 protein family. It was first identified and purified more than 30 years ago. Initial structural studies, focused mostly on the mode and affinity of Ca²⁺ binding and resolution of the resultant conformational changes, were soon complemented by research on its expression, localization and identification of binding partners. With time, the use of biophysical methods helped to resolve the structure and versatility of S100A6 complexes with some of its ligands. Meanwhile, it became clear that S100A6 expression was altered in various pathological states and correlated with the stage/progression of many diseases, including cancers, indicative of its important, and possibly causative, role in some of these diseases. This, in turn, prompted researchers to look for the mechanism of S100A6 action and to identify the intermediary signaling pathways and effectors. After all these years, our knowledge on various aspects of S100A6 biology is robust but still incomplete. The list of S100A6 ligands is growing all the time, as is our understanding of the physiological importance of these interactions. The present review summarizes available data concerning S100A6 expression/localization, interaction with intracellular and extracellular targets, involvement in Ca²⁺-dependent cellular processes and association with various pathologies. Full article

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15 pages, 2248 KiB

Open AccessReview

The Machinery of Exosomes: Biogenesis, Release, and Uptake

by Sofia V. Krylova and Daorong Feng

Int. J. Mol. Sci. 2023, 24(2), 1337; https://doi.org/10.3390/ijms24021337 - 10 Jan 2023

Cited by 136 | Viewed by 14138

Abstract

Exosomes are a subtype of membrane-contained vesicles 40–200 nm in diameter that are secreted by cells into their surroundings. By transporting proteins, lipids, mRNA, miRNA, lncRNA, and DNA, exosomes are able to perform such vital functions as maintaining cellular homeostasis, removing cellular debris, [...] Read more.

Exosomes are a subtype of membrane-contained vesicles 40–200 nm in diameter that are secreted by cells into their surroundings. By transporting proteins, lipids, mRNA, miRNA, lncRNA, and DNA, exosomes are able to perform such vital functions as maintaining cellular homeostasis, removing cellular debris, and facilitating intercellular and interorgan communication. Exosomes travel in all body fluids and deliver their molecular messages in autocrine, paracrine as well as endocrine manners. In recent years, there has been an increased interest in studying exosomes as diagnostic markers and therapeutic targets, since in many disease conditions this machinery becomes dysregulated or hijacked by pathological processes. Additionally, delivery of exosomes and exosomal miRNA has already been shown to improve systemic metabolism and inhibit progression of cancer development in mice. However, the subcellular machinery of exosomes, including their biogenesis, release and uptake, remains largely unknown. This review will bring molecular details of these processes up to date with the goal of expanding the knowledge basis for designing impactful exosome experiments in the future. Full article

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11 pages, 1971 KiB

Open AccessCase Report

The Pitfall of White Blood Cell Cystine Measurement to Diagnose Juvenile Cystinosis

by Tjessa Bondue, Anas Kouraich, Sante Princiero Berlingerio, Koenraad Veys, Sandrine Marie, Khaled O. Alsaad, Essam Al-Sabban, Elena Levtchenko and Lambertus van den Heuvel

Int. J. Mol. Sci. 2023, 24(2), 1253; https://doi.org/10.3390/ijms24021253 - 9 Jan 2023

Cited by 1 | Viewed by 3095

Abstract

Cystinosis is an autosomal recessive lysosomal storage disease, caused by mutations in the CTNS gene, resulting in multi-organ cystine accumulation. Three forms of cystinosis are distinguished: infantile and juvenile nephropathic cystinosis affecting kidneys and other organs such as the eyes, endocrine system, muscles, [...] Read more.

Cystinosis is an autosomal recessive lysosomal storage disease, caused by mutations in the CTNS gene, resulting in multi-organ cystine accumulation. Three forms of cystinosis are distinguished: infantile and juvenile nephropathic cystinosis affecting kidneys and other organs such as the eyes, endocrine system, muscles, and brain, and adult ocular cystinosis affecting only the eyes. Currently, elevated white blood cell (WBC) cystine content is the gold standard for the diagnosis of cystinosis. We present a patient with proteinuria at adolescent age and corneal cystine crystals, but only slightly elevated WBC cystine levels (1.31 ½ cystine/mg protein), precluding the diagnosis of nephropathic cystinosis. We demonstrate increased levels of cystine in skin fibroblasts and urine-derived kidney cells (proximal tubular epithelial cells and podocytes), that were higher than the values observed in the WBC and healthy control. CTNS gene analysis shows the presence of a homozygous missense mutation (c.590 A > G; p.Asn177Ser), previously described in the Arab population. Our observation underlines that low WBC cystine levels can be observed in patients with juvenile cystinosis, which may delay the diagnosis and timely administration of cysteamine. In such patients, the diagnosis can be confirmed by cystine measurement in slow-dividing cells and by molecular analysis of the CTNS gene. Full article

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12 pages, 12916 KiB

Open AccessArticle

Rab44 Deficiency Induces Impaired Immune Responses to Nickel Allergy

by Mayuko Noguromi, Yu Yamaguchi, Keiko Sato, Shun Oyakawa, Kuniaki Okamoto, Hiroshi Murata, Takayuki Tsukuba and Tomoko Kadowaki

Int. J. Mol. Sci. 2023, 24(2), 994; https://doi.org/10.3390/ijms24020994 - 4 Jan 2023

Cited by 4 | Viewed by 2192

Abstract

Rab44 was recently identified as an atypical Rab GTPase that possesses EF-hand and coiled-coil domains at the N-terminus, and a Rab-GTPase domain at the C-terminus. Rab44 is highly expressed in immune-related cells such as mast cells, macrophages, osteoclasts, and granulocyte-lineage cells in the [...] Read more.

Rab44 was recently identified as an atypical Rab GTPase that possesses EF-hand and coiled-coil domains at the N-terminus, and a Rab-GTPase domain at the C-terminus. Rab44 is highly expressed in immune-related cells such as mast cells, macrophages, osteoclasts, and granulocyte-lineage cells in the bone marrow. Therefore, it is speculated that Rab44 is involved in the inflammation and differentiation of immune cells. However, little is known about the role of Rab44 in inflammation. In this study, we showed that Rab44 was upregulated during the early phase of differentiation of M1- and M2-type macrophages. Rab44-deficient mice exhibited impaired tumor necrosis factor alpha and interleukin-10 production after lipopolysaccharide (LPS) stimulation. The number of granulocytes in Rab44-deficient mice was lower, but the lymphocyte count in Rab44-deficient mice was significantly higher than that in wild-type mice after LPS stimulation. Moreover, Rab44-deficient macrophages showed impaired nickel-induced toxicity, and Rab44-deficient mice showed impaired nickel-induced hypersensitivity. Upon nickel hypersensitivity induction, Rab44-deficient mice showed different frequencies of immune cells in the blood and ears. Thus, it is likely that Rab44 is implicated in immune cell differentiation and inflammation, and Rab44 deficiency induces impaired immune responses to nickel allergies. Full article

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17 pages, 2472 KiB

Open AccessArticle

The KDET Motif in the Intracellular Domain of the Cell Adhesion Molecule L1 Interacts with Several Nuclear, Cytoplasmic, and Mitochondrial Proteins Essential for Neuronal Functions

by Ralf Kleene, Gabriele Loers and Melitta Schachner

Int. J. Mol. Sci. 2023, 24(2), 932; https://doi.org/10.3390/ijms24020932 - 4 Jan 2023

Cited by 5 | Viewed by 2054

Abstract

Abnormal functions of the cell adhesion molecule L1 are linked to several neural diseases. Proteolytic L1 fragments were reported to interact with nuclear and mitochondrial proteins to regulate events in the developing and the adult nervous system. Recently, we identified a 55 kDa [...] Read more.

Abnormal functions of the cell adhesion molecule L1 are linked to several neural diseases. Proteolytic L1 fragments were reported to interact with nuclear and mitochondrial proteins to regulate events in the developing and the adult nervous system. Recently, we identified a 55 kDa L1 fragment (L1-55) that interacts with methyl CpG binding protein 2 (MeCP2) and heterochromatin protein 1 (HP1) via the KDET motif. We now show that L1-55 also interacts with histone H1.4 (HistH1e) via this motif. Moreover, we show that this motif binds to NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), splicing factor proline/glutamine-rich (SFPQ), the non-POU domain containing octamer-binding protein (NonO), paraspeckle component 1 (PSPC1), WD-repeat protein 5 (WDR5), heat shock cognate protein 71 kDa (Hsc70), and synaptotagmin 1 (SYT1). Furthermore, applications of HistH1e, NDUFV2, SFPQ, NonO, PSPC1, WDR5, Hsc70, or SYT1 siRNAs or a cell-penetrating KDET-carrying peptide decrease L1-dependent neurite outgrowth and the survival of cultured neurons. These findings indicate that L1’s KDET motif binds to an unexpectedly large number of molecules that are essential for nervous system-related functions, such as neurite outgrowth and neuronal survival. In summary, L1 interacts with cytoplasmic, nuclear and mitochondrial proteins to regulate development and, in adults, the formation, maintenance, and flexibility of neural functions. Full article

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13 pages, 2503 KiB

Open AccessArticle

Plasma-Functionalised Dressings for Enhanced Wound Healing

by Xanthe L. Strudwick, Jason D. Whittle, Allison J. Cowin and Louise E. Smith

Int. J. Mol. Sci. 2023, 24(1), 797; https://doi.org/10.3390/ijms24010797 - 2 Jan 2023

Cited by 3 | Viewed by 2458

Abstract

Fundamental knowledge about cell–surface interactions can be applied in the development of wound dressings and scaffolds to encourage wounds to heal. As surfaces produced with acid-functionalised monomers encourage keratinocyte adhesion, proliferation and migration, whilst amine functionalisation enhances fibroblast proliferation and migration in vitro, [...] Read more.

Fundamental knowledge about cell–surface interactions can be applied in the development of wound dressings and scaffolds to encourage wounds to heal. As surfaces produced with acid-functionalised monomers encourage keratinocyte adhesion, proliferation and migration, whilst amine functionalisation enhances fibroblast proliferation and migration in vitro, standard care wound dressings were plasma-coated with either acrylic acid or allylamine and applied to 6 mm excisional wounds on the backs of mice to test their effectiveness in vivo. At day 3, the rate of wound healing was increased in mice treated with dressings that were plasma-coated with allylamine compared to uncoated dressings, with a significantly reduced wound area. However, healing may be impaired following prolonged treatment with allylamine-functionalised dressings, with delayed re-epithelialisation and increased cellularisation of the wound site at later timepoints. Acrylic acid functionalisation, however, offered no early improvement in wound healing, but wounds treated with these dressings displayed increased collagen deposition at day 7 post wounding. These results suggest that plasma polymerisation may allow for the development of new dressings which can enhance wound closure by directing cell behaviour, but that the application of these dressings may require a timed approach to enhance specific phases of the wound healing response. Full article

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2022

Jump to: 2024, 2023, 2021

25 pages, 15301 KiB

Open AccessArticle

Forced Remyelination Promotes Axon Regeneration in a Rat Model of Spinal Cord Injury

by Małgorzata Zawadzka, Marine Yeghiazaryan, Sylwia Niedziółka, Krzysztof Miazga, Anna Kwaśniewska, Marek Bekisz and Urszula Sławińska

Int. J. Mol. Sci. 2023, 24(1), 495; https://doi.org/10.3390/ijms24010495 - 28 Dec 2022

Cited by 3 | Viewed by 2519

Abstract

Spinal cord injuries result in the loss of motor and sensory functions controlled by neurons located at the site of the lesion and below. We hypothesized that experimentally enhanced remyelination supports axon preservation and/or growth in the total spinal cord transection in rats. [...] Read more.

Spinal cord injuries result in the loss of motor and sensory functions controlled by neurons located at the site of the lesion and below. We hypothesized that experimentally enhanced remyelination supports axon preservation and/or growth in the total spinal cord transection in rats. Multifocal demyelination was induced by injection of ethidium bromide (EB), either at the time of transection or twice during transection and at 5 days post-injury. We demonstrated that the number of oligodendrocyte progenitor cells (OPCs) significantly increased 14 days after demyelination. Most OPCs differentiated into mature oligodendrocytes by 60–90 dpi in double-EB-injected rats; however, most axons were remyelinated by Schwann cells. A significant number of axons passed the injury epicenter and entered the distant segments of the spinal cord in the double-EB-injected rats. Moreover, some serotoninergic fibers, not detected in control animals, grew caudally through the injury site. Behavioral tests performed at 60–90 dpi revealed significant improvement in locomotor function recovery in double-EB-injected rats, which was impaired by the blockade of serotonin receptors, confirming the important role of restored serotonergic fibers in functional recovery. Our findings indicate that enhanced remyelination per se, without substantial inhibition of glial scar formation, is an important component of spinal cord injury regeneration. Full article

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17 pages, 3962 KiB

Open AccessArticle

The Landscape of Gene Expression during Hyperfilamentous Biofilm Development in Oral Candida albicans Isolated from a Lung Cancer Patient

by Beata Chudzik-Rząd, Daniel Zalewski, Martyna Kasela, Rafał Sawicki, Jolanta Szymańska, Anna Bogucka-Kocka and Anna Malm

Int. J. Mol. Sci. 2023, 24(1), 368; https://doi.org/10.3390/ijms24010368 - 26 Dec 2022

Cited by 1 | Viewed by 2056

Abstract

The filamentation ability of Candida albicans represents one of the main virulence factors allowing for host tissue penetration and biofilm formation. The aim of this paper was to study the genetic background of the hyperfilamentous biofilm development in vitro in C. albicans isolated [...] Read more.

The filamentation ability of Candida albicans represents one of the main virulence factors allowing for host tissue penetration and biofilm formation. The aim of this paper was to study the genetic background of the hyperfilamentous biofilm development in vitro in C. albicans isolated from the oral cavity of a lung cancer patient. Analyzed C. albicans isolates (CA1, CA2, CA3) were chosen based on their different structures of mature biofilm. The CA3 isolate possessing hyperfilamentation properties and forming high biofilm was compared with CA1 and CA2 isolates exhibiting low or average biofilm-forming ability, respectively. The detailed biofilm organization was studied with the use of confocal scanning laser microscopy. The whole transcriptome analysis was conducted during three stages of biofilm development (24 h, 48 h, 72 h). In contrast to CA1 and/or CA2 isolate, the CA3 isolate was characterized by a significant upregulation of genes encoding for cell wall proteins (HWP1, PGA13, PGA44, ALS3) and candidalysin (ECE1), as well as being involved in iron metabolism (FRE1, ALS3), sulfur metabolism (HAL21), the degradation of aromatic compounds (HQD2), and membrane transport (DIP5, PHO89, TNA1). In contrast, some genes (SCW11, FGR41, RBE1) in the CA3 were downregulated. We also observed the overexpression of a few genes over time—mainly FRE1, ATX1, CSA2 involved in iron metabolism. This is the first insight into the potential function of multiple genes in the hyperfilamentous biofilm formation in C. albicans, primarily isolated from host tissue, which may have an important clinical impact on cancer patients. Moreover, the presented data can lay the foundation for further research on novel pathogen-specific targets for antifungal drugs. Full article

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9 pages, 1601 KiB

Open AccessArticle

Porcine Relaxin but Not Serelaxin Shows Residual Bioactivity after In Vitro Simulated Intestinal Digestion—Clues for the Development of New Relaxin Peptide Agonists Suitable for Oral Delivery

by Lorenzo Pacini, Annunziata D’Ercole, Anna Maria Papini, Daniele Bani, Silvia Nistri and Paolo Rovero

Int. J. Mol. Sci. 2023, 24(1), 48; https://doi.org/10.3390/ijms24010048 - 20 Dec 2022

Viewed by 1808

Abstract

Despite human recombinant H2 relaxin or serelaxin holding promise as a cardiovascular drug, its actual efficacy in chronic treatment of heart failure patients was hampered by the need to be administered by multiple daily IV injections for a long time, with obvious drawbacks [...] Read more.

Despite human recombinant H2 relaxin or serelaxin holding promise as a cardiovascular drug, its actual efficacy in chronic treatment of heart failure patients was hampered by the need to be administered by multiple daily IV injections for a long time, with obvious drawbacks in terms of patients’ compliance. This in vitro study aimed at exploring the molecular background for a possible administration of the peptide hormone relaxin by the oral route. Serelaxin and purified porcine relaxin (pRLX) were subjected to simulated intestinal fluid (SIF) enzymatic digestion in vitro to mimic the behavior of gastroprotective formulations. The digestion time course was studied by HPLC, and the relative bio-potency of the intact molecules and their proteolytic fragments was assessed by second messenger (cAMP) response in RXFP1 relaxin receptor-bearing THP-1 human monocytic cells. Both intact proteins (100 ng/mL) induced a significant cAMP rise in THP-1 cells. Conversely, SIF-treated serelaxin showed a brisk (30 s) bioactivity decay, dropping down to the levels of the unstimulated controls at 120 s, whereas SIF-treated pRLX retained significant bioactivity for up to 120 s. After that, it progressively declined to the levels of the unstimulated controls. HPLC analysis indicates that this bioactivity could be ascribed to a minor component of the pRLX sample more resistant to proteolysis. When identified and better characterized, this peptide could be exploited for the development of synthetic relaxin agonists suitable for oral formulations. Full article

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8 pages, 1071 KiB

Open AccessCase Report

Expanding the Etiology of Oculo–Auriculo–Vertebral Spectrum: A Novel Interstitial Microdeletion at 1p36

by Mónica García-Castro, Teresa Martinez-Merino, Nuria Puente and José A. Riancho

Int. J. Mol. Sci. 2023, 24(1), 36; https://doi.org/10.3390/ijms24010036 - 20 Dec 2022

Cited by 1 | Viewed by 1643

Abstract

The etiology of oculo–auriculo–vertebral spectrum (OAVS) is not well established. About half of patients show a positive family history. The etiology of familiar cases is unclear but appears genetically heterogeneous. This motivated us to report a case of OAVS with microtia, ptosis, facial [...] Read more.

The etiology of oculo–auriculo–vertebral spectrum (OAVS) is not well established. About half of patients show a positive family history. The etiology of familiar cases is unclear but appears genetically heterogeneous. This motivated us to report a case of OAVS with microtia, ptosis, facial microsomy, and fusion of vertebral bodies associated with a novel genetic etiology, including a deletion at 1p36.12-13. This case report expands on the genetic etiology of OAVS. Furthermore, it also expands the clinical manifestations of patients with interstitial deletions of the de 1p36.12-13 region. Full article

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14 pages, 4831 KiB

Open AccessArticle

Regulating Th17/Treg Balance Contributes to the Therapeutic Effect of Ziyuglycoside I on Collagen-Induced Arthritis

by Manman Wang, Tiantian Su, Hanfei Sun, Huijuan Cheng, Chunru Jiang, Paipai Guo, Zhenduo Zhu, Ruhong Fang, Feng He, Mingli Ge, Qiuyun Guan, Wei Wei and Qingtong Wang

Int. J. Mol. Sci. 2022, 23(24), 16105; https://doi.org/10.3390/ijms232416105 - 17 Dec 2022

Cited by 3 | Viewed by 2622

Abstract

To investigate the therapeutic effect and primary pharmacological mechanism of Ziyuglycoside I (Ziyu I) on collagen-induced arthritis (CIA) mice. CIA mice were treated with 5, 10, or 20 mg/kg of Ziyu I or 2 mg/kg of methotrexate (MTX), and clinical manifestations, as well [...] Read more.

To investigate the therapeutic effect and primary pharmacological mechanism of Ziyuglycoside I (Ziyu I) on collagen-induced arthritis (CIA) mice. CIA mice were treated with 5, 10, or 20 mg/kg of Ziyu I or 2 mg/kg of methotrexate (MTX), and clinical manifestations, as well as pathological changes, were observed. T cell viability and subset type were determined, and serum levels of transforming growth factor-beta (TGF-β) and interleukin-17 (IL-17) were detected. The mRNA expression of retinoid-related orphan receptor-γt (RORγt) and transcription factor forkhead box protein 3 (Foxp3) in mouse spleen lymphocytes was ascertained by the real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). Molecular docking was used to detect whether there was a molecular interaction between Ziyu I and protein kinase B (Akt). The activation of mechanistic target of rapamycin (mTOR) in T cells was verified by Western blotting or immunofluorescence. Ziyu I treatment effectively alleviated arthritis symptoms of CIA mice, including body weight, global score, arthritis index, and a number of swollen joints. Similarly, pathological changes of joints and spleens in arthritic mice were improved. The thymic index, T cell activity, and RORγt production of Ziyu I-treated mice were significantly reduced. Notably, through molecular docking, western blotting, and immunofluorescence data analysis, it was found that Ziyu I could interact directly with Akt to reduce downstream mTOR activation and inhibit helper T cell 17 (Th17) differentiation, thereby regulating Th17/regulatory T cell (Treg) balance and improving arthritis symptoms. Ziyu I effectively improves arthritic symptoms in CIA mice by inhibiting mTOR activation, thereby affecting Th17 differentiation and regulating Th17/Treg balance. Full article

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19 pages, 3011 KiB

Open AccessArticle

Deep Brain Stimulation in the Subthalamic Nucleus Can Improve Skilled Forelimb Movements and Retune Dynamics of Striatal Networks in a Rat Stroke Model

by Stefanie D. Krämer, Michael K. Schuhmann, Jens Volkmann and Felix Fluri

Int. J. Mol. Sci. 2022, 23(24), 15862; https://doi.org/10.3390/ijms232415862 - 14 Dec 2022

Cited by 3 | Viewed by 2668

Abstract

Recovery of upper limb (UL) impairment after stroke is limited in stroke survivors. Since stroke can be considered as a network disorder, neuromodulation may be an approach to improve UL motor dysfunction. Here, we evaluated the effect of high-frequency stimulation (HFS) of the [...] Read more.

Recovery of upper limb (UL) impairment after stroke is limited in stroke survivors. Since stroke can be considered as a network disorder, neuromodulation may be an approach to improve UL motor dysfunction. Here, we evaluated the effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) in rats on forelimb grasping using the single-pellet reaching (SPR) test after stroke and determined costimulated brain regions during STN-HFS using 2-[¹⁸F]Fluoro-2-deoxyglucose-([¹⁸F]FDG)-positron emission tomography (PET). After a 4-week training of SPR, photothrombotic stroke was induced in the sensorimotor cortex of the dominant hemisphere. Thereafter, an electrode was implanted in the STN ipsilateral to the infarction, followed by a continuous STN-HFS or sham stimulation for 7 days. On postinterventional day 2 and 7, an SPR test was performed during STN-HFS. Success rate of grasping was compared between these two time points. [¹⁸F]FDG-PET was conducted on day 2 and 3 after stroke, without and with STN-HFS, respectively. STN-HFS resulted in a significant improvement of SPR compared to sham stimulation. During STN-HFS, a significantly higher [¹⁸F]FDG-uptake was observed in the corticosubthalamic/pallidosubthalamic circuit, particularly ipsilateral to the stimulated side. Additionally, STN-HFS led to an increased glucose metabolism within the brainstem. These data demonstrate that STN-HFS supports rehabilitation of skilled forelimb movements, probably by retuning dysfunctional motor centers within the cerebral network. Full article

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20 pages, 1874 KiB

Open AccessReview

CC Chemokine Receptor 4 (CCR4) as a Possible New Target for Therapy

by Joanna Bogacka, Katarzyna Pawlik, Katarzyna Ciapała, Agata Ciechanowska and Joanna Mika

Int. J. Mol. Sci. 2022, 23(24), 15638; https://doi.org/10.3390/ijms232415638 - 9 Dec 2022

Cited by 17 | Viewed by 6387

Abstract

Chemokines and their receptors participate in many biological processes, including the modulation of neuroimmune interactions. Approximately fifty chemokines are distinguished in humans, which are classified into four subfamilies based on the N-terminal conserved cysteine motifs: CXC, CC, C, and CX3C. Chemokines activate specific [...] Read more.

Chemokines and their receptors participate in many biological processes, including the modulation of neuroimmune interactions. Approximately fifty chemokines are distinguished in humans, which are classified into four subfamilies based on the N-terminal conserved cysteine motifs: CXC, CC, C, and CX3C. Chemokines activate specific receptors localized on the surface of various immune and nervous cells. Approximately twenty chemokine receptors have been identified, and each of these receptors is a seven-transmembrane G-protein coupled receptor. Recent studies provide new evidence that CC chemokine receptor 4 (CCR4) is important in the pathogenesis of many diseases, such as diabetes, multiple sclerosis, asthma, dermatitis, and cancer. This review briefly characterizes CCR4 and its ligands (CCL17, CCL22, and CCL2), and their contributions to immunological and neoplastic diseases. The review notes a significant role of CCR4 in nociceptive transmission, especially in painful neuropathy, which accompanies many diseases. The pharmacological blockade of CCR4 seems beneficial because of its pain-relieving effects and its influence on opioid efficacy. The possibilities of using the CCL2/CCL17/CCL22/CCR4 axis as a target in new therapies for many diseases are also discussed. Full article

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11 pages, 3346 KiB

Open AccessArticle

In Vitro Susceptibility of HIV Isolates with High Growth Capability to Antiretroviral Drugs

by Alfredo A. Hinay, Jr., Kyosuke Kanai, Akeno Tsuneki-Tokunaga, Mizuki Komatsu, Elizabeth O. Telan and Seiji Kageyama

Int. J. Mol. Sci. 2022, 23(23), 15380; https://doi.org/10.3390/ijms232315380 - 6 Dec 2022

Viewed by 1843

Abstract

It has been considered that reduced susceptibility to antiretroviral drugs is influenced by drug adherence, drug tolerance and drug-resistance-related mutations in the HIV genome. In the present study, we assessed the intrinsic high viral growth capability as a potential viral factor that may [...] Read more.

It has been considered that reduced susceptibility to antiretroviral drugs is influenced by drug adherence, drug tolerance and drug-resistance-related mutations in the HIV genome. In the present study, we assessed the intrinsic high viral growth capability as a potential viral factor that may influence their susceptibility to antiretroviral drugs using an in vitro model. Phytohemagglutinin-activated peripheral blood mononuclear cells (1.5 × 10⁶ cells) were infected with HIV isolates (10⁶ copies/mL). The culture was carried out at different concentrations (0.001–20 μM) of 13 synthetic antiretroviral compounds (six nucleoside/nucleotide reverse transcriptase inhibitors, one non-nucleoside reverse transcriptase inhibitor, four integrase inhibitors, and two protease inhibitors), and HIV production was assessed using HIV-RNA copies in culture. The 90% inhibitory concentration (IC₉₀) and pharmacokinetics of an antiretroviral agent were used as parameters to determine the reduced antiretroviral drug susceptibility of HIV isolates with high growth capability to synthetic antiretroviral compounds. The high growth capability of HIV isolates without any known drug resistance-related mutation affected their susceptibility to tenofovir (IC₉₀ = 2.05 ± 0.40 μM), lamivudine (IC₉₀ = 6.83 ± 3.96 μM), emtricitabine (IC₉₀ = 0.68 ± 0.37 μM), and efavirenz (IC₉₀ = 3.65 ± 0.77 μM). These antiretroviral drugs showed IC₉₀ values close to or above the maximum plasma concentration against HIV isolates with high growth capability without any known drug resistance-related mutation. Our results may contribute to the development of effective strategies to tailor and individualize antiretroviral therapy in patients harboring HIV isolates with high growth capability. Full article

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13 pages, 1344 KiB

Open AccessArticle

Plasma Fibulin-5 Levels as an Independent Predictor of a Poor Outcome after an Aneurysmal Subarachnoid Hemorrhage

by Yume Suzuki, Hiroki Oinaka, Hideki Nakajima, Mai Nampei, Fumihiro Kawakita, Yoichi Miura, Ryuta Yasuda, Naoki Toma, Hidenori Suzuki and pSEED Group

Int. J. Mol. Sci. 2022, 23(23), 15184; https://doi.org/10.3390/ijms232315184 - 2 Dec 2022

Cited by 4 | Viewed by 1722

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) is a poor-outcome disease with a delayed neurological exacerbation. Fibulin-5 (FBLN5) is one of matricellular proteins, some of which have been involved in SAH pathologies. However, no study has investigated FBLN5’s roles in SAH. This study was aimed at [...] Read more.

Aneurysmal subarachnoid hemorrhage (SAH) is a poor-outcome disease with a delayed neurological exacerbation. Fibulin-5 (FBLN5) is one of matricellular proteins, some of which have been involved in SAH pathologies. However, no study has investigated FBLN5’s roles in SAH. This study was aimed at examining the relationships between serially measured plasma FBLN5 levels and neurovascular events or outcomes in 204 consecutive aneurysmal SAH patients, including 77 patients (37.7%) with poor outcomes (90-day modified Rankin Scale 3–6). Plasma FBLN5 levels were not related to angiographic vasospasm, delayed cerebral ischemia, and delayed cerebral infarction, but elevated levels were associated with severe admission clinical grades, any neurological exacerbation and poor outcomes. Receiver-operating characteristic curves indicated that the most reasonable cut-off values of plasma FBLN5, in order to differentiate 90-day poor from good outcomes, were obtained from analyses at days 4–6 for all patients (487.2 ng/mL; specificity, 61.4%; and sensitivity, 62.3%) and from analyses at days 7–9 for only non-severe patient (476.8 ng/mL; specificity, 66.0%; and sensitivity, 77.8%). Multivariate analyses revealed that the plasma FBLN5 levels were independent determinants of the 90-day poor outcomes in both all patients’ and non-severe patients’ analyses. These findings suggest that the delayed elevation of plasma FBLN5 is related to poor outcomes, and that FBLN5 may be a new molecular target to reveal a post-SAH pathophysiology. Full article

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15 pages, 2729 KiB

Open AccessArticle

Using Genomic Variation to Distinguish Ovarian High-Grade Serous Carcinoma from Benign Fallopian Tubes

by Jesus Gonzalez-Bosquet, Nicholas D. Cardillo, Henry D. Reyes, Brian J. Smith, Kimberly K. Leslie, David P. Bender, Michael J. Goodheart and Eric J. Devor

Int. J. Mol. Sci. 2022, 23(23), 14814; https://doi.org/10.3390/ijms232314814 - 26 Nov 2022

Cited by 3 | Viewed by 1898

Abstract

The preoperative diagnosis of pelvic masses has been elusive to date. Methods for characterization such as CA-125 have had limited specificity. We hypothesize that genomic variation can be used to create prediction models which accurately distinguish high grade serous ovarian cancer (HGSC) from [...] Read more.

The preoperative diagnosis of pelvic masses has been elusive to date. Methods for characterization such as CA-125 have had limited specificity. We hypothesize that genomic variation can be used to create prediction models which accurately distinguish high grade serous ovarian cancer (HGSC) from benign tissue. Methods: In this retrospective, pilot study, we extracted DNA and RNA from HGSC specimens and from benign fallopian tubes. Then, we performed whole exome sequencing and RNA sequencing, and identified single nucleotide variants (SNV), copy number variants (CNV) and structural variants (SV). We used these variants to create prediction models to distinguish cancer from benign tissue. The models were then validated in independent datasets and with a machine learning platform. Results: The prediction model with SNV had an AUC of 1.00 (95% CI 1.00–1.00). The models with CNV and SV had AUC of 0.87 and 0.73, respectively. Validated models also had excellent performances. Conclusions: Genomic variation of HGSC can be used to create prediction models which accurately discriminate cancer from benign tissue. Further refining of these models (early-stage samples, other tumor types) has the potential to lead to detection of ovarian cancer in blood with cell free DNA, even in early stage. Full article

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15 pages, 1851 KiB

Open AccessCommunication

Salivary microRNA and Metabolic Profiles in a Mouse Model of Subchronic and Mild Social Defeat Stress

by Yuta Yoshida, Yuhei Yajima, Kina Kawakami, Shin-ichi Nakamura, Takamitsu Tsukahara, Katsutaka Oishi and Atsushi Toyoda

Int. J. Mol. Sci. 2022, 23(22), 14479; https://doi.org/10.3390/ijms232214479 - 21 Nov 2022

Cited by 2 | Viewed by 3158

Abstract

Identification of early biomarkers of stress is important for preventing mood and anxiety disorders. Saliva is an easy-to-collect and non-invasive diagnostic target. The aim of this study was to characterize the changes in salivary whole microRNAs (miRNAs) and metabolites in mice subjected to [...] Read more.

Identification of early biomarkers of stress is important for preventing mood and anxiety disorders. Saliva is an easy-to-collect and non-invasive diagnostic target. The aim of this study was to characterize the changes in salivary whole microRNAs (miRNAs) and metabolites in mice subjected to subchronic and mild social defeat stress (sCSDS). In this study, we identified seven upregulated and one downregulated miRNAs/PIWI-interacting RNA (piRNA) in the saliva of sCSDS mice. One of them, miR-208b-3p, which is reported as a reliable marker for myocardial infarction, was upregulated in the saliva of sCSDS mice. Histological analysis showed frequent myocardial interstitial fibrosis in the heart of such mice. In addition, gene ontology and pathway analyses suggested that the pathways related to energy metabolism, such as the oxidative phosphorylation and the pentose phosphate pathway, were significantly related to the miRNAs affected by sCSDS in saliva. In contrast, salivary metabolites were not significantly changed in the sCSDS mice, which is consistent with our previous metabolomic study on the plasma of sCSDS mice. Taken in the light of previous studies, the present study provides novel potential stress biomarkers for future diagnosis using saliva. Full article

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12 pages, 780 KiB

Open AccessReview

Sodium-Glucose Cotransporter-2 Inhibitors—Miracle Drugs for the Treatment of Chronic Kidney Disease Irrespective of the Diabetes Status: Lessons from the Dedicated Kidney Disease-Focused CREDENCE and DAPA-CKD Trials

by Tomohito Gohda and Maki Murakoshi

Int. J. Mol. Sci. 2022, 23(22), 13749; https://doi.org/10.3390/ijms232213749 - 9 Nov 2022

Cited by 9 | Viewed by 9290

Abstract

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease worldwide. In Japan, the proportion of new patients requiring dialysis due to DKD has remained unchanged over the past five years. Early diagnosis and treatment are [...] Read more.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease worldwide. In Japan, the proportion of new patients requiring dialysis due to DKD has remained unchanged over the past five years. Early diagnosis and treatment are extremely important for the prevention of DKD progression. Albuminuria is the most promising biomarker currently available for diagnosing DKD and predicting its prognosis at an early stage; however, it has relatively poor specificity and sensitivity for DKD. Measuring the serum levels of tumor necrosis factor receptors (TNFRs; TNFR1 and TNFR2) is an alternative for predicting the prognosis of patients with CKD, irrespective of their diabetes status. Cardiorenal risk factor management and renin–angiotensin system inhibitor usage are effective in slowing the DKD progression, although the residual risk remains high in patients with DKD. Recently, two classes of antihyperglycemic agents, sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists, in addition to nonsteroidal selective mineralocorticoid receptor antagonists, which are less potent blood pressure-lowering and potassium-sparing agents, have emerged as cardiorenal disease-modifying therapies for preventing the DKD progression. This review focused on the SGLT2 inhibitor-based therapeutic strategies that have demonstrated cardiorenal benefits in patients with type 2 diabetes. Full article

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36 pages, 1047 KiB

Open AccessReview

Vulnerable Atherosclerotic Plaque: Is There a Molecular Signature?

by Roxana Mihaela Chiorescu, Mihaela Mocan, Andreea Ioana Inceu, Andreea Paula Buda, Dan Blendea and Sonia Irina Vlaicu

Int. J. Mol. Sci. 2022, 23(21), 13638; https://doi.org/10.3390/ijms232113638 - 7 Nov 2022

Cited by 21 | Viewed by 5102

Abstract

Atherosclerosis and its clinical manifestations, coronary and cerebral artery diseases, are the most common cause of death worldwide. The main pathophysiological mechanism for these complications is the rupture of vulnerable atherosclerotic plaques and subsequent thrombosis. Pathological studies of the vulnerable lesions showed that [...] Read more.

Atherosclerosis and its clinical manifestations, coronary and cerebral artery diseases, are the most common cause of death worldwide. The main pathophysiological mechanism for these complications is the rupture of vulnerable atherosclerotic plaques and subsequent thrombosis. Pathological studies of the vulnerable lesions showed that more frequently, plaques rich in lipids and with a high level of inflammation, responsible for mild or moderate stenosis, are more prone to rupture, leading to acute events. Identifying the vulnerable plaques helps to stratify patients at risk of developing acute vascular events. Traditional imaging methods based on plaque appearance and size are not reliable in prediction the risk of rupture. Intravascular imaging is a novel technique able to identify vulnerable lesions, but it is invasive and an operator-dependent technique. This review aims to summarize the current data from literature regarding the main biomarkers involved in the attempt to diagnose vulnerable atherosclerotic lesions. These biomarkers could be the base for risk stratification and development of the new therapeutic drugs in the treatment of patients with vulnerable atherosclerotic plaques. Full article

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9 pages, 666 KiB

Open AccessArticle

Serum Level of MMP-3 and MMP-9 in Patients with Diabetes Mellitus Type 2 Infected with Epstein-Barr Virus

by Ewa Stępień, Jakub Dworzański, Anna Dworzańska, Bartłomiej Drop and Małgorzata Polz-Dacewicz

Int. J. Mol. Sci. 2022, 23(21), 13599; https://doi.org/10.3390/ijms232113599 - 6 Nov 2022

Cited by 3 | Viewed by 1840

Abstract

Diabetes mellitus type 2 (DM2) has recently become one of the most important health problems in the world. Patients with DM2 with long-term glycaemia are more likely to become infected than the healthy population. Matrix metalloproteinases (MMPs) play a key role in tissue [...] Read more.

Diabetes mellitus type 2 (DM2) has recently become one of the most important health problems in the world. Patients with DM2 with long-term glycaemia are more likely to become infected than the healthy population. Matrix metalloproteinases (MMPs) play a key role in tissue remodeling during various physiological processes. However, it has been reported that certain MMPs are overexpressed during the development of various human diseases. In this study, we analyzed the levels of MMP-3 and MMP-9 in the serum of DM2 patients with and without Epstein-Barr virus (EBV) infection. The study included 115 patients with DM2 hospitalized in the Internal Ward of the Masovian Specialist Hospital in Radom, Poland, who were divided into two groups: EBV-positive and EBV-negative. The levels of MMP-3 and MMP-9 were tested in the serum of patients using the ELISA method, while the presence of EBV in saliva was tested by polymerase chain reaction (PCR). The presented studies showed a significant difference in the concentration of both MMPs in diabetic patients additionally infected with EBV compared to the group of non-infected individuals. It seems that MMPs may be useful biomarkers in the diagnosis, prognosis, and monitoring of diabetes associated with EBV infection. Full article

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16 pages, 27198 KiB

Open AccessArticle

External Hemin as an Inhibitor of Mitochondrial Large-Conductance Calcium-Activated Potassium Channel Activity

by Agnieszka Walewska, Adam Szewczyk and Piotr Koprowski

Int. J. Mol. Sci. 2022, 23(21), 13391; https://doi.org/10.3390/ijms232113391 - 2 Nov 2022

Cited by 1 | Viewed by 1918

Abstract

The mitochondrial large-conductance calcium-activated potassium channel (mitoBK_Ca) is located in the inner mitochondrial membrane and seems to play a crucial role in cytoprotection. The mitoBK_Ca channel is regulated by many modulators, including activators, such as calcium ions and inhibitors, such [...] Read more.

The mitochondrial large-conductance calcium-activated potassium channel (mitoBK_Ca) is located in the inner mitochondrial membrane and seems to play a crucial role in cytoprotection. The mitoBK_Ca channel is regulated by many modulators, including activators, such as calcium ions and inhibitors, such as heme and its oxidized form hemin. Heme/hemin binds to the heme-binding motif (CXXCH) located between two RCK domains present in the mitochondrial matrix. In the present study, we used the patch-clamp technique in the outside-out configuration to record the activity of mitoBK_Ca channels. This allowed for the application of channel modulators to the intermembrane-space side of the mitoBK_Ca. We found that hemin applied in this configuration inhibits the activity of mitoBK_Ca. In addition, we proved that the observed hemin effect is specific and it is not due to its interaction with the inner mitochondrial membrane. Our data suggest the existence of a new potential heme/hemin binding site in the structure of the mitoBK_Ca channel located on the mitochondrial intermembrane space side, which could constitute a new way for the regulation of mitoBK_Ca channel activity. Full article

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16 pages, 3719 KiB

Open AccessArticle

Rethinking the Dilated Encoder in TE-YOLOF: An Approach Based on Attention Mechanism to Improve Performance for Blood Cell Detection

by Fanxin Xu, He Lyu and Wei Xiang

Int. J. Mol. Sci. 2022, 23(21), 13355; https://doi.org/10.3390/ijms232113355 - 1 Nov 2022

Cited by 1 | Viewed by 1913

Abstract

Blood cell detection is an essential branch of microscopic imaging for disease diagnosis. TE-YOLOF is an effective model for blood cell detection, and was recently found to have an outstanding trade-off between accuracy and model complexity. However, there is a lack of understanding [...] Read more.

Blood cell detection is an essential branch of microscopic imaging for disease diagnosis. TE-YOLOF is an effective model for blood cell detection, and was recently found to have an outstanding trade-off between accuracy and model complexity. However, there is a lack of understanding of whether the dilated encoder in TE-YOLOF works well for blood cell detection. To address this issue, we perform a thorough experimental analysis and find the interesting fact that the dilated encoder is not necessary for TE-YOLOF to perform the blood cell detection task. For the purpose of increasing performance on blood cell detection, in this research, we use the attention mechanism to dominate the dilated encoder place in TE-YOLOF and find that the attention mechanism is effective to address this problem. Based upon these findings, we propose a novel approach, named Enhanced Channel Attention Module (ECAM), based on attention mechanism to achieve precision improvement with less growth on model complexity. Furthermore, we examine the proposed ECAM method compared with other tip-top attention mechanisms and find that the proposed attention method is more effective on blood cell detection task. We incorporate the spatial attention mechanism in CBAM with our ECAM to form a new module, which is named Enhanced-CBAM. We propose a new network named Enhanced Channel Attention Network (ENCANet) based upon Enhanced-CBAM to perform blood cell detection on BCCD dataset. This network can increase the accuracy to 90.3 AP while the parameter is only 6.5 M. Our ENCANet is also effective for conducting cross-domain blood cell detection experiments. Full article

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18 pages, 1116 KiB

Open AccessReview

The Role of Tβ4-POP-Ac-SDKP Axis in Organ Fibrosis

by Wei Wang, Wenning Jia and Chunping Zhang

Int. J. Mol. Sci. 2022, 23(21), 13282; https://doi.org/10.3390/ijms232113282 - 31 Oct 2022

Cited by 2 | Viewed by 3160

Abstract

Fibrosis is a pathological process in which parenchymal cells are necrotic and excess extracellular matrix (ECM) is accumulated due to dysregulation of tissue injury repair. Thymosin β4 (Tβ4) is a 43 amino acid multifunctional polypeptide that is involved in wound healing. Prolyl oligopeptidase [...] Read more.

Fibrosis is a pathological process in which parenchymal cells are necrotic and excess extracellular matrix (ECM) is accumulated due to dysregulation of tissue injury repair. Thymosin β4 (Tβ4) is a 43 amino acid multifunctional polypeptide that is involved in wound healing. Prolyl oligopeptidase (POP) is the main enzyme that hydrolyzes Tβ4 to produce its derivative N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) which is found to play a role in the regulation of fibrosis. Accumulating evidence suggests that the Tβ4-POP-Ac-SDKP axis widely exists in various tissues and organs including the liver, kidney, heart, and lung, and participates in the process of fibrogenesis. Herein, we aim to elucidate the role of Tβ4-POP-Ac-SDKP axis in hepatic fibrosis, renal fibrosis, cardiac fibrosis, and pulmonary fibrosis, as well as the underlying mechanisms. Based on this, we attempted to provide novel therapeutic strategies for the regulation of tissue damage repair and anti-fibrosis therapy. The Tβ4-POP-Ac-SDKP axis exerts protective effects against organ fibrosis. It is promising that appropriate dosing regimens that rely on this axis could serve as a new therapeutic strategy for alleviating organ fibrosis in the early and late stages. Full article

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18 pages, 5093 KiB

Open AccessArticle

Enhanced Expression of ARK5 in Hepatic Stellate Cell and Hepatocyte Synergistically Promote Liver Fibrosis

by Yang You, Chongqing Gao, Junru Wu, Hengdong Qu, Yang Xiao, Ziwei Kang, Jinying Li and Jian Hong

Int. J. Mol. Sci. 2022, 23(21), 13084; https://doi.org/10.3390/ijms232113084 - 28 Oct 2022

Cited by 1 | Viewed by 2677

Abstract

AMPK-related protein kinase 5 (ARK5) is involved in a broad spectrum of physiological and cell events, and aberrant expression of ARK5 has been observed in a wide variety of solid tumors, including liver cancer. However, the role of ARK5 in liver fibrosis remains [...] Read more.

AMPK-related protein kinase 5 (ARK5) is involved in a broad spectrum of physiological and cell events, and aberrant expression of ARK5 has been observed in a wide variety of solid tumors, including liver cancer. However, the role of ARK5 in liver fibrosis remains largely unexplored. We found that ARK5 expression was elevated in mouse fibrotic livers, and showed a positive correlation with the progression of liver fibrosis. ARK5 was highly expressed not only in activated hepatic stellate cells (HSCs), but also in hepatocytes. In HSCs, ARK5 prevents the degradation of transforming growth factor β type I receptor (TβRI) and mothers against decapentaplegic homolog 4 (Smad4) proteins by inhibiting the expression of Smad ubiquitin regulatory factor 2 (Smurf2), thus maintaining the continuous transduction of the transforming growth factor β (TGF-β) signaling pathway, which is essential for cell activation, proliferation and survival. In hepatocytes, ARK5 induces the occurrence of epithelial-mesenchymal transition (EMT), and also promotes the secretion of inflammatory factors. Inflammatory factors, in turn, further enhance the activation of HSCs and deepen the degree of liver fibrosis. Notably, we demonstrated in a mouse model that targeting ARK5 with the selective inhibitor HTH-01-015 attenuates CCl₄-induced liver fibrosis in mice. Taken together, the results indicate that ARK5 is a critical driver of liver fibrosis, and promotes liver fibrosis by synergy between HSCs and hepatocytes. Full article

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1 pages, 161 KiB

Open AccessCorrection

Correction: Jellinger, K.A. Pathomechanisms of Vascular Depression in Older Adults. Int. J. Mol. Sci. 2022, 23, 308

by Kurt A. Jellinger

Int. J. Mol. Sci. 2022, 23(21), 12949; https://doi.org/10.3390/ijms232112949 - 26 Oct 2022

Cited by 3 | Viewed by 1423

Abstract

In the original publication [...] Full article

11 pages, 1245 KiB

Open AccessArticle

Longitudinal Serum Protein Analysis of Women with a High Risk of Developing Breast Cancer Reveals Large Interpatient Versus Small Intrapatient Variations: First Results from the TESTBREAST Study

by Sophie C. Hagenaars, Lennard J. M. Dekker, Bob Ravesteijn, Ronald L. P. van Vlierberghe, Fred P. H. T. M. Romijn, Linda Verhoeff, Arjen J. Witkamp, Karin E. Schenk, Kristien B. I. M. Keymeulen, Marian B. E. Menke-Pluijmers, Anneriet E. Dassen, Birgitta A. Kortmann, Jakob de Vries, Emiel J. T. Rutgers, Yuri E. M. van der Burgt, Elma Meershoek-Klein Kranenbarg, Christa M. Cobbaert, Theo M. Luider, Wilma E. Mesker and Rob A. E. M. Tollenaar

Int. J. Mol. Sci. 2022, 23(20), 12399; https://doi.org/10.3390/ijms232012399 - 17 Oct 2022

Cited by 2 | Viewed by 2738

Abstract

The prospective, multicenter TESTBREAST study was initiated with the aim of identifying a novel panel of blood-based protein biomarkers to enable early breast cancer detection for moderate-to-high-risk women. Serum samples were collected every (half) year up until diagnosis. Protein levels were longitudinally measured [...] Read more.

The prospective, multicenter TESTBREAST study was initiated with the aim of identifying a novel panel of blood-based protein biomarkers to enable early breast cancer detection for moderate-to-high-risk women. Serum samples were collected every (half) year up until diagnosis. Protein levels were longitudinally measured to determine intrapatient and interpatient variabilities. To this end, protein cluster patterns were evaluated to form a conceptual basis for further clinical analyses. Using a mass spectrometry-based bottom-up proteomics strategy, the protein abundance of 30 samples was analyzed: five sequential serum samples from six high-risk women; three who developed a breast malignancy (cases) and three who did not (controls). Serum samples were chromatographically fractionated and an in-depth serum proteome was acquired. Cluster analyses were applied to indicate differences between and within protein levels in serum samples of individuals. Statistical analyses were performed using ANOVA to select proteins with a high level of clustering. Cluster analyses on 30 serum samples revealed unique patterns of protein clustering for each patient, indicating a greater interpatient than intrapatient variability in protein levels of the longitudinally acquired samples. Moreover, the most distinctive proteins in the cluster analysis were identified. Strong clustering patterns within longitudinal intrapatient samples have demonstrated the importance of identifying small changes in protein levels for individuals over time. This underlines the significance of longitudinal serum measurements, that patients can serve as their own controls, and the relevance of the current study set-up for early detection. The TESTBREAST study will continue its pursuit toward establishing a protein panel for early breast cancer detection. Full article

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22 pages, 2872 KiB

Open AccessArticle

MicroRNAs of Milk in Cells, Plasma, and Lipid Fractions of Human Milk, and Abzymes Catalyzing Their Hydrolysis

by Ivan Yu. Kompaneets, Evgeny A. Ermakov, Valentina N. Buneva and Georgy A. Nevinsky

Int. J. Mol. Sci. 2022, 23(20), 12070; https://doi.org/10.3390/ijms232012070 - 11 Oct 2022

Cited by 3 | Viewed by 1842

Abstract

Human milk provides neonates with various components that ensure newborns’ growth, including protection from bacterial and viral infections. In neonates, the biological functions of many breast milk components can be very different compared with their functions in the body fluids of healthy adults. [...] Read more.

Human milk provides neonates with various components that ensure newborns’ growth, including protection from bacterial and viral infections. In neonates, the biological functions of many breast milk components can be very different compared with their functions in the body fluids of healthy adults. Catalytic antibodies (abzymes) that hydrolyze peptides, proteins, DNAs, RNAs, and oligosaccharides were detected, not only in the blood sera of autoimmune patients, but also in human milk. Non-coding microRNAs (18–25 nucleotides) are intra- and extracellular molecules of different human fluids. MiRNAs possess many different biological functions, including the regulation of several hundred genes. Five of them, miR-148a-3p, miR-200c-3p, miR-378a-3p, miR-146b-5p, and let-7f-5p, were previously found in milk in high concentrations. Here, we determined relative numbers of miRNA copies in 1 mg of analyzed cells, lipid fractions, and plasmas of human milk samples. The relative amount of microRNA decreases in the following order: cells ≈ lipid fraction > plasma. IgGs and sIgAs were isolated from milk plasma, and their activities in the hydrolysis of five microRNAs was compared. In general, sIgAs demonstrated higher miRNA-hydrolyzing activities than IgGs antibodies. The hydrolysis of five microRNAs by sIgAs and IgGs was site-specific. The relative activity of each microRNA hydrolysis was very dependent on the milk preparation. The correlation coefficients between the contents of five RNAs in milk plasma, and the relative activities of sIgAs compared to IgGs in hydrolyses, strongly depended on individual microRNA, and changed from −0.01 to 0.80. Thus, it was shown that milk contains specific antibodies (abzymes) that hydrolyze microRNAs specific for human milk. Full article

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16 pages, 2811 KiB

Open AccessArticle

Selective Anti-Leishmanial Strathclyde Minor Groove Binders Using an N-Oxide Tail-Group Modification

by Marina C. Perieteanu, Leah M. C. McGee, Craig D. Shaw, Donna S. MacMillan, Abedawn I. Khalaf, Kirsten Gillingwater, Rebecca Beveridge, Katharine C. Carter, Colin J. Suckling and Fraser J. Scott

Int. J. Mol. Sci. 2022, 23(19), 11912; https://doi.org/10.3390/ijms231911912 - 7 Oct 2022

Cited by 3 | Viewed by 1940

Abstract

The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class [...] Read more.

The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class of anti-infective agent that have been shown to have potent activity against various bacteria, viruses, fungi and parasites. Herein, it is shown that S-MGBs have potent activity against L. donovani, and that an N-oxide derivation of the tertiary amine tail of typical S-MGBs leads to selective anti-leishmanial activity. Additionally, using S-MGB-219, the N-oxide derivation is shown to retain strong binding to DNA as a 2:1 dimer. These findings support the further study of anti-leishmanial S-MGBs as novel therapeutics. Full article

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17 pages, 5884 KiB

Open AccessArticle

by Daniel Halloran, Venu Pandit, Connor MacMurray, Victoria Stone, Kailey DeGeorge, Mark Eskander, Denise Root, Sean McTague, Heather Pelkey and Anja Nohe

Int. J. Mol. Sci. 2022, 23(19), 11205; https://doi.org/10.3390/ijms231911205 - 23 Sep 2022

Cited by 1 | Viewed by 2403

Abstract

Osteoporosis (OP) is a bone disorder characterized by decreased bone mineral density (BMD). Bone Morphogenetic Protein-2 (BMP-2) injections are used to promote bone formation in OP patients. However, patients are unresponsive to BMP-2 while displaying an upregulation of BMP Receptor Type 1a (BMPRIa) [...] Read more.

Osteoporosis (OP) is a bone disorder characterized by decreased bone mineral density (BMD). Bone Morphogenetic Protein-2 (BMP-2) injections are used to promote bone formation in OP patients. However, patients are unresponsive to BMP-2 while displaying an upregulation of BMP Receptor Type 1a (BMPRIa) and protein kinase CK2α (CK2α). A synthetically produced peptide named casein kinase 2.3 (CK2.3) utilizes the BMP-signaling pathway as it enhances osteogenesis of primary osteoblasts isolated from OP patients, whereas BMP-2 does not. Although shown in OP patients, there is currently no reliable mouse model to study BMP-2 and CK2.3 signaling. In this publication, we show that BMPRIa was required for CK2.3-mediated osteogenesis in C2C12 cells with a CRISPR-Cas9-mediated gene knockout for BMPRIa. We utilized the C57BL/6 (B6) mouse strain as an aging-model to study aberrant BMP-2 signaling, demonstrating that, like OP patients, in 15 and 20-month mice, BMP-2 did not increase bone growth and displayed upregulated BMPRIa and CK2α protein expression. Furthermore, CK2.3 enhanced osteogenesis and decreased osteoclastogenesis in all age groups, whereas BMP-2 only increased mineralization in 6-month mice while increasing osteoclast formation in all age groups. These data demonstrated that aging B6 mice were a reliable model and mimicked data obtained from OP patients. Full article

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10 pages, 1362 KiB

Open AccessArticle

Comparison between Immunocytochemistry, FISH and NGS for ALK and ROS1 Rearrangement Detection in Cytological Samples

by Diane Frankel, Isabelle Nanni, L’Houcine Ouafik, Clara Camilla, Eric Pellegrino, Nathalie Beaufils, Laurent Greillier, Hervé Dutau, Philippe Astoul, Elise Kaspi and Patrice Roll

Int. J. Mol. Sci. 2022, 23(18), 10556; https://doi.org/10.3390/ijms231810556 - 12 Sep 2022

Cited by 5 | Viewed by 2220

Abstract

The detection of ROS1 and ALK rearrangements is performed for advanced-stage non-small cell lung cancer. Several techniques can be used on cytological samples, such as immunocytochemistry (ICC), fluorescence in situ hybridization (FISH) and, more recently, next-generation sequencing (NGS), which is gradually becoming the [...] Read more.

The detection of ROS1 and ALK rearrangements is performed for advanced-stage non-small cell lung cancer. Several techniques can be used on cytological samples, such as immunocytochemistry (ICC), fluorescence in situ hybridization (FISH) and, more recently, next-generation sequencing (NGS), which is gradually becoming the gold standard. We performed a retrospective study to compare ALK and ROS1 rearrangement results from immunocytochemistry, FISH and NGS methods from 131 cytological samples. Compared to NGS, the sensitivity and specificity of ICC were 0.79 and 0.91, respectively, for ALK, and 1 and 0.87 for ROS1. Regarding FISH, the sensitivity and specificity were both at 1 for ALK and ROS1 probes. False-positive cases obtained by ICC were systematically corrected by FISH. When using ICC and FISH techniques, results are very close to NGS. The false-positive cases obtained by ICC are corrected by FISH, and the true-positive cases are confirmed. NGS has the potential to improve the detection of ALK and ROS1 rearrangements in cytological samples; however, the cost of this technique is still much higher than the sequential use of ICC and FISH. Full article

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21 pages, 1439 KiB

Open AccessReview

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

by John R. Walker and Xu-Dong Zhu

Int. J. Mol. Sci. 2022, 23(18), 10212; https://doi.org/10.3390/ijms231810212 - 6 Sep 2022

Cited by 5 | Viewed by 2759

Abstract

A variety of endogenous and exogenous insults are capable of impeding replication fork progression, leading to replication stress. Several SNF2 fork remodelers have been shown to play critical roles in resolving this replication stress, utilizing different pathways dependent upon the nature of the [...] Read more.

A variety of endogenous and exogenous insults are capable of impeding replication fork progression, leading to replication stress. Several SNF2 fork remodelers have been shown to play critical roles in resolving this replication stress, utilizing different pathways dependent upon the nature of the DNA lesion, location on the DNA, and the stage of the cell cycle, to complete DNA replication in a manner preserving genetic integrity. Under certain conditions, however, the attempted repair may lead to additional genetic instability. Cockayne syndrome group B (CSB) protein, a SNF2 chromatin remodeler best known for its role in transcription-coupled nucleotide excision repair, has recently been shown to catalyze fork reversal, a pathway that can provide stability of stalled forks and allow resumption of DNA synthesis without chromosome breakage. Prolonged stalling of replication forks may collapse to give rise to DNA double-strand breaks, which are preferentially repaired by homology-directed recombination. CSB plays a role in repairing collapsed forks by promoting break-induced replication in S phase and early mitosis. In this review, we discuss roles of CSB in regulating the sources of replication stress, replication stress response, as well as the implications of CSB for cancer therapy. Full article

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6 pages, 693 KiB

Open AccessBrief Report

Blockade of Platelet Glycoprotein Ibα Augments Neuroprotection in Orai2-Deficient Mice during Middle Cerebral Artery Occlusion

by Michael Bieber, Michael K. Schuhmann, Maximilian Bellut, David Stegner, Katrin G. Heinze, Mirko Pham, Bernhard Nieswandt and Guido Stoll

Int. J. Mol. Sci. 2022, 23(16), 9496; https://doi.org/10.3390/ijms23169496 - 22 Aug 2022

Viewed by 2116

Abstract

During ischemic stroke, infarct growth before recanalization diminishes functional outcome. Hence, adjunct treatment options to protect the ischemic penumbra before recanalization are eagerly awaited. In experimental stroke targeting two different pathways conferred protection from penumbral tissue loss: (1) enhancement of hypoxic tolerance of [...] Read more.

During ischemic stroke, infarct growth before recanalization diminishes functional outcome. Hence, adjunct treatment options to protect the ischemic penumbra before recanalization are eagerly awaited. In experimental stroke targeting two different pathways conferred protection from penumbral tissue loss: (1) enhancement of hypoxic tolerance of neurons by deletion of the calcium channel subunit Orai2 and (2) blocking of detrimental lymphocyte–platelet responses. However, until now, no preclinical stroke study has assessed the potential of combining neuroprotective with anti-thrombo-inflammatory interventions to augment therapeutic effects. We induced focal cerebral ischemia in Orai2-deficient (Orai2^-/-) mice by middle cerebral artery occlusion (MCAO). Animals were treated with anti-glycoprotein Ib alpha (GPIbα) Fab fragments (p0p/B Fab) blocking GPIbα–von Willebrand factor (vWF) interactions. Rat immunoglobulin G (IgG) Fab was used as the control treatment. The extent of infarct growth before recanalization was assessed at 4 h after MCAO. Moreover, infarct volumes were determined 6 h after recanalization (occlusion time: 4 h). Orai2 deficiency significantly halted cerebral infarct progression under occlusion. Inhibition of platelet GPIbα further reduced primary infarct growth in Orai2^-/- mice. During ischemia–reperfusion, upon recanalization, mice were likewise protected. All in all, we show that neuroprotection in Orai2^-/- mice can be augmented by targeting thrombo-inflammation. This supports the clinical development of combined neuroprotective/anti-platelet strategies in hyper-acute stroke. Full article

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23 pages, 6248 KiB

Open AccessReview

Cyclophilin A/CD147 Interaction: A Promising Target for Anticancer Therapy

by Jang Mi Han and Hye Jin Jung

Int. J. Mol. Sci. 2022, 23(16), 9341; https://doi.org/10.3390/ijms23169341 - 19 Aug 2022

Cited by 20 | Viewed by 3586

Abstract

Cyclophilin A (CypA), which has peptidyl–prolyl cis-trans isomerase (PPIase) activity, regulates multiple functions of cells by binding to its extracellular receptor CD147. The CypA/CD147 interaction plays a crucial role in the progression of several diseases, including inflammatory diseases, coronavirus infection, and cancer, by [...] Read more.

Cyclophilin A (CypA), which has peptidyl–prolyl cis-trans isomerase (PPIase) activity, regulates multiple functions of cells by binding to its extracellular receptor CD147. The CypA/CD147 interaction plays a crucial role in the progression of several diseases, including inflammatory diseases, coronavirus infection, and cancer, by activating CD147-mediated intracellular downstream signaling pathways. Many studies have identified CypA and CD147 as potential therapeutic targets for cancer. Their overexpression promotes growth, metastasis, therapeutic resistance, and the stem-like properties of cancer cells and is related to the poor prognosis of patients with cancer. This review aims to understand the biology and interaction of CypA and CD147 and to review the roles of the CypA/CD147 interaction in cancer pathology and the therapeutic potential of targeting the CypA/CD147 axis. To validate the clinical significance of the CypA/CD147 interaction, we analyzed the expression levels of PPIA and BSG genes encoding CypA and CD147, respectively, in a wide range of tumor types using The Cancer Genome Atlas (TCGA) database. We observed a significant association between PPIA/BSG overexpression and poor prognosis, such as a low survival rate and high cancer stage, in several tumor types. Furthermore, the expression of PPIA and BSG was positively correlated in many cancers. Therefore, this review supports the hypothesis that targeting the CypA/CD147 interaction may improve treatment outcomes for patients with cancer. Full article

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22 pages, 2332 KiB

Open AccessArticle

Experimental Autoimmune Encephalomyelitis of Mice: Enzymatic Cross Site-Specific Hydrolysis of H4 Histone by IgGs against Histones and Myelin Basic Protein

by Andrey E. Urusov, Kseniya S. Aulova, Pavel S. Dmitrenok, Valentina N. Buneva and Georgy A. Nevinsky

Int. J. Mol. Sci. 2022, 23(16), 9182; https://doi.org/10.3390/ijms23169182 - 16 Aug 2022

Cited by 5 | Viewed by 1879

Abstract

Histones play vital roles in chromatin functioning and gene transcription, but in intercellular space, they are harmful due to stimulating systemic inflammatory and toxic responses. Myelin basic protein (MBP) is the most important protein of the axon myelin–proteolipid sheath. Antibodies-abzymes with different catalytic [...] Read more.

Histones play vital roles in chromatin functioning and gene transcription, but in intercellular space, they are harmful due to stimulating systemic inflammatory and toxic responses. Myelin basic protein (MBP) is the most important protein of the axon myelin–proteolipid sheath. Antibodies-abzymes with different catalytic activities are critical and specific features of some autoimmune diseases. Five IgG preparations against histones (H4, H1, H2A, H2B, and H3) and against MBP corresponding to different spontaneous, MOG (myelin oligodendrocyte glycoprotein of mice), and DNA–histones that accelerated onset, acute, and remission stages of experimental autoimmune encephalomyelitis (EAE; model of human multiple sclerosis) development were obtained from EAE-prone C57BL/6 mice by several affinity chromatographies. IgG-abzymes against five histones and MBP possess unusual polyreactivity in complexation and catalytic cross-reactivity in the hydrolysis of histone H4. IgGs against five histones and MBP corresponding to 3 month-old mice (zero time) in comparison with Abs corresponding to spontaneous development of EAE during 60 days differ in type and number of H4 sites for hydrolysis. Immunization of mice with MOG and DNA–histones complex results in an acceleration of EAE development associated with an increase in the activity of antibodies in H4 hydrolysis. Twenty days after mouse immunization with MOG or DNA–histones complex, the IgGs hydrolyze H4 at other additional sites compared to zero time. The maximum number of different sites of H4 hydrolysis was revealed for IgGs against five histones and MBP at 60 days after immunization of mice with MOG and DNA–histones. Overall, it first showed that at different stages of EAE development, abzymes could significantly differ in specific sites of H4 hydrolysis. Full article

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15 pages, 2677 KiB

Open AccessArticle

A Novel Cell-Based Model for a Rare Disease: The Tks4-KO Human Embryonic Stem Cell Line as a Frank-Ter Haar Syndrome Model System

by Loretta László, Hédi Maczelka, Tamás Takács, Anita Kurilla, Álmos Tilajka, László Buday, Virag Vas and Ágota Apáti

Int. J. Mol. Sci. 2022, 23(15), 8803; https://doi.org/10.3390/ijms23158803 - 8 Aug 2022

Cited by 3 | Viewed by 2622

Abstract

Tyrosine kinase substrate with four SH3 domains (Tks4) scaffold protein plays roles in cell migration and podosome formation and regulates systemic mechanisms such as adult bone homeostasis and adipogenesis. Mutations in the Tks4 gene (SH3PXD2b) cause a rare developmental disorder called [...] Read more.

Tyrosine kinase substrate with four SH3 domains (Tks4) scaffold protein plays roles in cell migration and podosome formation and regulates systemic mechanisms such as adult bone homeostasis and adipogenesis. Mutations in the Tks4 gene (SH3PXD2b) cause a rare developmental disorder called Frank-Ter Haar syndrome (FTHS), which leads to heart abnormalities, bone tissue defects, and reduced adiposity. We aimed to produce a human stem cell-based in vitro FTHS model system to study the effects of the loss of the Tks4 protein in different cell lineages and the accompanying effects on the cell signalome. To this end, we used CRISPR/Cas9 (clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated (Cas9)) to knock out the SH3PXD2b gene in the HUES9 human embryonic stem cell line (hESC), and we obtained stable homo- and heterozygous knock out clones for use in studying the potential regulatory roles of Tks4 protein in embryonic stem cell biology. Based on pluripotency marker measurements and spontaneous differentiation capacity assays, we concluded that the newly generated Tks4-KO HUES9 cells retained their embryonic stem cell characteristics. We propose that the Tks4-KO HUES9 cells could serve as a tool for further cell differentiation studies to investigate the involvement of Tks4 in the complex disorder FTHS. Moreover, we successfully differentiated all of the clones into mesenchymal stem cells (MSCs). The derived MSC cultures showed mesenchymal morphology and expressed MSC markers, although the expression levels of mesodermal and osteogenic marker genes were reduced, and several EMT (epithelial mesenchymal transition)-related features were altered in the Tks4-KO MSCs. Our results suggest that the loss of Tks4 leads to FTHS by altering cell lineage differentiation and cell maturation processes, rather than by regulating embryonic stem cell potential. Full article

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18 pages, 2664 KiB

Open AccessArticle

Functional Characterization of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells

by Xuehui Fan, Lukas Cyganek, Katja Nitschke, Stefanie Uhlig, Philipp Nuhn, Karen Bieback, Daniel Duerschmied, Ibrahim El-Battrawy, Xiaobo Zhou and Ibrahim Akin

Int. J. Mol. Sci. 2022, 23(15), 8507; https://doi.org/10.3390/ijms23158507 - 31 Jul 2022

Cited by 7 | Viewed by 4080

Abstract

Endothelial cells derived from human induced pluripotent stem cells (hiPSC-ECs) provide a new opportunity for mechanistic research on vascular regeneration and drug screening. However, functions of hiPSC-ECs still need to be characterized. The objective of this study was to investigate electrophysiological and functional [...] Read more.

Endothelial cells derived from human induced pluripotent stem cells (hiPSC-ECs) provide a new opportunity for mechanistic research on vascular regeneration and drug screening. However, functions of hiPSC-ECs still need to be characterized. The objective of this study was to investigate electrophysiological and functional properties of hiPSC-ECs compared with primary human cardiac microvascular endothelial cells (HCMECs), mainly focusing on ion channels and membrane receptor signaling, as well as specific cell functions. HiPSC-ECs were derived from hiPS cells that were generated from human skin fibroblasts of three independent healthy donors. Phenotypic and functional comparison to HCMECs was performed by flow cytometry, immunofluorescence staining, quantitative reverse-transcription polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), tube formation, LDL uptake, exosome release assays and, importantly, patch clamp techniques. HiPSC-ECs were successfully generated from hiPS cells and were identified by endothelial markers. The mRNA levels of KCNN2, KCNN4, KCNMA1, TRPV2, and SLC8A1 in hiPSC-ECs were significantly higher than HCMECs. AT1 receptor mRNA level in hiPSC-ECs was higher than in HCMECs. AT2 receptor mRNA level was the highest among all receptors. Adrenoceptor ADRA2 expression in hiPSC-ECs was lower than in HCMECs, while ADRA1, ADRB1, ADRB2, and G-protein GNA11 and Gai expression were similar in both cell types. The expression level of muscarinic and dopamine receptors CHRM3, DRD2, DRD3, and DRD4 in hiPSC-ECs were significantly lower than in HCMECs. The functional characteristics of endothelial cells, such as tube formation and LDL uptake assay, were not statistically different between hiPSC-ECs and HCMECs. Phenylephrine similarly increased the release of the vasoconstrictor endothelin-1 (ET-1) in hiPSC-ECs and HCMECs. Acetylcholine also similarly increased nitric oxide generation in hiPSC-ECs and HCMECs. The resting potentials (RPs), I_SK1–3, I_SK4 and I_K1 were similar in hiPSC-ECs and HCMECs. I_BK was larger and I_KATP was smaller in hiPSC-ECs. In addition, we also noted a higher expression level of exosomes marker CD81 in hiPSC-ECs and a higher expression of CD9 and CD63 in HCMECs. However, the numbers of exosomes extracted from both types of cells did not differ significantly. The study demonstrates that hiPSC-ECs are similar to native endothelial cells in ion channel function and membrane receptor-coupled signaling and physiological cell functions, although some differences exist. This information may be helpful for research using hiPSC-ECs. Full article

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22 pages, 3525 KiB

Open AccessArticle

Low-Dose Tacrolimus Promotes the Migration and Invasion and Nitric Oxide Production in the Human-Derived First Trimester Extravillous Trophoblast Cells In Vitro

by Ahmad J. H. Albaghdadi, Kassandra Coyle and Frederick W. K. Kan

Int. J. Mol. Sci. 2022, 23(15), 8426; https://doi.org/10.3390/ijms23158426 - 29 Jul 2022

Cited by 2 | Viewed by 2892

Abstract

Placentation is one of the most important determinants for a successful pregnancy, and this is dependent on the process of trophoblast migration and invasion. Progesterone receptors (PGR) are critical effectors of progesterone (P4) signaling that is required for trophoblast migration and invasion conducive [...] Read more.

Placentation is one of the most important determinants for a successful pregnancy, and this is dependent on the process of trophoblast migration and invasion. Progesterone receptors (PGR) are critical effectors of progesterone (P4) signaling that is required for trophoblast migration and invasion conducive to a successful gestation. In immune complicated pregnancies, evidence has shown that abnormal placentation occurs because of aberrant expression of PGR. Therapeutic intervention with tacrolimus (FK506) was able to restore PGR expression and improve pregnancy outcomes in immune-complicated gestations; however, the exact mode of action of tacrolimus in assisting placentation is not clear. Here, we attempt to uncover the mode of action of tacrolimus by examining its effects on trophoblast invasion and migration in the human-derived extravillous trophoblast (EVT) cell line, the HTR-8/SVneo cells. Using a variety of functional assays, we demonstrated that low-dose tacrolimus (10 ng/mL) was sufficient to significantly (p < 0.001) stimulate the migration and invasion of the HTR-8/SVneo cells, inducing their cytosolic/nuclear progesterone receptor expression and activation, and modulating their Nitric Oxide (NO) production. Moreover, tacrolimus abrogated the suppressive effect of the NOS inhibitor N^ω- Nitro-L-Arginine Methyl Ester (L-NAME) on these vital processes critically involved in the establishment of human pregnancy. Collectively, our data suggest an immune-independent mode of action of tacrolimus in positively influencing placentation in complicated gestations, at least in part, through promoting the migration and invasion of the first trimester extravillous trophoblast cells by modulating their NO production and activating their cytosolic/nuclear progesterone-receptors. To our knowledge, this is the first report to show that the mode of action of tacrolimus as a monotherapy for implantation failure is plausibly PGR-dependent. Full article

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17 pages, 2786 KiB

Open AccessArticle

Catalytic Antibodies in Bipolar Disorder: Serum IgGs Hydrolyze Myelin Basic Protein

by Daria A. Kamaeva, Liudmila P. Smirnova, Svetlana N. Vasilieva, Daria V. Kazantseva, Alisa R. Vasilieva and Svetlana A. Ivanova

Int. J. Mol. Sci. 2022, 23(13), 7397; https://doi.org/10.3390/ijms23137397 - 2 Jul 2022

Cited by 6 | Viewed by 2598

Abstract

The pathogenesis of bipolar affective disorder is associated with immunological imbalances, a general pro-inflammatory status, neuroinflammation, and impaired white matter integrity. Myelin basic protein (MBP) is one of the major proteins in the myelin sheath of brain oligodendrocytes. For the first time, we [...] Read more.

The pathogenesis of bipolar affective disorder is associated with immunological imbalances, a general pro-inflammatory status, neuroinflammation, and impaired white matter integrity. Myelin basic protein (MBP) is one of the major proteins in the myelin sheath of brain oligodendrocytes. For the first time, we have shown that IgGs isolated from sera of bipolar patients can effectively hydrolyze human myelin basic protein (MBP), unlike other test proteins. Several stringent criteria were applied to assign the studied activity to serum IgG. The level of MBP-hydrolyzing activity of IgG from patients with bipolar disorder was statistically significantly 1.6-folds higher than that of healthy individuals. This article presents a detailed characterization of the catalytic properties of MBP-hydrolyzing antibodies in bipolar disorder, including the substrate specificity, inhibitory analysis, pH dependence of hydrolysis, and kinetic parameters of IgG-dependent MBP hydrolysis, providing the heterogeneity of polyclonal MBP-hydrolyzing IgGs and their difference from canonical proteases. The ability of serum IgG to hydrolyze MBP in bipolar disorder may become an additional link between the processes of myelin damage and inflammation. Full article

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13 pages, 1767 KiB

Open AccessArticle

TAS2R38 Bitter Taste Receptor Expression in Chronic Rhinosinusitis with Nasal Polyps: New Data on Polypoid Tissue

by Joanna Jeruzal-Świątecka, Edyta Borkowska, Mateusz Łaszczych, Zuzanna Nowicka and Wioletta Pietruszewska

Int. J. Mol. Sci. 2022, 23(13), 7345; https://doi.org/10.3390/ijms23137345 - 1 Jul 2022

Cited by 4 | Viewed by 4211

Abstract

Studies have shown differences in TAS2R38 receptor expression in patients with chronic rhinosinusitis (CRS) compared to healthy controls. Known agonists of TAS2R38 stimulate epithelial cells, leading to robust intracellular nitric oxide (NO) production, which damages bacterial membranes, enzymes, and DNA, but also increases [...] Read more.

Studies have shown differences in TAS2R38 receptor expression in patients with chronic rhinosinusitis (CRS) compared to healthy controls. Known agonists of TAS2R38 stimulate epithelial cells, leading to robust intracellular nitric oxide (NO) production, which damages bacterial membranes, enzymes, and DNA, but also increases ciliary beat frequency. In this study we examined, using qRT-PCR, the expression of TAS2R38 receptor in nasal polyps (NP) of patients with CRS (N = 107) and in inferior turbinate mucosa (ITM) of patients with CRS and controls (N = 39), and confronted it with clinical features and the severity of the disease. The expression was shown in 43 (50.00%) samples of ITM in the study group (N = 107), in 28 (71.79%) in the control group (N = 39) (p = 0.037), and in 43 (46.24%) of NP. There were no differences in levels of the expression in all analyzed tissues. Patients who rated their symptoms at 0–3 showed higher TAS2R38 expression in ITM in comparison to the patients with 8–10 points on the VAS scale (p = 0.020). A noticeable, however not significant, correlation between the TAS2R38 expression in ITM and the Lund–Mackay CT score was shown (p = 0.068; R = −0.28). Patients with coexisting asthma had significantly higher receptor expression in the NP (p = 0.012). Our study is the first to confirm the presence of the TAS2R38 receptor in NP. Expression of the TAS2R38 receptor is reduced in the sinonasal mucosa in patients with more advanced CRS with NP. Full article

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14 pages, 1714 KiB

Open AccessArticle

Nerve Growth Factor (NGF) as Partaker in the Modulation of UV-Response in Cultured Human Conjunctival Fibroblasts

by Graziana Esposito, Bijorn Omar Balzamino, Maria Luisa Rocco, Luigi Aloe and Alessandra Micera

Int. J. Mol. Sci. 2022, 23(11), 6337; https://doi.org/10.3390/ijms23116337 - 6 Jun 2022

Cited by 2 | Viewed by 2851

Abstract

Corroborating data sustain the pleiotropic effect of nerve growth factor (NGF) in the protection of the visual system from dangerous stimuli, including ultraviolet (UV). Since UV exposure might promote ocular surface changes (conjunctival inflammation and matrix rearrangement), as previously reported from in vivo [...] Read more.

Corroborating data sustain the pleiotropic effect of nerve growth factor (NGF) in the protection of the visual system from dangerous stimuli, including ultraviolet (UV). Since UV exposure might promote ocular surface changes (conjunctival inflammation and matrix rearrangement), as previously reported from in vivo studies sustaining some protective NGF effects, in vitro cultures of human conjunctival fibroblasts (FBs) were developed and exposed to a single UV exposure over 15 min (0.277 W/m²), either alone or supplemented with NGF (1–10–100 ng/mL). Conditioned media and cell monolayers were collected and analyzed for protein release (ELISA, ELLA microfluidic) and transcript expression (real-time PCR). A specific “inflammatory to remodeling” pattern (IL8, VEGF, IL33, OPN, and CYR61) as well as a few epigenetic transcripts (known as modulator of cell differentiation and matrix-remodeling (DNMT3a, HDAC1, NRF2 and KEAP1)) were investigated in parallel. UV-exposed FBs (i), showed no proliferation or significant cytoskeleton rearrangement; (ii), displayed a trkA^NGFR/p75^NTR phenotype; and (iii), synthesized/released IL8, VEGF-A, IL33, OPN, and CYR61, as compared to unexposed ones. NGF addition counteracted IL8, IL33, OPN, and CYR61 protein release merely at lower NGF concentrations but not VEGF. NGF supplementation did not affect DNMT3a or HDAC1 transcripts, while it significantly upregulated NRF2 at lowest NGF doses and did not change KEAP1 expression. Taken together, a single UV exposure activated conjunctival FBs to release pro-inflammatory/fibrogenic factors in association with epigenetic changes. The effects were selectively counteracted by NGF supplementation in a dose-dependent fashion, most probably accountable to the trkA^NGFR/p75^NTR phenotype. Further in vitro studies are underway to better understand this additional NGF pleiotropic effect. Since UV-shield impairments represent a worldwide alert and UV radiation can slowly affect ocular surface homeostasis (photo-ageing, cataract) or might exacerbate ocular diseases with a preexisting fibrosis (pterygium, VKC), these findings on NGF modulation of UV-exposed FBs might provide additional information for protecting the ocular surface (homeostasis) from low-grade long-lasting UV insults. Full article

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21 pages, 1449 KiB

Open AccessReview

MITF in Normal Melanocytes, Cutaneous and Uveal Melanoma: A Delicate Balance

by Maria Chiara Gelmi, Laurien E. Houtzagers, Thomas Strub, Imène Krossa and Martine J. Jager

Int. J. Mol. Sci. 2022, 23(11), 6001; https://doi.org/10.3390/ijms23116001 - 26 May 2022

Cited by 39 | Viewed by 5868

Abstract

Microphthalmia-associated transcription factor (MITF) is an important regulator of melanogenesis and melanocyte development. Although it has been studied extensively in cutaneous melanoma, the role of MITF in uveal melanoma (UM) has not been explored in much detail. We review the literature about the [...] Read more.

Microphthalmia-associated transcription factor (MITF) is an important regulator of melanogenesis and melanocyte development. Although it has been studied extensively in cutaneous melanoma, the role of MITF in uveal melanoma (UM) has not been explored in much detail. We review the literature about the role of MITF in normal melanocytes, in cutaneous melanoma, and in UM. In normal melanocytes, MITF regulates melanocyte development, melanin synthesis, and melanocyte survival. The expression profile and the behaviour of MITF-expressing cells suggest that MITF promotes local proliferation and inhibits invasion, inflammation, and epithelial-to-mesenchymal (EMT) transition. Loss of MITF expression leads to increased invasion and inflammation and is more prevalent in malignant cells. Cutaneous melanoma cells switch between MITF-high and MITF-low states in different phases of tumour development. In UM, MITF loss is associated with loss of BAP1 protein expression, which is a marker of poor prognosis. These data indicate a dual role for MITF in benign and malignant melanocytic cells. Full article

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16 pages, 1652 KiB

Open AccessReview

Monoclonal Antibodies and Invasive Aspergillosis: Diagnostic and Therapeutic Perspectives

by Xihua Lian, Amy Scott-Thomas, John G. Lewis, Madhav Bhatia, Sean A. MacPherson, Yiming Zeng and Stephen T. Chambers

Int. J. Mol. Sci. 2022, 23(10), 5563; https://doi.org/10.3390/ijms23105563 - 16 May 2022

Cited by 11 | Viewed by 5715

Abstract

Invasive aspergillosis (IA) is a life-threatening fungal disease that causes high morbidity and mortality in immunosuppressed patients. Early and accurate diagnosis and treatment of IA remain challenging. Given the broad range of non-specific clinical symptoms and the shortcomings of current diagnostic techniques, most [...] Read more.

Invasive aspergillosis (IA) is a life-threatening fungal disease that causes high morbidity and mortality in immunosuppressed patients. Early and accurate diagnosis and treatment of IA remain challenging. Given the broad range of non-specific clinical symptoms and the shortcomings of current diagnostic techniques, most patients are either diagnosed as “possible” or “probable” cases but not “proven”. Moreover, because of the lack of sensitive and specific tests, many high-risk patients receive an empirical therapy or a prolonged treatment of high-priced antifungal agents, leading to unnecessary adverse effects and a high risk of drug resistance. More precise diagnostic techniques alongside a targeted antifungal treatment are fundamental requirements for reducing the morbidity and mortality of IA. Monoclonal antibodies (mAbs) with high specificity in targeting the corresponding antigen(s) may have the potential to improve diagnostic tests and form the basis for novel IA treatments. This review summarizes the up-to-date application of mAb-based approaches in assisting IA diagnosis and therapy. Full article

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11 pages, 3100 KiB

Open AccessArticle

Spatiotemporal Gene Expression Regions along the Anterior–Posterior Axis in Mouse Embryos before and after Palatal Elevation

by Arata Nagasaka, Koji Sakiyama, Yasuhiko Bando, Masahito Yamamoto, Shinichi Abe and Osamu Amano

Int. J. Mol. Sci. 2022, 23(9), 5160; https://doi.org/10.3390/ijms23095160 - 5 May 2022

Cited by 1 | Viewed by 2013

Abstract

The mammalian secondary palate is formed through complex developmental processes: growth, elevation, and fusion. Although it is known that the palatal elevation pattern changes along the anterior–posterior axis, it is unclear what molecules are expressed and whether their locations change before and after [...] Read more.

The mammalian secondary palate is formed through complex developmental processes: growth, elevation, and fusion. Although it is known that the palatal elevation pattern changes along the anterior–posterior axis, it is unclear what molecules are expressed and whether their locations change before and after elevation. We examined the expression regions of molecules associated with palatal shelf elevation (Pax9, Osr2, and Tgfβ3) and tissue deformation (F-actin, E-cadherin, and Ki67) using immunohistochemistry and RT–PCR in mouse embryos at E13.5 (before elevation) and E14.5 (after elevation). Pax9 was expressed at significantly higher levels in the lingual/nasal region in the anterior and middle parts, as well as in the buccal/oral region in the posterior part at E13.5. At E14.5, Pax9 was expressed at significantly higher levels in both the lingual/nasal and buccal/oral regions in the anterior and middle parts and the buccal/oral regions in the posterior part. Osr2 was expressed at significantly higher levels in the buccal/oral region in all parts at E13.5 and was more strongly expressed at E13.5 than at E14.5 in all regions. No spatiotemporal changes were found in the other molecules. These results suggested that Pax9 and Osr2 are critical molecules leading to differences in the elevation pattern in palatogenesis. Full article

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20 pages, 4881 KiB

Open AccessArticle

Transcriptomic Profiling of Peripheral Edge of Lesions to Elucidate the Pathogenesis of Psoriasis Vulgaris

by Suphagan Boonpethkaew, Jitlada Meephansan, Onjira Jumlongpim, Pattarin Tangtanatakul, Wipasiri Soonthornchai, Jongkonnee Wongpiyabovorn, Ratchanee Vipanurat and Mayumi Komine

Int. J. Mol. Sci. 2022, 23(9), 4983; https://doi.org/10.3390/ijms23094983 - 30 Apr 2022

Cited by 8 | Viewed by 4004

Abstract

Elucidating transcriptome in the peripheral edge of the lesional (PE) skin could provide a better understanding of the molecules or signalings that intensify inflammation in the PE skin. Full-thickness biopsies of PE skin and uninvolved (UN) skin were obtained from psoriasis patients for [...] Read more.

Elucidating transcriptome in the peripheral edge of the lesional (PE) skin could provide a better understanding of the molecules or signalings that intensify inflammation in the PE skin. Full-thickness biopsies of PE skin and uninvolved (UN) skin were obtained from psoriasis patients for RNA-seq. Several potential differentially expressed genes (DEGs) in the PE skin compared to those in the UN skin were identified. These DEGs enhanced functions such as angiogenesis, growth of epithelial tissue, chemotaxis and homing of cells, growth of connective tissues, and degranulation of myeloid cells beneath the PE skin. Moreover, the canonical pathways of IL-17A, IL-6, and IL-22 signaling were enriched by the DEGs. Finally, we proposed that inflammation in the PE skin might be driven by the IL-36/TLR9 axis or IL-6/Th17 axis and potentiated by IL-36α, IL-36γ, IL-17C, IL-8, S100A7, S100A8, S100A9, S100A15, SERPINB4, and hBD-2. Along with IL-36α, IL-17C, and IκBζ, ROCK2 could be an equally important factor in the pathogenesis of psoriasis, which may involve self-sustaining circuits between innate and adaptive immune responses via regulation of IL-36α and IL-36γ expression. Our finding provides new insight into signaling pathways in PE skin, which could lead to the discovery of new psoriasis targets. Full article

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18 pages, 3275 KiB

Open AccessArticle

Low-Dose SARS-CoV-2 S-Trimer with an Emulsion Adjuvant Induced Th1-Biased Protective Immunity

by Hung-Chun Liao, Wan-Ling Wu, Chen-Yi Chiang, Min-Syuan Huang, Kuan-Yin Shen, Yu-Ling Huang, Suh-Chin Wu, Ching-Len Liao, Hsin-Wei Chen and Shih-Jen Liu

Int. J. Mol. Sci. 2022, 23(9), 4902; https://doi.org/10.3390/ijms23094902 - 28 Apr 2022

Cited by 10 | Viewed by 3053

Abstract

During the sustained COVID-19 pandemic, global mass vaccination to achieve herd immunity can prevent further viral spread and mutation. A protein subunit vaccine that is safe, effective, stable, has few storage restrictions, and involves a liable manufacturing process would be advantageous to distribute [...] Read more.

During the sustained COVID-19 pandemic, global mass vaccination to achieve herd immunity can prevent further viral spread and mutation. A protein subunit vaccine that is safe, effective, stable, has few storage restrictions, and involves a liable manufacturing process would be advantageous to distribute around the world. Here, we designed and produced a recombinant spike (S)-Trimer that is maintained in a prefusion state and exhibits a high ACE2 binding affinity. Rodents received different doses of S-Trimer (0.5, 5, or 20 μg) antigen formulated with aluminum hydroxide (Alum) or an emulsion-type adjuvant (SWE), or no adjuvant. After two vaccinations, the antibody response, T-cell responses, and number of follicular helper T-cells (Tfh) or germinal center (GC) B cells were assessed in mice; the protective efficacy was evaluated on a Syrian hamster infection model. The mouse studies demonstrated that adjuvating the S-Trimer with SWE induced a potent humoral immune response and Th1-biased cellular immune responses (in low dose) that were superior to those induced by Alum. In the Syrian hamster studies, when S-Trimer was adjuvanted with SWE, higher levels of neutralizing antibodies were induced against live SARS-CoV-2 from the original lineage and against the emergence of variants (Beta or Delta) with a slightly decreased potency. In addition, the SWE adjuvant demonstrated a dose-sparing effect; thus, a lower dose of S-Trimer as an antigen (0.5 μg) can induce comparable antisera and provide complete protection from viral infection. These data support the utility of SWE as an adjuvant to enhance the immunogenicity of the S-Trimer vaccine, which is feasible for further clinical testing. Full article

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15 pages, 2919 KiB

Open AccessArticle

Ostarine-Induced Myogenic Differentiation in C2C12, L6, and Rat Muscles

by Natalia Leciejewska, Paweł A. Kołodziejski, Maciej Sassek, Leszek Nogowski, Emilian Małek and Ewa Pruszyńska-Oszmałek

Int. J. Mol. Sci. 2022, 23(8), 4404; https://doi.org/10.3390/ijms23084404 - 15 Apr 2022

Cited by 5 | Viewed by 6454

Abstract

Ostarine (also known as enobosarm or Gtx-024) belongs to the selective androgen receptor modulators (SARMs). It is a substance with an aryl-propionamide structure, classified as a non-steroidal compound that is not subjected to the typical steroid transformations of aromatization and reduction by α5 [...] Read more.

Ostarine (also known as enobosarm or Gtx-024) belongs to the selective androgen receptor modulators (SARMs). It is a substance with an aryl-propionamide structure, classified as a non-steroidal compound that is not subjected to the typical steroid transformations of aromatization and reduction by α5 reductase. Despite ongoing research on ostarine, knowledge about it is still limited. Earlier studies indicated that ostarine may affect the metabolism of muscle tissue, but this mechanism has not been yet described. We aimed to investigate the effect of ostarine on the differentiation and metabolism of muscle. Using C2C12 and L6 cells, as well as muscles obtained from rats administered ostarine, we showed that ostarine stimulates C2C12 and L6 proliferation and cell viability and that this effect is mediated by androgen receptor (AR) and ERK1/2 kinase activation (p < 0.01). We also found that ostarine stimulates muscle cell differentiation by increasing myogenin, MyoD, and MyH expression in both types of cells (p < 0.01). Moreover, pharmacological blocking of AR inhibits the stimulatory effect of ostarine. We further demonstrated that 30 days of ostarine administration increases myogenin, MyoD, and MyH expression, as well as muscle mass, in rats (p < 0.01). Based on our research, we conclude that ostarine stimulates muscle tissue proliferation and differentiation via the androgen receptor. Full article

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17 pages, 3974 KiB

Open AccessArticle

The Tumor Microenvironment Drives Intrahepatic Cholangiocarcinoma Progression

by Serena Mancarella, Grazia Serino, Sergio Coletta, Raffaele Armentano, Francesco Dituri, Francesco Ardito, Andrea Ruzzenente, Isabel Fabregat and Gianluigi Giannelli

Int. J. Mol. Sci. 2022, 23(8), 4187; https://doi.org/10.3390/ijms23084187 - 10 Apr 2022

Cited by 8 | Viewed by 2721

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with limited therapeutic options and short overall survival. iCCA is characterized by a strong desmoplastic reaction in the surrounding ecosystem that likely affects tumoral progression. Overexpression of the Notch pathway is implicated in iCCA development [...] Read more.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with limited therapeutic options and short overall survival. iCCA is characterized by a strong desmoplastic reaction in the surrounding ecosystem that likely affects tumoral progression. Overexpression of the Notch pathway is implicated in iCCA development and progression. Our aim was to investigate the effectiveness of Crenigacestat, a selective inhibitor of NOTCH1 signaling, against the cross-talk between cancer cells and the surrounding ecosystem in an in vivo HuCCT1-xenograft model. In the present study, a transcriptomic analysis approach, validated by Western blotting and qRT-PCR on iCCA tumor masses treated with Crenigacestat, was used to study the molecular pathways responsive to drug treatment. Our results indicate that Crenigacestat significantly inhibited NOTCH1 and HES1, whereas tumor progression was not affected. In addition, the drug triggered a strong immune response and blocked neovascularization in the tumor ecosystem of the HuCCT1-xenograft model without affecting the occurrence of fibrotic reactions. Therefore, although these data need further investigation, our observations confirm that Crenigacestat selectively targets NOTCH1 and that the desmoplastic response in iCCA likely plays a key role in both drug effectiveness and tumor progression. Full article

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29 pages, 794 KiB

Open AccessReview

Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects

by Kamil Kośmider, Katarzyna Karska, Agata Kozakiewicz, Monika Lejman and Joanna Zawitkowska

Int. J. Mol. Sci. 2022, 23(7), 3795; https://doi.org/10.3390/ijms23073795 - 30 Mar 2022

Cited by 9 | Viewed by 5605

Abstract

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Despite the enormous progress in ALL therapy, resulting in achieving a 5-year survival rate of up to 90%, the ambitious goal of reaching a 100% survival rate is still being pursued. A [...] Read more.

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Despite the enormous progress in ALL therapy, resulting in achieving a 5-year survival rate of up to 90%, the ambitious goal of reaching a 100% survival rate is still being pursued. A typical ALL treatment includes three phases: remission induction and consolidation and maintenance, preceded by a prednisone prephase. Poor prednisone response (PPR) is defined as the presence of ≥1.0 × 10⁹ blasts/L in the peripheral blood on day eight of therapy and results in significantly frequent relapses and worse outcomes. Hence, identifying risk factors of steroid resistance and finding methods of overcoming that resistance may significantly improve patients’ outcomes. A mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway seems to be a particularly attractive target, as its activation leads to steroid resistance via a phosphorylating Bcl-2-interacting mediator of cell death (BIM), which is crucial in the steroid-induced cell death. Several mutations causing activation of MAPK-ERK were discovered, notably the interleukin-7 receptor (IL-7R) pathway mutations in T-cell ALL and rat sarcoma virus (Ras) pathway mutations in precursor B-cell ALL. MAPK-ERK pathway inhibitors were demonstrated to enhance the results of dexamethasone therapy in preclinical ALL studies. This report summarizes steroids’ mechanism of action, resistance to treatment, and prospects of steroids therapy in pediatric ALL. Full article

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16 pages, 4449 KiB

Open AccessArticle

ELK3 Controls Gastric Cancer Cell Migration and Invasion by Regulating ECM Remodeling-Related Genes

by Minwook Lee, Hyeon-Ju Cho, Kyung-Soon Park and Hae-Yun Jung

Int. J. Mol. Sci. 2022, 23(7), 3709; https://doi.org/10.3390/ijms23073709 - 28 Mar 2022

Cited by 21 | Viewed by 3215

Abstract

Current therapeutic strategies for gastric cancer, including surgery and chemotherapy improve patient survival; however, the survival rate of patients with metastatic gastric cancer is very low. The molecular mechanisms underlying the dissemination of gastric cancer cells to distant organs are currently unknown. Here, [...] Read more.

Current therapeutic strategies for gastric cancer, including surgery and chemotherapy improve patient survival; however, the survival rate of patients with metastatic gastric cancer is very low. The molecular mechanisms underlying the dissemination of gastric cancer cells to distant organs are currently unknown. Here, we demonstrate that the E26 transformation-specific (ETS) transcription factor ELK3 (ELK3) gene is required for the migration and invasion of gastric cancer cells. The ELK3 gene modulates the expression of extracellular matrix (ECM) remodeling-related genes, such as bone morphogenetic protein (BMP1), lysyl oxidase like 2 (LOXL2), Snail family transcriptional repressor 1 (SNAI1), serpin family F member 1 (SERPINF1), decorin (DCN), and nidogen 1 (NID1) to facilitate cancer cell dissemination. Our in silico analyses indicated that ELK3 expression was positively associated with these ECM remodeling-related genes in gastric cancer cells and patient samples. The high expressions of ELK3 and other ECM remodeling-related genes were also closely associated with a worse prognosis of patients with gastric cancer. Collectively, these findings suggest that ELK3 acts as an important regulator of gastric cancer cell dissemination by regulating ECM remodeling. Full article

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23 pages, 13298 KiB

Open AccessArticle

Heme Oxygenase-1 Has a Greater Effect on Melanoma Stem Cell Properties Than the Expression of Melanoma-Initiating Cell Markers

by Anna Kusienicka, Karolina Bukowska-Strakova, Maciej Cieśla, Witold Norbert Nowak, Iwona Bronisz-Budzyńska, Agnieszka Seretny, Monika Żukowska, Mateusz Jeż, Rościsław Krutyhołowa, Hevidar Taha, Neli Kachamakova-Trojanowska, Halina Waś, Claudine Kieda and Alicja Józkowicz

Int. J. Mol. Sci. 2022, 23(7), 3596; https://doi.org/10.3390/ijms23073596 - 25 Mar 2022

Cited by 9 | Viewed by 3181

Abstract

Melanoma-initiating cells (MICs) contribute to the tumorigenicity and heterogeneity of melanoma. MICs are identified by surface and functional markers and have been shown to display cancer stem cell (CSC) properties. However, the existence of MICs that follow the hierarchical CSC model has been [...] Read more.

Melanoma-initiating cells (MICs) contribute to the tumorigenicity and heterogeneity of melanoma. MICs are identified by surface and functional markers and have been shown to display cancer stem cell (CSC) properties. However, the existence of MICs that follow the hierarchical CSC model has been questioned by studies showing that single unselected melanoma cells are highly tumorigenic in xenotransplantation assays. Herein, we characterize cells expressing MIC markers (CD20, CD24, CD133, Sca-1, ABCB1, ABCB5, ALDH^high) in the B16-F10 murine melanoma cell line. We use flow cytometric phenotyping, single-cell sorting followed by in vitro clonogenic assays, and syngeneic in vivo serial transplantation assays to demonstrate that the expression of MIC markers does not select CSC-like cells in this cell line. Previously, our group showed that heme-degrading enzyme heme oxygenase-1 (HO-1) can be upregulated in melanoma and increase its aggressiveness. Here, we show that HO-1 activity is important for non-adherent growth of melanoma and HO-1 overexpression enhances the vasculogenic mimicry potential, which can be considered protumorigenic activity. However, HO-1 overexpression decreases clone formation in vitro and serial tumor initiation in vivo. Thus, HO-1 plays a dual role in melanoma, improving the progression of growing tumors but reducing the risk of melanoma initiation. Full article

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13 pages, 1033 KiB

Open AccessReview

The Role of Endoplasmic Reticulum Stress and NLRP3 Inflammasome in Liver Disorders

by Xueqin Lu, Haitao Huang, Xiaodi Fu, Chaoran Chen, Huiyang Liu, Honggang Wang and Dongdong Wu

Int. J. Mol. Sci. 2022, 23(7), 3528; https://doi.org/10.3390/ijms23073528 - 24 Mar 2022

Cited by 14 | Viewed by 3852

Abstract

The endoplasmic reticulum (ER) is a key organelle responsible for the synthesis, modification, folding and assembly of proteins; calcium storage; and lipid synthesis. When ER homeostatic balance is disrupted by a variety of physiological and pathological factors—such as glucose deficiency, environmental toxins, Ca [...] Read more.

The endoplasmic reticulum (ER) is a key organelle responsible for the synthesis, modification, folding and assembly of proteins; calcium storage; and lipid synthesis. When ER homeostatic balance is disrupted by a variety of physiological and pathological factors—such as glucose deficiency, environmental toxins, Ca²⁺ level changes, etc.—ER stress can be induced. Abnormal ER stress can be involved in many diseases. NOD-like receptor family pyrin domain-containing 3 (NLRP3), an intracellular receptor, can perceive internal and external stimuli. It binds to apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 to assemble into a protein complex called the NLRP3 inflammasome. Evidence indicates that ER stress and the NLRP3 inflammasome participate in many pathological processes; however, the exact mechanism remains to be understood. In this review, we summarized the role of ER stress and the NLRP3 inflammasome in liver disorders and analyzed the mechanisms, to provide references for future related research. Full article

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22 pages, 4017 KiB

Open AccessArticle

Inhaled Placental Mesenchymal Stromal Cell Secretome from Two- and Three-Dimensional Cell Cultures Promotes Survival and Regeneration in Acute Lung Injury Model in Mice

by Vasily A. Kudinov, Rafael I. Artyushev, Irina M. Zurina, Elena S. Zorina, Roman D. Lapshin, Ludmila B. Snopova, Irina V. Mukhina and Irina N. Saburina

Int. J. Mol. Sci. 2022, 23(7), 3417; https://doi.org/10.3390/ijms23073417 - 22 Mar 2022

Cited by 9 | Viewed by 3787

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is a common clinical problem, leading to significant morbidity and mortality, and no effective pharmacotherapy exists. The problem of ARDS causing mortality became more apparent during the COVID-19 pandemic. Biotherapeutic products containing multipotent [...] Read more.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is a common clinical problem, leading to significant morbidity and mortality, and no effective pharmacotherapy exists. The problem of ARDS causing mortality became more apparent during the COVID-19 pandemic. Biotherapeutic products containing multipotent mesenchymal stromal cell (MMSC) secretome may provide a new therapeutic paradigm for human healthcare due to their immunomodulating and regenerative abilities. The content and regenerative capacity of the secretome depends on cell origin and type of cultivation (two- or three-dimensional (2D/3D)). In this study, we investigated the proteomic profile of the secretome from 2D- and 3D-cultured placental MMSC and lung fibroblasts (LFBs) and the effect of inhalation of freeze-dried secretome on survival, lung inflammation, lung tissue regeneration, fibrin deposition in a lethal ALI model in mice. We found that three inhaled administrations of freeze-dried secretome from 2D- and 3D-cultured placental MMSC and LFB protected mice from death, restored the histological structure of damaged lungs, and decreased fibrin deposition. At the same time, 3D MMSC secretome exhibited a more pronounced trend in lung recovery than 2D MMSC and LFB-derived secretome in some measures. Taking together, these studies show that inhalation of cell secretome may also be considered as a potential therapy for the management of ARDS in patients suffering from severe pneumonia, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, their effectiveness requires further investigation. Full article

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13 pages, 44800 KiB

Open AccessArticle

Alteration of Oral and Perioral Soft Tissue in Mice following Incisor Tooth Extraction

by Takahiro Takagi, Masahito Yamamoto, Aki Sugano, Chiemi Kanehira, Kei Kitamura, Masateru Katayama, Katsuhiko Sakai, Masaki Sato and Shinichi Abe

Int. J. Mol. Sci. 2022, 23(6), 2987; https://doi.org/10.3390/ijms23062987 - 10 Mar 2022

Cited by 4 | Viewed by 2944

Abstract

Oral and perioral soft tissues cooperate with other oral and pharyngeal organs to facilitate mastication and swallowing. It is essential for these tissues to maintain their morphology for efficient function. Recently, it was reported that the morphology of oral and perioral soft tissue [...] Read more.

Oral and perioral soft tissues cooperate with other oral and pharyngeal organs to facilitate mastication and swallowing. It is essential for these tissues to maintain their morphology for efficient function. Recently, it was reported that the morphology of oral and perioral soft tissue can be altered by aging or orthodontic treatment. However, it remains unclear whether tooth loss can alter these tissues’ morphology. This study examined whether tooth loss could alter lip morphology. First, an analysis of human anatomy suggested that tooth loss altered lip morphology. Next, a murine model of tooth loss was established by extracting an incisor; micro-computed tomography revealed that a new bone replaced the extraction socket. Body weight was significantly lower in the tooth loss (UH) group than in the non-extraction control (NH) group. The upper lip showed a greater degree of morphological variation in the UH group. Proteomic analysis and immunohistochemical staining of the upper lip illustrated that S100A8/9 expression was higher in the UH group, suggesting that tooth loss induced lip inflammation. Finally, soft-diet feeding improved lip deformity associated with tooth loss, but not inflammation. Therefore, soft-diet feeding is essential for preventing lip morphological changes after tooth loss. Full article

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21 pages, 4623 KiB

Open AccessArticle

Sodium-Iodate Injection Can Replicate Retinal Degenerative Disease Stages in Pigmented Mice and Rats: Non-Invasive Follow-Up Using OCT and ERG

by Céline Koster, Koen T. van den Hurk, Jacoline B. ten Brink, Colby F. Lewallen, Boris V. Stanzel, Kapil Bharti and Arthur A. Bergen

Int. J. Mol. Sci. 2022, 23(6), 2918; https://doi.org/10.3390/ijms23062918 - 8 Mar 2022

Cited by 13 | Viewed by 4473

Abstract

Purpose: The lack of suitable animal models for (dry) age-related macular degeneration (AMD) has hampered therapeutic research into the disease, so far. In this study, pigmented rats and mice were systematically injected with various doses of sodium iodate (SI). After injection, the retinal [...] Read more.

Purpose: The lack of suitable animal models for (dry) age-related macular degeneration (AMD) has hampered therapeutic research into the disease, so far. In this study, pigmented rats and mice were systematically injected with various doses of sodium iodate (SI). After injection, the retinal structure and visual function were non-invasively characterized over time to obtain in-depth data on the suitability of these models for studying experimental therapies for retinal degenerative diseases, such as dry AMD. Methods: SI was injected into the tail vein (i.v.) using a series of doses (0–70 mg/kg) in adolescent C57BL/6J mice and Brown Norway rats. The retinal structure and function were assessed non-invasively at baseline (day 1) and at several time points (1–3, 5, and 10-weeks) post-injection by scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and electroretinography (ERG). Results: After the SI injection, retinal degeneration in mice and rats yielded similar results. The lowest dose (10 mg/kg) resulted in non-detectable structural or functional effects. An injection with 20 mg/kg SI did not result in an evident retinal degeneration as judged from the OCT data. In contrast, the ERG responses were temporarily decreased but returned to baseline within two-weeks. Higher doses (30, 40, 50, and 70 mg/kg) resulted in moderate to severe structural RPE and retinal injury and decreased the ERG amplitudes, indicating visual impairment in both mice and rat strains. Conclusions: After the SI injections, we observed dose-dependent structural and functional pathological effects on the retinal pigment epithelium (RPE) and retina in the pigmented mouse and rat strains that were used in this study. Similar effects were observed in both species. In particular, a dose of 30 mg/kg seems to be suitable for future studies on developing experimental therapies. These relatively easily induced non-inherited models may serve as useful tools for evaluating novel therapies for RPE-related retinal degenerations, such as AMD. Full article

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11 pages, 2691 KiB

Open AccessArticle

SPATA18 Expression Predicts Favorable Clinical Outcome in Colorectal Cancer

by Akane Sugimura-Nagata, Akira Koshino, Kazuhiro Nagao, Aya Nagano, Masayuki Komura, Akane Ueki, Masahide Ebi, Naotaka Ogasawara, Toyonori Tsuzuki, Kenji Kasai, Satoru Takahashi, Kunio Kasugai and Shingo Inaguma

Int. J. Mol. Sci. 2022, 23(5), 2753; https://doi.org/10.3390/ijms23052753 - 2 Mar 2022

Cited by 5 | Viewed by 2466

Abstract

Dysregulation of mitochondrial quality control has been reported to be associated with cancer and degenerative diseases. SPATA18 (spermatogenesis-associated 18, also known as Mieap) encodes a p53-inducible protein that can induce lysosome-like organelles within mitochondria that eliminate oxidized mitochondrial proteins and has tumor suppressor [...] Read more.

Dysregulation of mitochondrial quality control has been reported to be associated with cancer and degenerative diseases. SPATA18 (spermatogenesis-associated 18, also known as Mieap) encodes a p53-inducible protein that can induce lysosome-like organelles within mitochondria that eliminate oxidized mitochondrial proteins and has tumor suppressor functions in mitochondrial quality control. In the present study, 268 primary colorectal cancers (CRCs) were evaluated immunohistochemically for SPATA18 expression to assess its predictive utility and its association with cellular proliferation activity. Furthermore, the association with p53 immunoreactivity, a surrogate marker for TP53 mutation, was analyzed. Non-neoplastic colonic mucosa showed cytoplasmic SPATA18 expression. Seventy-two percent of the lesions (193/268) displayed high SPATA18 expression in the cytoplasm of CRC cells. Univariate analyses revealed significant associations between SPATA18 expression and tumor size (p < 0.0001), histological differentiation (p = 0.0017), and lymph node metastasis (p = 0.00039). The log-rank test revealed that patients with SPATA18-high CRCs had significantly better survival than SPATA18-low patients (p < 0.0001). Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio [HR] = 0.25), age < 70 years (HR = 0.50), and SPATA18-high (HR = 0.55) as potential favorable factors. Lymph node metastasis (HR = 1.98) and peritoneal metastasis (HR = 5.45) were cited as potential independent risk factors. Cellular proliferation activity was significantly higher in SPATA18-high tumors. However, no significant correlation was detected between SPATA18 expression and p53 immunoreactivity or KRAS/BRAF mutation status. On the basis of our observations, SPATA18 immunohistochemistry can be used in the prognostication of CRC patients. Full article

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14 pages, 2000 KiB

Open AccessArticle

Micro-Current Stimulation Suppresses Inflammatory Responses in Peptidoglycan-Treated Raw 264.7 Macrophages and Propionibacterium acnes-Induced Skin Inflammation via TLR2/NF-κB Signaling Pathway

by Hana Lee, Donghyun Hwang, Minjoo Lee, Jinho Lee, Seungkwan Cho, Tack-Joong Kim and Han Sung Kim

Int. J. Mol. Sci. 2022, 23(5), 2508; https://doi.org/10.3390/ijms23052508 - 24 Feb 2022

Cited by 12 | Viewed by 3749

Abstract

Acne is a common inflammatory disorder of the human skin and a multifactorial disease caused by the sebaceous gland and Propionibacterium acnes (P. acnes). This study aimed to evaluate the anti-inflammatory effect of micro-current stimulation (MC) on peptidoglycan (PGN)-treated raw 264.7 [...] Read more.

Acne is a common inflammatory disorder of the human skin and a multifactorial disease caused by the sebaceous gland and Propionibacterium acnes (P. acnes). This study aimed to evaluate the anti-inflammatory effect of micro-current stimulation (MC) on peptidoglycan (PGN)-treated raw 264.7 macrophages and P. acnes-induced skin inflammation. To specify the intensity with anti-inflammatory effects, nitric oxide (NO) production was compared according to various levels of MC. As the lowest NO production was shown at an intensity of 50 μA, subsequent experiments used this intensity. The changes of expression of the proteins related to TLR2/NF-κB signaling were examined by immunoblotting. Also, immunofluorescence analysis was performed for observing NF-κB p65 localization. All of the expression levels of proteins regarding TLR2/NF−κB signaling were decreased by the application of MC. Moreover, the application of MC to PGN−treated raw 264.7 cells showed a significant decrease in the amount of nuclear p65−protein. In the case of animal models with P. acnes−induced skin inflammation, various pro−inflammatory cytokines and mediators significantly decreased in MC−applied mice. In particular, the concentration of IL−1β in serum decreased, and the area of acne lesions, decreased from the histological analysis. We suggest for the first time that MC can be a novel treatment for acne. Full article

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20 pages, 12238 KiB

Open AccessArticle

Amyloid Beta Pathology Exacerbates Weight Loss and Brain Cytokine Responses following Low-Dose Lipopolysaccharide in Aged Female Tg2576 Mice

by Rachel C. Knopp, Kristen K. Baumann, Miranda L. Wilson, William A. Banks and Michelle A. Erickson

Int. J. Mol. Sci. 2022, 23(4), 2377; https://doi.org/10.3390/ijms23042377 - 21 Feb 2022

Cited by 10 | Viewed by 3021

Abstract

Systemic inflammation has been implicated in the progression of Alzheimer’s disease (AD); however, less is understood about how existing AD pathology contributes to adverse outcomes following acute inflammatory insults. In the present study, our goal was to determine how AD-associated amyloid beta (Aβ) [...] Read more.

Systemic inflammation has been implicated in the progression of Alzheimer’s disease (AD); however, less is understood about how existing AD pathology contributes to adverse outcomes following acute inflammatory insults. In the present study, our goal was to determine how AD-associated amyloid beta (Aβ) pathology influences the acute neuroinflammatory and behavioral responses to a moderate systemic inflammatory insult. We treated 16–18-month-old female Tg2576 (Tg) mice, which overproduce human Aβ and develop plaques, and age-matched wild-type (WT) littermate mice with an intraperitoneal injection of 0.33 mg/kg lipopolysaccharide (LPS) or saline. Mice were then evaluated over the next 28 h for sickness/depressive-like behaviors (food intake, weight loss, locomotion, and sucrose preference), systemic inflammation (serum amyloid A, SAA), blood-brain barrier (BBB) disruption, astrogliosis (glial fibrillary acidic protein/GFAP), Aβ, and cytokine levels in the brain. We found that LPS caused a larger reduction in body weight in Tg vs. WT mice, but that other behavioral responses to LPS did not differ by genotype. BBB disruption was not apparent in either genotype following LPS. Concentrations of the systemic inflammatory marker, SAA, in the blood and brain were significantly increased with LPS but did not significantly differ by genotype. GFAP was increased in Tg mice vs. WT but was not significantly affected by LPS in either genotype. Finally, LPS-induced increases of eight cytokines (IL-1β, IL-6, IL-12 (p40), IL-10, IL-17A, MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5) were found to be significantly higher in Tg mice vs. WT. In summary, our data show that Aβ pathology exacerbates the neuroinflammatory response to LPS and identifies cytokines that are selectively regulated by Aβ. The association of worse neuroinflammation with greater weight loss in Tg mice suggests that Aβ pathology could contribute to poor outcomes following a systemic inflammatory insult. Full article

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17 pages, 7368 KiB

Open AccessArticle

Association of Tim-3/Gal-9 Axis with NLRC4 Inflammasome in Glioma Malignancy: Tim-3/Gal-9 Induce the NLRC4 Inflammasome

by JeongMin Sim, JeongMan Park, Suwan Kim, Sojung Hwang, KyoungSu Sung, Jung-Eun Lee, SeungHo Yang, Kyunggi Cho, SungHwan Lee, Jong-Seok Moon, JuWon Ahn and Jaejoon Lim

Int. J. Mol. Sci. 2022, 23(4), 2028; https://doi.org/10.3390/ijms23042028 - 12 Feb 2022

Cited by 9 | Viewed by 3015

Abstract

Tim-3/Gal-9 and the NLRC4 inflammasome contribute to glioma progression. However, the underlying mechanisms involved are unclear. Here, we observed that Tim-3/Gal-9 expression increased with glioma malignancy and found that Tim-3/Gal-9 regulate NLRC4 inflammasome formation and activation. Tim-3/Gal-9 and NLRC4 inflammasome-related molecule expression levels [...] Read more.

Tim-3/Gal-9 and the NLRC4 inflammasome contribute to glioma progression. However, the underlying mechanisms involved are unclear. Here, we observed that Tim-3/Gal-9 expression increased with glioma malignancy and found that Tim-3/Gal-9 regulate NLRC4 inflammasome formation and activation. Tim-3/Gal-9 and NLRC4 inflammasome-related molecule expression levels increased with WHO glioma grade, and this association was correlated with low survival. We investigated NLRC4 inflammasome formation by genetically regulating Tim-3 and its ligand Gal-9. Tim-3/Gal-9 regulation was positively correlated with the NLRC4 inflammasome, NLRC4, and caspase-1 expression. Tim-3/Gal-9 did not trigger IL-1β secretion but were strongly positively correlated with caspase-1 activity as they induced programmed cell death in glioma cells. A protein–protein interaction analysis revealed that the FYN-JAK1-ZNF384 pathways are bridges in NLRC4 inflammasome regulation by Tim-3/Gal-9. The present study showed that Tim-3/Gal-9 are associated with poor prognosis in glioma patients and induce NLRC4 inflammasome formation and activation. We proposed that a Tim-3/Gal-9 blockade could be beneficial in glioma therapy as it would reduce the inflammatory microenvironment by downregulating the NLRC4 inflammasome. Full article

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16 pages, 983 KiB

Open AccessReview

New Insights on the Nuclear Functions and Targeting of FAK in Cancer

by Silvia Pomella, Matteo Cassandri, Maria Rita Braghini, Francesco Marampon, Anna Alisi and Rossella Rota

Int. J. Mol. Sci. 2022, 23(4), 1998; https://doi.org/10.3390/ijms23041998 - 11 Feb 2022

Cited by 20 | Viewed by 3674

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed and activated in both adult and pediatric cancers, where it plays important roles in the regulation of pathogenesis and progression of the malignant phenotype. FAK exerts its functions in cancer by two different [...] Read more.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed and activated in both adult and pediatric cancers, where it plays important roles in the regulation of pathogenesis and progression of the malignant phenotype. FAK exerts its functions in cancer by two different ways: a kinase activity in the cytoplasm, mainly dependent on the integrin signaling, and a scaffolding activity into the nucleus by networking with different gene expression regulators. For this reason, FAK has to be considered a target with high therapeutic values. Indeed, evidence suggests that FAK targeting could be effective, either alone or in combination, with other already available treatments. Here, we propose an overview of the novel insights about FAK’s structure and nuclear functions, with a special focus on the recent findings concerning the roles of this protein in cancer. Additionally, we provide a recent update on FAK inhibitors that are currently in clinical trials for patients with cancer, and discuss the challenge and future directions of drug-based anti-FAK targeted therapies. Full article

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18 pages, 346 KiB

Open AccessReview

Epigenetic Links between Microbiota and Gestational Diabetes

by Olimpia Mora-Janiszewska, Anna Faryniak-Zuzak and Dorota Darmochwał-Kolarz

Int. J. Mol. Sci. 2022, 23(3), 1831; https://doi.org/10.3390/ijms23031831 - 6 Feb 2022

Cited by 12 | Viewed by 3814

Abstract

Gestational diabetes mellitus (GDM) is considered a significant and increasing worldwide problem. The growing body of evidence on this topic has allowed us to point out that a hostile intrauterine environment in mothers with GDM via epigenetic mechanisms induces “diabetogenic” and “obesogenic” changes [...] Read more.

Gestational diabetes mellitus (GDM) is considered a significant and increasing worldwide problem. The growing body of evidence on this topic has allowed us to point out that a hostile intrauterine environment in mothers with GDM via epigenetic mechanisms induces “diabetogenic” and “obesogenic” changes in an offspring’s DNA. This sets a vicious intergenerational cycle of metabolic diseases in motion, gradually deteriorating the health of the human population. One of the most important participants of this process seems to be altered microbiota. There is a chance that the identification of specific epigenetic marks may provide a key for future diagnostic, prognostic and therapeutic solutions in the field of personalised medicine. Given the reversibility of most epigenetic changes, there is an opportunity to improve the long-term health of the human population. In this manuscript, we aim to summarise available data on epigenetic changes among women suffering from GDM and their progeny, in association with alterations in the microbiome. Full article

19 pages, 8996 KiB

Open AccessArticle

The Isoxazole Derivative of Usnic Acid Induces an ER Stress Response in Breast Cancer Cells That Leads to Paraptosis-like Cell Death

by Agnieszka Pyrczak-Felczykowska, Tristan A. Reekie, Marcin Jąkalski, Aleksandra Hać, Marcelina Malinowska, Anna Pawlik, Kamil Ryś, Beata Guzow-Krzemińska and Anna Herman-Antosiewicz

Int. J. Mol. Sci. 2022, 23(3), 1802; https://doi.org/10.3390/ijms23031802 - 4 Feb 2022

Cited by 19 | Viewed by 3119

Abstract

Derivatives of usnic acid (UA), a secondary metabolite from lichens, were synthesized to improve its anticancer activity and selectivity. Recently we reported the synthesis and activity of an UA isoxazole derivative, named 2b, against cancer cells of different origins. Herein, the molecular [...] Read more.

Derivatives of usnic acid (UA), a secondary metabolite from lichens, were synthesized to improve its anticancer activity and selectivity. Recently we reported the synthesis and activity of an UA isoxazole derivative, named 2b, against cancer cells of different origins. Herein, the molecular mechanisms underlying its activity and efficacy in vivo were tested. The viability of breast cancer or normal cells has been tested using an MTT assay. Cell and organelle morphology was analyzed using light, electron and fluorescence microscopy. Gene expression was evaluated by RNAseq and protein levels were evaluated by Western blotting. In vivo anticancer activity was evaluated in a mice xenograft model. We found that 2b induced massive vacuolization which originated from the endoplasmic reticulum (ER). ER stress markers were upregulated both at the mRNA and protein levels. ER stress was caused by the release of Ca²⁺ ions from the ER by IP3R channels which was mediated, at least partly, by phospholipase C (PLC)-synthetized 1,4,5-inositol triphosphate (IP3). ER stress led to cell death with features of apoptosis and paraptosis. When applied to nude mice with xenografted breast cancer cells, 2b stopped tumour growth. In mice treated with 2b, vacuolization was observed in tumour cells, but not in other organs. This study shows that the antiproliferative activity of 2b relates to the induction of ER stress in cancer, not in healthy, cells and it leads to breast cancer cell death in vitro and in vivo. Full article

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18 pages, 2846 KiB

Open AccessArticle

Magnesium Modified β-Tricalcium Phosphate Induces Cell Osteogenic Differentiation In Vitro and Bone Regeneration In Vivo

by Eisner Salamanca, Yu-Hwa Pan, Ying-Sui Sun, Hao-Wen Hsueh, Odontuya Dorj, Wan-Ling Yao, Jerry Chin-Yi Lin, Nai-Chia Teng, Ikki Watanabe, Shinichi Abe, Yi-Fan Wu and Wei-Jen Chang

Int. J. Mol. Sci. 2022, 23(3), 1717; https://doi.org/10.3390/ijms23031717 - 2 Feb 2022

Cited by 12 | Viewed by 3308

Abstract

In vitro, in vivo, and clinical studies have shown how the physicochemical and biological properties of β-tricalcium phosphate (β-TCP) work in bone regeneration. This study aimed to improve the properties of β-TCP by achieving optimum surface and bulk β-TCP chemical/physical properties through the [...] Read more.

In vitro, in vivo, and clinical studies have shown how the physicochemical and biological properties of β-tricalcium phosphate (β-TCP) work in bone regeneration. This study aimed to improve the properties of β-TCP by achieving optimum surface and bulk β-TCP chemical/physical properties through the hydrothermal addition of magnesium (Mg) and to later establish the biocompatibility of β-TCP/Mg for bone grafting and tissue engineering treatments. Multiple in vitro and in vivo analyses were used to complete β-TCP/Mg physicochemical and biological characterization. The addition of MgO brought about a modest rise in the number of β-TCP surface particles, indicating improvements in alkaline phosphatase (ALP) activity on day 21 (p < 0.05) and in the WST-1assay on all days (p < 0.05), with a corresponding increase in the upregulation of ALP and bone sialoprotein. SEM analyses stated that the surfaces of the β-TCP particles were not altered after the addition of Mg. Micro-CT and histomorphometric analysis from rabbit calvaria critical defects resulted in β-TCP/Mg managing to reform more new bone than the control defects and β-TCP control at 2, 6, and 8 weeks (* p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, and **** p ≤ 0.0001). The hydrothermal addition of MgO to the β-TCP surfaces ameliorated its biocompatibility without altering its surface roughness resulting from the elemental composition while enhancing cell viability and proliferation, inducing more bone regeneration by osteoconduction in vivo and osteoblastic differentiation in vitro. Full article

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11 pages, 516 KiB

Open AccessReview

Therapeutic Potential of Human Fetal Mesenchymal Stem Cells in Musculoskeletal Disorders: A Narrative Review

by Insun Song, Jongseop Rim, Jaemin Lee, Inseok Jang, Bosung Jung, Kisoo Kim and Soonchul Lee

Int. J. Mol. Sci. 2022, 23(3), 1439; https://doi.org/10.3390/ijms23031439 - 27 Jan 2022

Cited by 7 | Viewed by 2943

Abstract

Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for diverse diseases and injuries. The biological and clinical advantages of human fetal MSCs (hfMSCs) have recently been reported. In terms of promising therapeutic approaches for diverse diseases and injuries, hfMSCs have [...] Read more.

Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for diverse diseases and injuries. The biological and clinical advantages of human fetal MSCs (hfMSCs) have recently been reported. In terms of promising therapeutic approaches for diverse diseases and injuries, hfMSCs have gained prominence as healing tools for clinical therapies. Therefore, this review assesses not the only biological advantages of hfMSCs for healing human diseases and regeneration, but also the research evidence for the engraftment and immunomodulation of hfMSCs based on their sources and biological components. Of particular clinical relevance, the present review also suggests the potential therapeutic feasibilities of hfMSCs for musculoskeletal disorders, including osteoporosis, osteoarthritis, and osteogenesis imperfecta. Full article

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32 pages, 19327 KiB

Open AccessReview

Wnt and PI3K/Akt/mTOR Survival Pathways as Therapeutic Targets in Glioblastoma

by Amir Barzegar Behrooz, Zahra Talaie, Fatemeh Jusheghani, Marek J. Łos, Thomas Klonisch and Saeid Ghavami

Int. J. Mol. Sci. 2022, 23(3), 1353; https://doi.org/10.3390/ijms23031353 - 25 Jan 2022

Cited by 105 | Viewed by 9381

Abstract

Glioblastoma (GBM) is a devastating type of brain tumor, and current therapeutic treatments, including surgery, chemotherapy, and radiation, are palliative at best. The design of effective and targeted chemotherapeutic strategies for the treatment of GBM require a thorough analysis of specific signaling pathways [...] Read more.

Glioblastoma (GBM) is a devastating type of brain tumor, and current therapeutic treatments, including surgery, chemotherapy, and radiation, are palliative at best. The design of effective and targeted chemotherapeutic strategies for the treatment of GBM require a thorough analysis of specific signaling pathways to identify those serving as drivers of GBM progression and invasion. The Wnt/β-catenin and PI3K/Akt/mTOR (PAM) signaling pathways are key regulators of important biological functions that include cell proliferation, epithelial–mesenchymal transition (EMT), metabolism, and angiogenesis. Targeting specific regulatory components of the Wnt/β-catenin and PAM pathways has the potential to disrupt critical brain tumor cell functions to achieve critical advancements in alternative GBM treatment strategies to enhance the survival rate of GBM patients. In this review, we emphasize the importance of the Wnt/β-catenin and PAM pathways for GBM invasion into brain tissue and explore their potential as therapeutic targets. Full article

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12 pages, 4338 KiB

Open AccessArticle

Sp1 Plays a Key Role in Vasculogenic Mimicry of Human Prostate Cancer Cells

by Deok-Soo Han and Eun-Ok Lee

Int. J. Mol. Sci. 2022, 23(3), 1321; https://doi.org/10.3390/ijms23031321 - 25 Jan 2022

Cited by 11 | Viewed by 3299

Abstract

Sp1 transcription factor regulates genes involved in various phenomena of tumor progression. Vasculogenic mimicry (VM) is the alternative neovascularization by aggressive tumor cells. However, there is no evidence of the relationship between Sp1 and VM. This study investigated whether and how Sp1 plays [...] Read more.

Sp1 transcription factor regulates genes involved in various phenomena of tumor progression. Vasculogenic mimicry (VM) is the alternative neovascularization by aggressive tumor cells. However, there is no evidence of the relationship between Sp1 and VM. This study investigated whether and how Sp1 plays a crucial role in the process of VM in human prostate cancer (PCa) cell lines, PC-3 and DU145. A cell viability assay and three-dimensional culture VM tube formation assay were performed. Protein and mRNA expression levels were detected by Western blot and reverse transcriptase-polymerase chain reaction, respectively. The nuclear twist expression was observed by immunofluorescence assay. A co-immunoprecipitation assay was performed. Mithramycin A (MiA) and Sp1 siRNA significantly decreased serum-induced VM, whereas Sp1 overexpression caused a significant induction of VM. Serum-upregulated vascular endothelial cadherin (VE-cadherin) protein and mRNA expression levels were decreased after MiA treatment or Sp1 silencing. The protein expression and the nuclear localization of twist were increased by serum, which was effectively inhibited after MiA treatment or Sp1 silencing. The interaction between Sp1 and twist was reduced by MiA. On the contrary, Sp1 overexpression enhanced VE-cadherin and twist expressions. Serum phosphorylated AKT and raised matrix metalloproteinase-2 (MMP-2) and laminin subunit 5 gamma-2 (LAMC2) expressions. MiA or Sp1 silencing impaired these effects. However, Sp1 overexpression upregulated phosphor-AKT, MMP-2 and LAMC2 expressions. Serum-upregulated Sp1 was significantly reduced by an AKT inhibitor, wortmannin. These results demonstrate that Sp1 mediates VM formation through interacting with the twist/VE-cadherin/AKT pathway in human PCa cells. Full article

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15 pages, 976 KiB

Open AccessReview

p27, The Cell Cycle and Alzheimer´s Disease

by Ana García-Osta, Jinya Dong, María Jesús Moreno-Aliaga and Maria Javier Ramirez

Int. J. Mol. Sci. 2022, 23(3), 1211; https://doi.org/10.3390/ijms23031211 - 21 Jan 2022

Cited by 17 | Viewed by 10697

Abstract

The cell cycle consists of successive events that lead to the generation of new cells. The cell cycle is regulated by different cyclins, cyclin-dependent kinases (CDKs) and their inhibitors, such as p27^Kip1. At the nuclear level, p27^Kip1 has the ability [...] Read more.

The cell cycle consists of successive events that lead to the generation of new cells. The cell cycle is regulated by different cyclins, cyclin-dependent kinases (CDKs) and their inhibitors, such as p27^Kip1. At the nuclear level, p27^Kip1 has the ability to control the evolution of different phases of the cell cycle and oppose cell cycle progression by binding to CDKs. In the cytoplasm, diverse functions have been described for p27^Kip1, including microtubule remodeling, axonal transport and phagocytosis. In Alzheimer’s disease (AD), alterations to cycle events and a purported increase in neurogenesis have been described in the early disease process before significant pathological changes could be detected. However, most neurons cannot progress to complete their cell division and undergo apoptotic cell death. Increased levels of both the p27^Kip1 levels and phosphorylation status have been described in AD. Increased levels of Aβ42, tau hyperphosphorylation or even altered insulin signals could lead to alterations in p27^Kip1 post-transcriptional modifications, causing a disbalance between the levels and functions of p27^Kip1 in the cytoplasm and nucleus, thus inducing an aberrant cell cycle re-entry and alteration of extra cell cycle functions. Further studies are needed to completely understand the role of p27^Kip1 in AD and the therapeutic opportunities associated with the modulation of this target. Full article

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17 pages, 3636 KiB

Open AccessArticle

Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease

by Jiraporn Ousingsawat, Raquel Centeio, Inês Cabrita, Khaoula Talbi, Oliver Zimmer, Moritz Graf, Achim Göpferich, Rainer Schreiber and Karl Kunzelmann

Int. J. Mol. Sci. 2022, 23(3), 1085; https://doi.org/10.3390/ijms23031085 - 19 Jan 2022

Cited by 13 | Viewed by 3581

Abstract

Repurposing of the anthelminthic drug niclosamide was proposed as an effective treatment for inflammatory airway diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Niclosamide may also be effective for the treatment of viral respiratory infections, such as SARS-CoV-2, respiratory syncytial [...] Read more.

Repurposing of the anthelminthic drug niclosamide was proposed as an effective treatment for inflammatory airway diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Niclosamide may also be effective for the treatment of viral respiratory infections, such as SARS-CoV-2, respiratory syncytial virus, and influenza. While systemic application of niclosamide may lead to unwanted side effects, local administration via aerosol may circumvent these problems, particularly when the drug is encapsulated into small polyethylene glycol (PEG) hydrospheres. In the present study, we examined whether PEG-encapsulated niclosamide inhibits the production of mucus and affects the pro-inflammatory mediator CLCA1 in mouse airways in vivo, while effects on mucociliary clearance were assessed in excised mouse tracheas. The potential of encapsulated niclosamide to inhibit TMEM16A whole-cell Cl⁻ currents and intracellular Ca²⁺ signalling was assessed in airway epithelial cells in vitro. We achieved encapsulation of niclosamide in PEG-microspheres and PEG-nanospheres (Niclo-spheres). When applied to asthmatic mice via intratracheal instillation, Niclo-spheres strongly attenuated overproduction of mucus, inhibited secretion of the major proinflammatory mediator CLCA1, and improved mucociliary clearance in tracheas ex vivo. These effects were comparable for niclosamide encapsulated in PEG-nanospheres and PEG-microspheres. Niclo-spheres inhibited the Ca²⁺ activated Cl⁻ channel TMEM16A and attenuated mucus production in CFBE and Calu-3 human airway epithelial cells. Both inhibitory effects were explained by a pronounced inhibition of intracellular Ca²⁺ signals. The data indicate that poorly dissolvable compounds such as niclosamide can be encapsulated in PEG-microspheres/nanospheres and deposited locally on the airway epithelium as encapsulated drugs, which may be advantageous over systemic application. Full article

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20 pages, 1403 KiB

Open AccessReview

Development of the Ontogenetic Self-Regulation Clock

by Sari Goldstein Ferber, Aron Weller, Michal Ben-Shachar, Gil Klinger and Ronny Geva

Int. J. Mol. Sci. 2022, 23(2), 993; https://doi.org/10.3390/ijms23020993 - 17 Jan 2022

Cited by 3 | Viewed by 3445

Abstract

To date, there is no overarching proposition for the ontogenetic-neurobiological basis of self-regulation. This paper suggests that the balanced self-regulatory reaction of the fetus, newborn and infant is based on a complex mechanism starting from early brainstem development and continuing to progressive control [...] Read more.

To date, there is no overarching proposition for the ontogenetic-neurobiological basis of self-regulation. This paper suggests that the balanced self-regulatory reaction of the fetus, newborn and infant is based on a complex mechanism starting from early brainstem development and continuing to progressive control of the cortex over the brainstem. It is suggested that this balance occurs through the synchronous reactivity between the sympathetic and parasympathetic systems, both which originate from the brainstem. The paper presents an evidence-based approach in which molecular excitation-inhibition balance, interchanges between excitatory and inhibitory roles of neurotransmitters as well as cardiovascular and white matter development across gestational ages, are shown to create sympathetic-parasympathetic synchrony, including the postnatal development of electroencephalogram waves and vagal tone. These occur in developmental milestones detectable in the same time windows (sensitive periods of development) within a convergent systematic progress. This ontogenetic stepwise process is termed “the self-regulation clock” and suggest that this clock is located in the largest connection between the brainstem and the cortex, the corticospinal tract. This novel evidence-based new theory paves the way towards more accurate hypotheses and complex studies of self-regulation and its biological basis, as well as pointing to time windows for interventions in preterm infants. The paper also describes the developing indirect signaling between the suprachiasmatic nucleus and the corticospinal tract. Finally, the paper proposes novel hypotheses for molecular, structural and functional investigation of the “clock” circuitry, including its associations with other biological clocks. This complex circuitry is suggested to be responsible for the developing self-regulatory functions and their neurobehavioral correlates. Full article

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18 pages, 1605 KiB

Open AccessReview

Neuroinflammation: A Potential Risk for Dementia

by Md Afroz Ahmad, Ozaifa Kareem, Mohammad Khushtar, Md Akbar, Md Rafiul Haque, Ashif Iqubal, Md Faheem Haider, Faheem Hyder Pottoo, Fatima S. Abdulla, Mahia B. Al-Haidar and Noora Alhajri

Int. J. Mol. Sci. 2022, 23(2), 616; https://doi.org/10.3390/ijms23020616 - 6 Jan 2022

Cited by 49 | Viewed by 6984

Abstract

Dementia is a neurodegenerative condition that is considered a major factor contributing to cognitive decline that reduces independent function. Pathophysiological pathways are not well defined for neurodegenerative diseases such as dementia; however, published evidence has shown the role of numerous inflammatory processes in [...] Read more.

Dementia is a neurodegenerative condition that is considered a major factor contributing to cognitive decline that reduces independent function. Pathophysiological pathways are not well defined for neurodegenerative diseases such as dementia; however, published evidence has shown the role of numerous inflammatory processes in the brain contributing toward their pathology. Microglia of the central nervous system (CNS) are the principal components of the brain’s immune defence system and can detect harmful or external pathogens. When stimulated, the cells trigger neuroinflammatory responses by releasing proinflammatory chemokines, cytokines, reactive oxygen species, and nitrogen species in order to preserve the cell’s microenvironment. These proinflammatory markers include cytokines such as IL-1, IL-6, and TNFα chemokines such as CCR3 and CCL2 and CCR5. Microglial cells may produce a prolonged inflammatory response that, in some circumstances, is indicated in the promotion of neurodegenerative diseases. The present review is focused on the involvement of microglial cell activation throughout neurodegenerative conditions and the link between neuroinflammatory processes and dementia. Full article

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7 pages, 556 KiB

Open AccessArticle

Glycosylation of Receptor Binding Domain of SARS-CoV-2 S-Protein Influences on Binding to Immobilized DNA Aptamers

by Fedor Grabovenko, Liudmila Nikiforova, Bogdan Yanenko, Andrey Ulitin, Eugene Loktyushov, Timofei Zatsepin, Elena Zavyalova and Maria Zvereva

Int. J. Mol. Sci. 2022, 23(1), 557; https://doi.org/10.3390/ijms23010557 - 5 Jan 2022

Cited by 12 | Viewed by 2875

Abstract

Nucleic acid aptamers specific to S-protein and its receptor binding domain (RBD) of SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2) virions are of high interest as potential inhibitors of viral infection and recognizing elements in biosensors. Development of specific therapy and biosensors is [...] Read more.

Nucleic acid aptamers specific to S-protein and its receptor binding domain (RBD) of SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2) virions are of high interest as potential inhibitors of viral infection and recognizing elements in biosensors. Development of specific therapy and biosensors is complicated by an emergence of new viral strains bearing amino acid substitutions and probable differences in glycosylation sites. Here, we studied affinity of a set of aptamers to two Wuhan-type RBD of S-protein expressed in Chinese hamster ovary cell line and Pichia pastoris that differ in glycosylation patterns. The expression system for the RBD protein has significant effects, both on values of dissociation constants and relative efficacy of the aptamer binding. We propose glycosylation of the RBD as the main force for observed differences. Moreover, affinity of a several aptamers was affected by a site of biotinylation. Thus, the robustness of modified aptamers toward new virus variants should be carefully tested. Full article

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19 pages, 4275 KiB

Open AccessArticle

The Beneficial Effects of Combining Anti-Aβ Antibody NP106 and Curcumin Analog TML-6 on the Treatment of Alzheimer’s Disease in APP/PS1 Mice

by Ih-Jen Su, Chia-Yu Hsu, Santai Shen, Po-Kuan Chao, John Tsu-An Hsu, Jung-Tsung Hsueh, Jia-Jun Liang, Ying-Ting Hsu and Feng-Shiun Shie

Int. J. Mol. Sci. 2022, 23(1), 556; https://doi.org/10.3390/ijms23010556 - 5 Jan 2022

Cited by 6 | Viewed by 3343

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a multifactorial etiology. A multitarget treatment that modulates multifaceted biological functions might be more effective than a single-target approach. Here, the therapeutic efficacy of combination treatment using anti-Aβ antibody NP106 and curcumin analog TML-6 [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a multifactorial etiology. A multitarget treatment that modulates multifaceted biological functions might be more effective than a single-target approach. Here, the therapeutic efficacy of combination treatment using anti-Aβ antibody NP106 and curcumin analog TML-6 versus monotherapy was investigated in an APP/PS1 mouse model of AD. Our data demonstrate that both combination treatment and monotherapy attenuated brain Aβ and improved the nesting behavioral deficit to varying degrees. Importantly, the combination treatment group had the lowest Aβ levels, and insoluble forms of Aβ were reduced most effectively. The nesting performance of APP/PS1 mice receiving combination treatment was better than that of other APP/PS1 groups. Further findings indicate that enhanced microglial Aβ phagocytosis and lower levels of proinflammatory cytokines were concurrent with the aforementioned effects of NP106 in combination with TML-6. Intriguingly, combination treatment also normalized the gut microbiota of APP/PS1 mice to levels resembling the wild-type control. Taken together, combination treatment outperformed NP106 or TML-6 monotherapy in ameliorating Aβ pathology and the nesting behavioral deficit in APP/PS1 mice. The superior effect might result from a more potent modulation of microglial function, cerebral inflammation, and the gut microbiota. This innovative treatment paradigm confers a new avenue to develop more efficacious AD treatments. Full article

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20 pages, 6238 KiB

Open AccessArticle

Mast Cells Differentiated in Synovial Fluid and Resident in Osteophytes Exalt the Inflammatory Pathology of Osteoarthritis

by Priya Kulkarni, Abhay Harsulkar, Anne-Grete Märtson, Siim Suutre, Aare Märtson and Sulev Koks

Int. J. Mol. Sci. 2022, 23(1), 541; https://doi.org/10.3390/ijms23010541 - 4 Jan 2022

Cited by 12 | Viewed by 3777

Abstract

Introduction: Osteophytes are a prominent feature of osteoarthritis (OA) joints and one of the clinical hallmarks of the disease progression. Research on osteophytes is fragmentary and modes of its contribution to OA pathology are obscure. Aim: To elucidate the role of osteophytes in [...] Read more.

Introduction: Osteophytes are a prominent feature of osteoarthritis (OA) joints and one of the clinical hallmarks of the disease progression. Research on osteophytes is fragmentary and modes of its contribution to OA pathology are obscure. Aim: To elucidate the role of osteophytes in OA pathology from a perspective of molecular and cellular events. Methods: RNA-seq of fully grown osteophytes, collected from tibial plateau of six OA patients revealed patterns corresponding to active extracellular matrix re-modulation and prominent participation of mast cells. Presence of mast cells was further confirmed by immunohistochemistry, performed on the sections of the osteophytes using anti-tryptase alpha/beta-1 and anti-FC epsilon RI antibodies and the related key up-regulated genes were validated by qRT-PCR. To test the role of OA synovial fluid (SF) in mast cell maturation as proposed by the authors, hematopoietic stem cells (HSCs) and ThP1 cells were cultured in a media supplemented with 10% SF samples, obtained from various grades of OA patients and were monitored using specific cell surface markers by flow cytometry. Proteomics analysis of SF samples was performed to detect additional markers specific to mast cells and inflammation that drive the cell differentiation and maturation. Results: Transcriptomics of osteophytes revealed a significant upregulation of mast cells specific genes such as chymase 1 (CMA1; 5-fold) carboxypeptidase A3 (CPA3; 4-fold), MS4A2/FCERI (FCERI; 4.2-fold) and interleukin 1 receptor-like 1 (IL1RL1; 2.5-fold) indicating their prominent involvement. (In IHC, anti-tryptase alpha/beta-1 and anti- FC epsilon RI-stained active mast cells were seen populated in cartilage, subchondral bone, and trabecular bone.) Based on these outcomes and previous learnings, the authors claim a possibility of mast cells invasion into osteophytes is mediated by SF and present in vitro cell differentiation assay results, wherein ThP1 and HSCs showed differentiation into HLA-DR+/CD206+ and FCERI+ phenotype, respectively, after exposing them to medium containing 10% SF for 9 days. Proteomics analysis of these SF samples showed an accumulation of mast cell-specific inflammatory proteins. Conclusions: RNA-seq analysis followed by IHC study on osteophyte samples showed a population of mast cells resident in them and may further accentuate inflammatory pathology of OA. Besides subchondral bone, the authors propose an alternative passage of mast cells invasion in osteophytes, wherein OA SF was found to be necessary and sufficient for maturation of mast cell precursor into effector cells. Full article

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12 pages, 429 KiB

Open AccessReview

Flubendazole Plays an Important Anti-Tumor Role in Different Types of Cancers

by Chaoran Chen, Yueming Ding, Huiyang Liu, Mengyao Sun, Honggang Wang and Dongdong Wu

Int. J. Mol. Sci. 2022, 23(1), 519; https://doi.org/10.3390/ijms23010519 - 4 Jan 2022

Cited by 10 | Viewed by 8199

Abstract

Flubendazole, belonging to benzimidazole, is a broad-spectrum insect repellent and has been repurposed as a promising anticancer drug. In recent years, many studies have shown that flubendazole plays an anti-tumor role in different types of cancers, including breast cancer, melanoma, prostate cancer, colorectal [...] Read more.

Flubendazole, belonging to benzimidazole, is a broad-spectrum insect repellent and has been repurposed as a promising anticancer drug. In recent years, many studies have shown that flubendazole plays an anti-tumor role in different types of cancers, including breast cancer, melanoma, prostate cancer, colorectal cancer, and lung cancer. Although the anti-tumor mechanism of flubendazole has been studied, it has not been fully understood. In this review, we summarized the recent studies regarding the anti-tumor effects of flubendazole in different types of cancers and analyzed the related mechanisms, in order to provide the theoretical reference for further studies in the future. Full article

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15 pages, 40078 KiB

Open AccessArticle

Activated Protein C Protects against Murine Contact Dermatitis by Suppressing Protease-Activated Receptor 2

by Meilang Xue, Haiyan Lin, Ruilong Zhao, Callum Fryer, Lyn March and Christopher J. Jackson

Int. J. Mol. Sci. 2022, 23(1), 516; https://doi.org/10.3390/ijms23010516 - 3 Jan 2022

Cited by 7 | Viewed by 3453

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with excessive inflammation and defective skin barrier function. Activated protein C (APC) is a natural anticoagulant with anti-inflammatory and barrier protective functions. However, the effect of APC on AD and its engagement with [...] Read more.

Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with excessive inflammation and defective skin barrier function. Activated protein C (APC) is a natural anticoagulant with anti-inflammatory and barrier protective functions. However, the effect of APC on AD and its engagement with protease activated receptor (PAR)1 and PAR2 are unknown. Methods: Contact hypersensitivity (CHS), a model for human AD, was induced in PAR1 knockout (KO), PAR2KO and matched wild type (WT) mice using 2,4-dinitrofluorobenzene (DNFB). Recombinant human APC was administered into these mice as preventative or therapeutic treatment. The effect of APC and PAR1KO or PARKO on CHS was assessed via measurement of ear thickness, skin histologic changes, inflammatory cytokine levels, Th cell phenotypes and keratinocyte function. Results: Compared to WT, PAR2KO but not PAR1KO mice displayed less severe CHS when assessed by ear thickness; PAR1KO CHS skin had less mast cells, lower levels of IFN-γ, IL-4, IL-17 and IL-22, and higher levels of IL-1β, IL-6 and TGF-β1, whereas PAR2KO CHS skin only contained lower levels of IL-22 and IgE. Both PAR1KO and PAR2KO spleen cells had less Th1/Th17/Th22/Treg cells. In normal skin, PAR1 was present at the stratum granulosum and spinosum, whereas PAR2 at the upper layers of the epidermis. In CHS, however, the expression of PAR1 and PAR2 were increased and spread to the whole epidermis. In vitro, compared to WT cells, PAR1KO keratinocytes grew much slower, had a lower survival rate and higher para permeability, while PAR2KO cells grew faster, were resistant to apoptosis and para permeability. APC inhibited CHS as a therapeutic but not as a preventative treatment only in WT and PAR1KO mice. APC therapy reduced skin inflammation, suppressed epidermal PAR2 expression, promoted keratinocyte growth, survival, and barrier function in both WT and PAR1KO cells, but not in PAR2KO cells. Conclusions: APC therapy can mitigate CHS. Although APC acts through both PAR1 and PAR2 to regulate Th and mast cells, suppression of clinical disease in mice is achieved mainly via inhibition of PAR2 alone. Thus, APC may confer broad therapeutic benefits as a disease-modifying treatment for AD. Full article

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2021

Jump to: 2024, 2023, 2022

13 pages, 2560 KiB

Open AccessArticle

CCN2 Increases TGF-β Receptor Type II Expression in Vascular Smooth Muscle Cells: Essential Role of CCN2 in the TGF-β Pathway Regulation

by Antonio Tejera-Muñoz, Laura Marquez-Exposito, Lucía Tejedor-Santamaría, Sandra Rayego-Mateos, Macarena Orejudo, Beatriz Suarez-Álvarez, Carlos López-Larrea, Marta Ruíz-Ortega and Raúl R. Rodrigues-Díez

Int. J. Mol. Sci. 2022, 23(1), 375; https://doi.org/10.3390/ijms23010375 - 29 Dec 2021

Cited by 5 | Viewed by 2987

Abstract

The cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a mediator of the fibrotic responses induced by other factors including the transforming growth factor β (TGF-β). However, several studies have defined a direct role of CCN2 acting as a growth [...] Read more.

The cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a mediator of the fibrotic responses induced by other factors including the transforming growth factor β (TGF-β). However, several studies have defined a direct role of CCN2 acting as a growth factor inducing oxidative and proinflammatory responses. The presence of CCN2 and TGF-β together in the cellular context has been described as a requisite to induce a persistent fibrotic response, but the precise mechanisms implicated in this relation are not described yet. Considering the main role of TGF-β receptors (TβR) in the TGF-β pathway activation, our aim was to investigate the effects of CCN2 in the regulation of TβRI and TβRII levels in vascular smooth muscle cells (VSMCs). While no differences were observed in TβRI levels, an increase in TβRII expression at both gene and protein level were found 48 h after stimulation with the C-terminal fragment of CCN2 (CCN2(IV)). Cell pretreatment with a TβRI inhibitor did not modify TβRII increment induced by CCN2(VI), demonstrating a TGF-β-independent response. Secondly, CCN2(IV) rapidly activated the SMAD pathway in VSMCs, this being crucial in the upregulation of TβRII since the preincubation with an SMAD3 inhibitor prevented it. Similarly, pretreatment with the epidermal growth factor receptor (EGFR) inhibitor erlotinib abolished TβRII upregulation, indicating the participation of this receptor in the observed responses. Our findings suggest a direct role of CCN2 maintaining the TGF-β pathway activation by increasing TβRII expression in an EGFR-SMAD dependent manner activation. Full article

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11 pages, 245 KiB

Open AccessArticle

Classification of Amyloidosis by Model-Assisted Mass Spectrometry-Based Proteomics

by Nicolai Bjødstrup Palstrøm, Aleksandra M. Rojek, Hanne E. H. Møller, Charlotte Toftmann Hansen, Rune Matthiesen, Lars Melholt Rasmussen, Niels Abildgaard and Hans Christian Beck

Int. J. Mol. Sci. 2022, 23(1), 319; https://doi.org/10.3390/ijms23010319 - 28 Dec 2021

Cited by 18 | Viewed by 2419

Abstract

Amyloidosis is a rare disease caused by the misfolding and extracellular aggregation of proteins as insoluble fibrillary deposits localized either in specific organs or systemically throughout the body. The organ targeted and the disease progression and outcome is highly dependent on the specific [...] Read more.

Amyloidosis is a rare disease caused by the misfolding and extracellular aggregation of proteins as insoluble fibrillary deposits localized either in specific organs or systemically throughout the body. The organ targeted and the disease progression and outcome is highly dependent on the specific fibril-forming protein, and its accurate identification is essential to the choice of treatment. Mass spectrometry-based proteomics has become the method of choice for the identification of the amyloidogenic protein. Regrettably, this identification relies on manual and subjective interpretation of mass spectrometry data by an expert, which is undesirable and may bias diagnosis. To circumvent this, we developed a statistical model-assisted method for the unbiased identification of amyloid-containing biopsies and amyloidosis subtyping. Based on data from mass spectrometric analysis of amyloid-containing biopsies and corresponding controls. A Boruta method applied on a random forest classifier was applied to proteomics data obtained from the mass spectrometric analysis of 75 laser dissected Congo Red positive amyloid-containing biopsies and 78 Congo Red negative biopsies to identify novel “amyloid signature” proteins that included clusterin, fibulin-1, vitronectin complement component C9 and also three collagen proteins, as well as the well-known amyloid signature proteins apolipoprotein E, apolipoprotein A4, and serum amyloid P. A SVM learning algorithm were trained on the mass spectrometry data from the analysis of the 75 amyloid-containing biopsies and 78 amyloid-negative control biopsies. The trained algorithm performed superior in the discrimination of amyloid-containing biopsies from controls, with an accuracy of 1.0 when applied to a blinded mass spectrometry validation data set of 103 prospectively collected amyloid-containing biopsies. Moreover, our method successfully classified amyloidosis patients according to the subtype in 102 out of 103 blinded cases. Collectively, our model-assisted approach identified novel amyloid-associated proteins and demonstrated the use of mass spectrometry-based data in clinical diagnostics of disease by the unbiased and reliable model-assisted classification of amyloid deposits and of the specific amyloid subtype. Full article

23 pages, 761 KiB

Open AccessReview

Pathomechanisms of Vascular Depression in Older Adults

by Kurt A. Jellinger

Int. J. Mol. Sci. 2022, 23(1), 308; https://doi.org/10.3390/ijms23010308 - 28 Dec 2021

Cited by 41 | Viewed by 7786 | Correction

Abstract

Depression in older individuals is a common complex mood disorder with high comorbidity of both psychiatric and physical diseases, associated with high disability, cognitive decline, and increased mortality The factors predicting the risk of late-life depression (LLD) are incompletely understood. The reciprocal relationship [...] Read more.

Depression in older individuals is a common complex mood disorder with high comorbidity of both psychiatric and physical diseases, associated with high disability, cognitive decline, and increased mortality The factors predicting the risk of late-life depression (LLD) are incompletely understood. The reciprocal relationship of depressive disorder and age- and disease-related processes has generated pathogenic hypotheses and provided various treatment options. The heterogeneity of depression complicates research into the underlying pathogenic cascade, and factors involved in LLD considerably differ from those involved in early life depression. Evidence suggests that a variety of vascular mechanisms, in particular cerebral small vessel disease, generalized microvascular, and endothelial dysfunction, as well as metabolic risk factors, including diabetes, and inflammation that may induce subcortical white and gray matter lesions by compromising fronto–limbic and other important neuronal networks, may contribute to the development of LLD. The “vascular depression” hypothesis postulates that cerebrovascular disease or vascular risk factors can predispose, precipitate, and perpetuate geriatric depression syndromes, based on their comorbidity with cerebrovascular lesions and the frequent development of depression after stroke. Vascular burden is associated with cognitive deficits and a specific form of LLD, vascular depression, which is marked by decreased white matter integrity, executive dysfunction, functional disability, and poorer response to antidepressive therapy than major depressive disorder without vascular risk factors. Other pathogenic factors of LLD, such as neurodegeneration or neuroimmune regulatory dysmechanisms, are briefly discussed. Treatment planning should consider a modest response of LLD to antidepressants, while vascular and metabolic factors may provide promising targets for its successful prevention and treatment. However, their effectiveness needs further investigation, and intervention studies are needed to assess which interventions are appropriate and effective in clinical practice. Full article

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31 pages, 1540 KiB

Open AccessReview

Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies

by Anamaria Jurcau and Aurel Simion

Int. J. Mol. Sci. 2022, 23(1), 14; https://doi.org/10.3390/ijms23010014 - 21 Dec 2021

Cited by 207 | Viewed by 11797

Abstract

Its increasing incidence has led stroke to be the second leading cause of death worldwide. Despite significant advances in recanalization strategies, patients are still at risk for ischemia/reperfusion injuries in this pathophysiology, in which neuroinflammation is significantly involved. Research has shown that in [...] Read more.

Its increasing incidence has led stroke to be the second leading cause of death worldwide. Despite significant advances in recanalization strategies, patients are still at risk for ischemia/reperfusion injuries in this pathophysiology, in which neuroinflammation is significantly involved. Research has shown that in the acute phase, neuroinflammatory cascades lead to apoptosis, disruption of the blood–brain barrier, cerebral edema, and hemorrhagic transformation, while in later stages, these pathways support tissue repair and functional recovery. The present review discusses the various cell types and the mechanisms through which neuroinflammation contributes to parenchymal injury and tissue repair, as well as therapeutic attempts made in vitro, in animal experiments, and in clinical trials which target neuroinflammation, highlighting future therapeutic perspectives. Full article

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16 pages, 4332 KiB

Open AccessArticle

Effect of Mineral-Balanced Deep-Sea Water on Kidney Function and Renal Oxidative Stress Markers in Rats Fed a High-Salt Diet

by So Min Jo, Jain Nam, Soo-yeon Park, Geonhee Park, Byeong Goo Kim, Gwi-Hwa Jeong, Byung Serk Hurh and Ji Yeon Kim

Int. J. Mol. Sci. 2021, 22(24), 13415; https://doi.org/10.3390/ijms222413415 - 14 Dec 2021

Cited by 4 | Viewed by 4863

Abstract

This study investigated the effect of mineral-balanced deep-sea water (DSW) on kidney health using an animal model of kidney injury due to a high-sodium diet. High magnesium/low sodium (HMLS) and high magnesium/high calcium (HMHC) DSW samples with different mineral contents were prepared. Sprague–Dawley [...] Read more.

This study investigated the effect of mineral-balanced deep-sea water (DSW) on kidney health using an animal model of kidney injury due to a high-sodium diet. High magnesium/low sodium (HMLS) and high magnesium/high calcium (HMHC) DSW samples with different mineral contents were prepared. Sprague–Dawley rats were fed an 8% sodium chloride (NaCl) diet for four weeks to induce kidney injury, and each group was supplied with purified water or mineral water. Kidney injury was observed in the NaCl group according to increased kidney injury markers and malondialdehydes, providing evidence of oxidative stress. However, the kidney injury was repaired by the intake of mineral-balanced DSW. It was confirmed that the HMLS and HMHC groups showed improved Na⁺ excretion through the urine. Kidney injury markers in urine decreased and upregulation of low-density lipoprotein receptor-related protein2 mRNA expression was observed in the HMLS and HMHC groups. In addition, superoxide dismutase activity was increased in the HMHC groups. The gene expression patterns of the RNA sequencing were similar between the CON and HMLS groups. These results suggest that DSW has beneficial effects on kidney health due to the balanced magnesium and calcium levels in models of kidney injury caused by excessive sodium intake. Full article

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17 pages, 2773 KiB

Open AccessArticle

The Secretome of Human Neonatal Mesenchymal Stem Cells Modulates Doxorubicin-Induced Cytotoxicity: Impact in Non-Tumor Cells

by Ana S. Serras, Sérgio P. Camões, Bernardo Antunes, Vera M. Costa, Flávio Dionísio, Volkan Yazar, Rui Vitorino, Fernando Remião, Matilde Castro, Nuno G. Oliveira and Joana P. Miranda

Int. J. Mol. Sci. 2021, 22(23), 13072; https://doi.org/10.3390/ijms222313072 - 3 Dec 2021

Cited by 10 | Viewed by 3917

Abstract

Doxorubicin (Dox) is one of the most widely used treatments for breast cancer, although limited by the well-documented cardiotoxicity and other off-target effects. Mesenchymal stem cell (MSC) secretome has shown immunomodulatory and regenerative properties, further potentiated under 3D conditions. This work aimed to [...] Read more.

Doxorubicin (Dox) is one of the most widely used treatments for breast cancer, although limited by the well-documented cardiotoxicity and other off-target effects. Mesenchymal stem cell (MSC) secretome has shown immunomodulatory and regenerative properties, further potentiated under 3D conditions. This work aimed to uncover the effect of the MSC-derived secretome from 3D (CM3D) or 2D (CM2D) cultures, in human malignant breast cells (MDA-MB-231), non-tumor breast epithelial cells (MCF10A) and differentiated AC16 cardiomyocytes, co-treated with Dox. A comprehensive proteomic analysis of CM3D/CM2D was also performed to unravel the underlying mechanism. CM3D/CM2D co-incubation with Dox revealed no significant differences in MDA-MB-231 viability when compared to Dox alone, whereas MCF10A and AC16 viability was consistently improved in Dox+CM3D-treated cells. Moreover, neither CM2D nor CM3D affected Dox anti-migratory and anti-invasive effects in MDA-MB-231. Notably, Ge-LC-MS/MS proteomic analysis revealed that CM3D displayed protective features that might be linked to the regulation of cell proliferation (CAPN1, CST1, LAMC2, RANBP3), migration (CCN3, MMP8, PDCD5), invasion (TIMP1/2), oxidative stress (COX6B1, AIFM1, CD9, GSR) and inflammation (CCN3, ANXA5, CDH13, GDF15). Overall, CM3D decreased Dox-induced cytotoxicity in non-tumor cells, without compromising Dox chemotherapeutic profile in malignant cells, suggesting its potential use as a chemotherapy adjuvant to reduce off-target side effects. Full article

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14 pages, 2011 KiB

Open AccessReview

Emerging Role of TCA Cycle-Related Enzymes in Human Diseases

by Woojin Kang, Miki Suzuki, Takako Saito and Kenji Miyado

Int. J. Mol. Sci. 2021, 22(23), 13057; https://doi.org/10.3390/ijms222313057 - 2 Dec 2021

Cited by 55 | Viewed by 11973

Abstract

The tricarboxylic acid (TCA) cycle is the main source of cellular energy and participates in many metabolic pathways in cells. Recent reports indicate that dysfunction of TCA cycle-related enzymes causes human diseases, such as neurometabolic disorders and tumors, have attracted increasing interest in [...] Read more.

The tricarboxylic acid (TCA) cycle is the main source of cellular energy and participates in many metabolic pathways in cells. Recent reports indicate that dysfunction of TCA cycle-related enzymes causes human diseases, such as neurometabolic disorders and tumors, have attracted increasing interest in their unexplained roles. The diseases which develop as a consequence of loss or dysfunction of TCA cycle-related enzymes are distinct, suggesting that each enzyme has a unique function. This review aims to provide a comprehensive overview of the relationship between each TCA cycle-related enzyme and human diseases. We also discuss their functions in the context of both mitochondrial and extra-mitochondrial (or cytoplasmic) enzymes. Full article

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12 pages, 538 KiB

Open AccessReview

Role and Perspectives of Inflammation and C-Reactive Protein (CRP) in Psychosis: An Economic and Widespread Tool for Assessing the Disease

by Irfan Ullah, Hashir Ali Awan, Alifiya Aamir, Mufaddal Najmuddin Diwan, Renato de Filippis, Sana Awan, Muhammad Irfan, Michele Fornaro, Antonio Ventriglio, Federica Vellante, Mauro Pettorruso, Giovanni Martinotti, Massimo Di Giannantonio and Domenico De Berardis

Int. J. Mol. Sci. 2021, 22(23), 13032; https://doi.org/10.3390/ijms222313032 - 2 Dec 2021

Cited by 18 | Viewed by 4178

Abstract

Schizophrenia is a major psychotic disorder affecting nearly 23.6 million people globally and greatly impacting the cognitive and social functioning of individuals. Multiple risk factors, including genetic, environmental, and epigenetic factors have been identified. However, the exact mechanism by which some factors aid [...] Read more.

Schizophrenia is a major psychotic disorder affecting nearly 23.6 million people globally and greatly impacting the cognitive and social functioning of individuals. Multiple risk factors, including genetic, environmental, and epigenetic factors have been identified. However, the exact mechanism by which some factors aid in the development of schizophrenia is still uncertain. Acute and/or long-standing inflammation has been implicated as both a cause and effect of schizophrenia. Heightened immune responses have been documented in large cohorts of individuals with schizophrenia. While not completely known, multiple hypotheses, such as disruption of the blood–brain barrier, alterations in the kynurenine/tryptophan pathway, and increased microglial activation, have been presented to correlate inflammation with schizophrenic symptoms. Measurement of C-reactive protein (CRP) is a commonly performed and inexpensive test on patients’ serum to determine levels of systemic inflammation in the body. Multiple studies have reported an elevated CRP level in different stages of schizophrenia, indicating its potential to be used as a viable biomarker in the diagnosis and monitoring of schizophrenia along with assessing treatment response to conventional and non-conventional treatment regimens. This review aims to evaluate the role of inflammation, in general, and CRP, in particular, in the pathogenesis of schizophrenia and its potential significance in diagnostic, therapeutic, and preventative approaches towards schizophrenia and psychosis. Full article

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14 pages, 3328 KiB

Open AccessArticle

PCSK9 Imperceptibly Affects Chemokine Receptor Expression In Vitro and In Vivo

by Sai Sahana Sundararaman, Linsey J. F. Peters, Sumra Nazir, Andrea Bonnin Marquez, Janneke E. Bouma, Soyolmaa Bayasgalan, Yvonne Döring and Emiel P. C. van der Vorst

Int. J. Mol. Sci. 2021, 22(23), 13026; https://doi.org/10.3390/ijms222313026 - 1 Dec 2021

Cited by 2 | Viewed by 2410

Abstract

Proprotein convertase subtilin/kexin type 9 (PCSK9) is a protease secreted mainly by hepatocytes and in lesser quantities by intestines, pancreas, and vascular cells. Over the years, this protease has gained importance in the field of cardiovascular biology due to its regulatory action on [...] Read more.

Proprotein convertase subtilin/kexin type 9 (PCSK9) is a protease secreted mainly by hepatocytes and in lesser quantities by intestines, pancreas, and vascular cells. Over the years, this protease has gained importance in the field of cardiovascular biology due to its regulatory action on the low-density lipoprotein receptor (LDLR). However, recently, it has also been shown that PCSK9 acts independent of LDLR to cause vascular inflammation and increase the severity of several cardiovascular disorders. We hypothesized that PCSK9 affects the expression of chemokine receptors, major mediators of inflammation, to influence cardiovascular health. However, using overexpression of PCSK9 in murine models in vivo and PCSK9 stimulation of myeloid and vascular cells in vitro did not reveal influences of PCSK9 on the expression of certain chemokine receptors that are known to be involved in the development and progression of atherosclerosis and vascular inflammation. Hence, we conclude that the inflammatory effects of PCSK9 are not associated with the here investigated chemokine receptors and additional research is required to elucidate which mechanisms mediate PCSK9 effects independent of LDLR. Full article

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15 pages, 3644 KiB

Open AccessArticle

AXIN2 Reduces the Survival of Porcine Induced Pluripotent Stem Cells (piPSCs)

by Rui Zhang, Shuai Yu, Qiaoyan Shen, Wenxu Zhao, Juqing Zhang, Xiaolong Wu, Zhenshuo Zhu, Xiaojie Wu, Na Li, Sha Peng and Jinlian Hua

Int. J. Mol. Sci. 2021, 22(23), 12954; https://doi.org/10.3390/ijms222312954 - 30 Nov 2021

Cited by 4 | Viewed by 2467

Abstract

The establishment of porcine pluripotent stem cells (piPSCs) is critical but remains challenging. All piPSCs are extremely sensitive to minor perturbations of culture conditions and signaling network. Inhibitors, such as CHIR99021 and XAV939 targeting the WNT signaling pathway, have been added in a [...] Read more.

The establishment of porcine pluripotent stem cells (piPSCs) is critical but remains challenging. All piPSCs are extremely sensitive to minor perturbations of culture conditions and signaling network. Inhibitors, such as CHIR99021 and XAV939 targeting the WNT signaling pathway, have been added in a culture medium to modify the cell regulatory network. However, potential side effects of inhibitors could confine the pluripotency and practicability of piPSCs. This study aimed to investigate the roles of AXIN, one component of the WNT pathway in piPSCs. Here, porcine AXIN1 and AXIN2 genes were knocked-down or overexpressed. Digital RNA-seq was performed to explore the mechanism of cell proliferation and apoptosis. We found that (1) overexpression of the porcine AXIN2 gene significantly reduced survival and negatively impacted the pluripotency of piPSCs, and (2) knockdown of AXIN2, a negative effector of the WNT signaling pathway, enhanced the expression of genes involved in cell cycle but reduced the expression of genes related to cell differentiation, death, and apoptosis. Full article

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13 pages, 2703 KiB

Open AccessArticle

Lentiviral-Induced Spinal Cord Gliomas in Rat Model

by Purva P. Nagarajan, Muhibullah S. Tora, Stewart G. Neill, Thais Federici, Pavlos Texakalidis, Anthony Donsante, Peter Canoll, Kecheng Lei and Nicholas M. Boulis

Int. J. Mol. Sci. 2021, 22(23), 12943; https://doi.org/10.3390/ijms222312943 - 30 Nov 2021

Cited by 5 | Viewed by 3036

Abstract

Intramedullary spinal cord tumors are a rare and understudied cancer with poor treatment options and prognosis. Our prior study used a combination of PDGF-B, HRAS, and p53 knockdown to induce the development of high-grade glioma in the spinal cords of minipigs. In this [...] Read more.

Intramedullary spinal cord tumors are a rare and understudied cancer with poor treatment options and prognosis. Our prior study used a combination of PDGF-B, HRAS, and p53 knockdown to induce the development of high-grade glioma in the spinal cords of minipigs. In this study, we evaluate the ability of each vector alone and combinations of vectors to produce high-grade spinal cord gliomas. Eight groups of rats (n = 8/group) underwent thoracolumbar laminectomy and injection of lentiviral vector in the lateral white matter of the spinal cord. Each group received a different combination of lentiviral vectors expressing PDGF-B, a constitutively active HRAS mutant, or shRNA targeting p53, or a control vector. All animals were monitored once per week for clinical deficits for 98 days. Tissues were harvested and analyzed using hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining. Rats injected with PDGF-B+HRAS+sh-p53 (triple cocktail) exhibited statistically significant declines in all behavioral measures (Basso Beattie Bresnahan scoring, Tarlov scoring, weight, and survival rate) over time when compared to the control. Histologically, all groups except the control and those injected with sh-p53 displayed the development of tumors at the injection site, although there were differences in the rate of tumor growth and the histopathological features of the lesions between groups. Examination of immunohistochemistry revealed rats receiving triple cocktail displayed the largest and most significant increase in the Ki67 proliferation index and GFAP positivity than any other group. PDGF-B+HRAS also displayed a significant increase in the Ki67 proliferation index. Rats receiving PDGF-B alone and PDGF-B+ sh-p53 displayed more a significant increase in SOX2-positive staining than in any other group. We found that different vector combinations produced differing high-grade glioma models in rodents. The combination of all three vectors produced a model of high-grade glioma more efficiently and aggressively with respect to behavioral, physiological, and histological characteristics than the rest of the vector combinations. Thus, the present rat model of spinal cord glioma may potentially be used to evaluate therapeutic strategies in the future. Full article

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15 pages, 1022 KiB

Open AccessReview

Ferroptosis: A Double-Edged Sword in Gastrointestinal Disease

by Chengfei Xu, Ziling Liu and Jiangwei Xiao

Int. J. Mol. Sci. 2021, 22(22), 12403; https://doi.org/10.3390/ijms222212403 - 17 Nov 2021

Cited by 41 | Viewed by 8152

Abstract

Ferroptosis is a novel form of regulated cell death (RCD) that is typically accompanied by iron accumulation and lipid peroxidation. In contrast to apoptosis, autophagy, and necroptosis, ferroptosis has unique biological processes and pathophysiological characteristics. Since it was first proposed in 2012, ferroptosis [...] Read more.

Ferroptosis is a novel form of regulated cell death (RCD) that is typically accompanied by iron accumulation and lipid peroxidation. In contrast to apoptosis, autophagy, and necroptosis, ferroptosis has unique biological processes and pathophysiological characteristics. Since it was first proposed in 2012, ferroptosis has attracted attention worldwide. Ferroptosis is involved in the progression of multiple diseases and could be a novel therapeutic target in the future. Recently, tremendous progress has been made regarding ferroptosis and gastrointestinal diseases, including intestinal ischemia/reperfusion (I/R) injury, inflammatory bowel disease (IBD), gastric cancer (GC), and colorectal cancer (CRC). In this review, we summarize the recent progress on ferroptosis and its interaction with gastrointestinal diseases. Understanding the role of ferroptosis in gastrointestinal disease pathogenesis could provide novel therapeutic targets for clinical treatment. Full article

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32 pages, 1281 KiB

Open AccessReview

Alveologenesis: What Governs Secondary Septa Formation

by Alexandra L. Rippa, Elena V. Alpeeva, Andrey V. Vasiliev and Ekaterina A. Vorotelyak

Int. J. Mol. Sci. 2021, 22(22), 12107; https://doi.org/10.3390/ijms222212107 - 9 Nov 2021

Cited by 18 | Viewed by 6746

Abstract

The simplification of alveoli leads to various lung pathologies such as bronchopulmonary dysplasia and emphysema. Deep insight into the process of emergence of the secondary septa during development and regeneration after pneumonectomy, and into the contribution of the drivers of alveologenesis and neo-alveolarization [...] Read more.

The simplification of alveoli leads to various lung pathologies such as bronchopulmonary dysplasia and emphysema. Deep insight into the process of emergence of the secondary septa during development and regeneration after pneumonectomy, and into the contribution of the drivers of alveologenesis and neo-alveolarization is required in an efficient search for therapeutic approaches. In this review, we describe the formation of the gas exchange units of the lung as a multifactorial process, which includes changes in the actomyosin cytoskeleton of alveocytes and myofibroblasts, elastogenesis, retinoic acid signaling, and the contribution of alveolar mesenchymal cells in secondary septation. Knowledge of the mechanistic context of alveologenesis remains incomplete. The characterization of the mechanisms that govern the emergence and depletion of αSMA will allow for an understanding of how the niche of fibroblasts is changing. Taking into account the intense studies that have been performed on the pool of lung mesenchymal cells, we present data on the typing of interstitial fibroblasts and their role in the formation and maintenance of alveoli. On the whole, when identifying cell subpopulations in lung mesenchyme, one has to consider the developmental context, the changing cellular functions, and the lability of gene signatures. Full article

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17 pages, 3089 KiB

Open AccessArticle

Affibody Functionalized Beads for the Highly Sensitive Detection of Cancer Cell-Derived Exosomes

by Nima Sayyadi, Sareh Zhand, Sajad Razavi Bazaz and Majid Ebrahimi Warkiani

Int. J. Mol. Sci. 2021, 22(21), 12014; https://doi.org/10.3390/ijms222112014 - 6 Nov 2021

Cited by 10 | Viewed by 4062

Abstract

Exosomes belong to the class of extracellular vesicles of endocytic origin, which are regarded as a promising source of cancer biomarkers in liquid biopsy. As a result, an accurate, sensitive, and specific quantification of these nano-sized particles is of significant importance. Affinity-based approaches [...] Read more.

Exosomes belong to the class of extracellular vesicles of endocytic origin, which are regarded as a promising source of cancer biomarkers in liquid biopsy. As a result, an accurate, sensitive, and specific quantification of these nano-sized particles is of significant importance. Affinity-based approaches are recognized as the most valuable technique for exosome isolation and characterization. Indeed, Affibody biomolecules are a type of protein scaffold engineered with small size and enjoy the features of high thermal stability, affinity, and specificity. While the utilization of antibodies, aptamers, and other biologically active substances for exosome detection has been reported widely, there are no reports describing Affibody molecules’ usage for exosome detection. In this study, for the first time, we have proposed a novel strategy of using Affibody functionalized microbeads (AffiBeads) for exosome detection with a high degree of efficiency. As a proof-of-concept, anti-EGFR-AffiBeads were fabricated and applied to capture and detect human lung A549 cancer cell-derived EGFR-positive exosomes using flow cytometry and fluorescent microscopy. Moreover, the capture efficiency of the AffiBeads were compared with its counterpart antibody. Our results showed that the Affibody probe had a detection limit of 15.6 ng exosomes per mL (~12 exosomes per AffiBead). The approach proposed in the current study can be used for sensitive detection of low expression level markers on tumor-derived exosomes, providing a basis for early-stage cancer diagnosis. Full article

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17 pages, 1738 KiB

Open AccessReview

Clinical and Molecular Biomarkers for Diagnosis and Staging of NAFLD

by Stefania Di Mauro, Alessandra Scamporrino, Agnese Filippello, Antonino Di Pino, Roberto Scicali, Roberta Malaguarnera, Francesco Purrello and Salvatore Piro

Int. J. Mol. Sci. 2021, 22(21), 11905; https://doi.org/10.3390/ijms222111905 - 2 Nov 2021

Cited by 46 | Viewed by 12103

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic pathology in industrialized countries, affecting about 25% of the general population. NAFLD is a benign condition, however, it could evolve toward more serious diseases, including non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and finally, hepatocellular [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic pathology in industrialized countries, affecting about 25% of the general population. NAFLD is a benign condition, however, it could evolve toward more serious diseases, including non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and finally, hepatocellular carcinoma (HCC). Liver biopsy is still the gold standard for NAFLD diagnosis. Due to the risks associated with liver biopsy and the impossibility to apply it on a large scale, it is now necessary to identify non-invasive biomarkers, which may reliably identify patients at higher risk of progression. Therefore, several lines of research have tried to address this issue by identifying novel biomarkers using omics approaches, including lipidomics, metabolomics and RNA molecules’ profiling. Thus, in this review, we firstly report the conventional biomarkers used in clinical practice for NAFL and NASH diagnosis as well as fibrosis staging, and secondly, we pay attention to novel biomarkers discovered through omics approaches with a particular focus on RNA biomarkers (microRNAs, long-noncoding RNAs), showing promising diagnostic performance for NAFL/NASH diagnosis and fibrosis staging. Full article

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20 pages, 1152 KiB

Open AccessReview

Sex-Specific MicroRNAs in Neurovascular Units in Ischemic Stroke

by Barend W. Florijn, Roel Bijkerk, Nyika D. Kruyt, Anton Jan van Zonneveld and Marieke J. H. Wermer

Int. J. Mol. Sci. 2021, 22(21), 11888; https://doi.org/10.3390/ijms222111888 - 2 Nov 2021

Cited by 10 | Viewed by 3280

Abstract

Accumulating evidence pinpoints sex differences in stroke incidence, etiology and outcome. Therefore, more understanding of the sex-specific mechanisms that lead to ischemic stroke and aggravation of secondary damage after stroke is needed. Our current mechanistic understanding of cerebral ischemia states that endothelial quiescence [...] Read more.

Accumulating evidence pinpoints sex differences in stroke incidence, etiology and outcome. Therefore, more understanding of the sex-specific mechanisms that lead to ischemic stroke and aggravation of secondary damage after stroke is needed. Our current mechanistic understanding of cerebral ischemia states that endothelial quiescence in neurovascular units (NVUs) is a major physiological parameter affecting the cellular response to neuron, astrocyte and vascular smooth muscle cell (VSMC) injury. Although a hallmark of the response to injury in these cells is transcriptional activation, noncoding RNAs such as microRNAs exhibit cell-type and context dependent regulation of gene expression at the post-transcriptional level. This review assesses whether sex-specific microRNA expression (either derived from X-chromosome loci following incomplete X-chromosome inactivation or regulated by estrogen in their biogenesis) in these cells controls NVU quiescence, and as such, could differentiate stroke pathophysiology in women compared to men. Their adverse expression was found to decrease tight junction affinity in endothelial cells and activate VSMC proliferation, while their regulation of paracrine astrocyte signaling was shown to neutralize sex-specific apoptotic pathways in neurons. As such, these microRNAs have cell type-specific functions in astrocytes and vascular cells which act on one another, thereby affecting the cell viability of neurons. Furthermore, these microRNAs display actual and potential clinical implications as diagnostic and prognostic biomarkers in ischemic stroke and in predicting therapeutic response to antiplatelet therapy. In conclusion, this review improves the current mechanistic understanding of the molecular mechanisms leading to ischemic stroke in women and highlights the clinical promise of sex-specific microRNAs as novel diagnostic biomarkers for (silent) ischemic stroke. Full article

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18 pages, 3721 KiB

Open AccessArticle

Fibulin 2 Is Hypermethylated and Suppresses Tumor Cell Proliferation through Inhibition of Cell Adhesion and Extracellular Matrix Genes in Non-Small Cell Lung Cancer

by Yunxia Ma, Miljana Nenkov, Desiree Charlotte Schröder, Mohamed Abubrig, Nikolaus Gassler and Yuan Chen

Int. J. Mol. Sci. 2021, 22(21), 11834; https://doi.org/10.3390/ijms222111834 - 31 Oct 2021

Cited by 13 | Viewed by 3124

Abstract

Fibulins (FBLNs), interacting with cell adhesion receptors and extracellular matrix (ECM) components, play multiple roles in ECM structures and tissue functions. Abnormal expression of FBLN2, one of the fibulin family members, contributes to tumor initiation and development. However, the function of FBLN2 in [...] Read more.

Fibulins (FBLNs), interacting with cell adhesion receptors and extracellular matrix (ECM) components, play multiple roles in ECM structures and tissue functions. Abnormal expression of FBLN2, one of the fibulin family members, contributes to tumor initiation and development. However, the function of FBLN2 in human non-small cell lung cancer (NSCLC) has not yet been elucidated. In this study, we found that FBLN2 was downregulated in 9 out of 11 lung cancer cell lines compared to normal bronchial epithelial cells, which was associated with DNA hypermethylation. Primary lung squamous cell carcinoma expressed significantly more FBLN2 protein compared to adenocarcinoma (p = 0.047). Ectopic expression of FBLN2 led to decreased cell proliferation, migration and invasion, accompanied by inactivated MAPK/ERK and AKT/mTOR pathways, while FBLN2 siRNA knockdown resulted in an opposite biological behaviour in NSCLC cells. Additionally, overexpression of FBLN2 led to dysregulation of cell adhesion molecules, ECM markers and a panel of lysate/exosome-derived-microRNAs, which are involved in cell adhesion and ECM remodelling. Taken together, our data indicate that FBLN2 is methylated and exerts a tumor suppressor function through modulation of MAPK/ERK and AKT pathways and regulation of cell adhesion and ECM genes. Moreover, FBLN2 might be a potential biomarker for the sub-classification of NSCLC. Full article

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13 pages, 1121 KiB

Open AccessArticle

Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice

by Elise L. Kessler, Jiong-Wei Wang, Bart Kok, Maike A. Brans, Angelique Nederlof, Leonie van Stuijvenberg, Chenyuan Huang, Aryan Vink, Fatih Arslan, Igor R. Efimov, Carolyn S. P. Lam, Marc A. Vos, Dominique P. V. de Kleijn, Magda S. C. Fontes and Toon A. B. van Veen

Int. J. Mol. Sci. 2021, 22(21), 11823; https://doi.org/10.3390/ijms222111823 - 30 Oct 2021

Cited by 6 | Viewed by 2705

Abstract

Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other [...] Read more.

Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other organs but were not investigated during cardiac dysfunction. We explored whether TLR2 deficiency leads to less adverse cardiac remodeling upon chronic pressure overload and whether TLR2 and TLR4 additively contribute to this. We subjected 35 male C57BL/6J mice (wildtype (WT) or TLR2 knockout (KO)) to sham or transverse aortic constriction (TAC) surgery. After 12 weeks, echocardiography and electrocardiography were performed, and hearts were extracted for molecular and histological analysis. TLR2 deficiency (n = 14) was confirmed in all KO mice by PCR and resulted in less hypertrophy (heart weight to tibia length ratio (HW/TL), smaller cross-sectional cardiomyocyte area and decreased brain natriuretic peptide (BNP) mRNA expression, p < 0.05), increased contractility (QRS and QTc, p < 0.05), and less inflammation (e.g., interleukins 6 and 1β, p < 0.05) after TAC compared to WT animals (n = 11). Even though TLR2 KO TAC animals presented with lower levels of ventricular TLR4 mRNA than WT TAC animals (13.2 ± 0.8 vs. 16.6 ± 0.7 mg/mm, p < 0.01), TLR4 mRNA expression was increased in animals with the largest ventricular mass, highest hypertrophy, and lowest ejection fraction, leading to two distinct groups of TLR2 KO TAC animals with variations in cardiac remodeling. This variation, however, was not seen in WT TAC animals even though heart weight/tibia length correlated with expression of TLR4 in these animals (r = 0.078, p = 0.005). Our data suggest that TLR2 deficiency ameliorates adverse cardiac remodeling and that ventricular TLR2 and TLR4 additively contribute to adverse cardiac remodeling during chronic pressure overload. Therefore, both TLRs may be therapeutic targets to prevent or interfere in the underlying molecular processes. Full article

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13 pages, 5270 KiB

Open AccessArticle

Retinal Degeneration and Microglial Dynamics in Mature Progranulin-Deficient Mice

by Kei Takahashi, Shinsuke Nakamura, Masamitsu Shimazawa and Hideaki Hara

Int. J. Mol. Sci. 2021, 22(21), 11557; https://doi.org/10.3390/ijms222111557 - 26 Oct 2021

Cited by 2 | Viewed by 2805

Abstract

Progranulin (PGRN) is a secreted glycoprotein that regulates numerous cellular processes. The role of PGRN as a regulator of lysosomes has recently received attention. The purpose of this study was to characterize the retinal phenotype in mature PGRN knockout (Grn^−/−) [...] Read more.

Progranulin (PGRN) is a secreted glycoprotein that regulates numerous cellular processes. The role of PGRN as a regulator of lysosomes has recently received attention. The purpose of this study was to characterize the retinal phenotype in mature PGRN knockout (Grn^−/−) mice. The a-wave amplitude of scotopic electroretinogram and outer nuclear thickness were significantly reduced at 6 months of age in Grn^−/− mice compared to wild-type (Grn^+/+) mice. In Grn^−/− mice, retinal microglial cells accumulated on the retinal pigment epithelium (RPE) apical layer, and the number of infiltrated microglia and white fundus lesions between 2 and 6 months of age showed a close affinity. In Grn^+/+ mice, PGRN was located in the retina, while the strongest PGRN signals were detected in the RPE-choroid. The different effects of PGRN deficiency on the expression of lysosomal proteins between the retina and RPE-choroid were demonstrated. Our data suggest that the subretinal translocation of microglia is a characteristic phenotype in the retina of mature PGRN knockout mice. The different effects of PGRN deficiency on the expression of lysosomal proteins between the retina and RPE-choroid might modulate microglial dynamics in PGRN knockout mice. Full article

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23 pages, 3502 KiB

Open AccessArticle

Expression Pattern of Purinergic Signaling Components in Colorectal Cancer Cells and Differential Cellular Outcomes Induced by Extracellular ATP and Adenosine

by Clémentine Dillard, Chloé Borde, Ammara Mohammad, Virginie Puchois, Laurent Jourdren, Annette K. Larsen, Michèle Sabbah, Vincent Maréchal, Alexandre E. Escargueil and Elodie Pramil

Int. J. Mol. Sci. 2021, 22(21), 11472; https://doi.org/10.3390/ijms222111472 - 25 Oct 2021

Cited by 16 | Viewed by 3582

Abstract

The purine nucleotide adenosine triphosphate (ATP) is known for its fundamental role in cellular bioenergetics. However, in the last decades, different works have described emerging functions for ATP, such as that of a danger signaling molecule acting in the extracellular space on both [...] Read more.

The purine nucleotide adenosine triphosphate (ATP) is known for its fundamental role in cellular bioenergetics. However, in the last decades, different works have described emerging functions for ATP, such as that of a danger signaling molecule acting in the extracellular space on both tumor and stromal compartments. Beside its role in immune cell signaling, several studies have shown that high concentrations of extracellular ATP can directly or indirectly act on cancer cells. Accordingly, it has been reported that purinergic receptors are widely expressed in tumor cells. However, their expression pattern is often associated with contradictory cellular outcomes. In this work, we first investigated gene expression profiles through “RNA-Sequencing” (RNA Seq) technology in four colorectal cancer (CRC) cell lines (HT29, LS513, LS174T, HCT116). Our results demonstrate that CRC cells mostly express the A2B, P2X4, P2Y1, P2Y2 and P2Y11 purinergic receptors. Among these, the P2Y1 and P2Y2 coding genes are markedly overexpressed in all CRC cells compared to the HCEC-1CT normal-like colonic cells. We then explored the cellular outcomes induced by extracellular ATP and adenosine. Our results show that in terms of cell death induction extracellular ATP is consistently more active than adenosine against CRC, while neither compound affected normal-like colonic cell survival. Intriguingly, while for the P2Y2 receptor pharmacological inhibition completely abolished the rise in cytoplasmic Ca²⁺ observed after ATP exposure in all CRC cell lines, Ca²⁺ mobilization only impacted the cellular outcome for HT29. In contrast, non-selective phosphodiesterase inhibition completely abolished the effects of extracellular ATP on CRC cells, suggesting that cAMP and/or cGMP levels might determine cellular outcome. Altogether, our study provides novel insights into the characterization of purinergic signaling in CRC. Full article

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16 pages, 3694 KiB

Open AccessArticle

Custodiol^® Supplemented with Synthetic Human Relaxin Decreases Ischemia-Reperfusion Injury after Porcine Kidney Transplantation

by Augustinas Bausys, Juste Maneikyte, Bettina Leber, Jennifer Weber, Nicole Feldbacher, Kestutis Strupas, Thomas Bernd Dschietzig, Peter Schemmer and Philipp Stiegler

Int. J. Mol. Sci. 2021, 22(21), 11417; https://doi.org/10.3390/ijms222111417 - 22 Oct 2021

Cited by 3 | Viewed by 2586

Abstract

Objective. Ischemia-reperfusion injury (IRI) is inevitable after kidney transplantation (KT), impairing outcomes. Relaxin-2 (RLX) is a promising insulin-related peptide hormone that protects against renal IRI in rodents, although large animal models are needed before RLX can be tested in a human setting. Methods. [...] Read more.

Objective. Ischemia-reperfusion injury (IRI) is inevitable after kidney transplantation (KT), impairing outcomes. Relaxin-2 (RLX) is a promising insulin-related peptide hormone that protects against renal IRI in rodents, although large animal models are needed before RLX can be tested in a human setting. Methods. In this blinded, randomized, and placebo-controlled experimental study kidneys from 19 donor pigs were retrieved after perfusion with Custodiol^® ± RLX (5 or 20 nmol/L) and underwent static cold storage (SCS) for 24 and 48 h, respectively. Subsequently, KT was performed after unilateral right nephrectomy. Study outcomes included markers for kidney function, oxidative stress, lipid peroxidation, and endothelial cell damage. PCR analysis for oxidative stress and apoptosis-related gene panels as well as immunohistochemistry were performed. Results. RLX upregulated SOD2 and NFKB expression to 135% (p = 0.042) and 125% (p = 0.019), respectively, while RIPK1 expression was downregulated to 82% (p = 0.016) of corresponding controls. Further RLX significantly downregulated RIPK1 and MLKL expression and decreased the number of Caspase 3- and MPO-positive cells in grafts after SCS. Conclusions. RLX supplemented Custodiol^® significantly decreased IRI via both antioxidant and anti-apoptotic mechanisms. Clinical trials are warranted to implement synthetic human RLX as a novel additive to preservation solutions against IRI. Full article

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20 pages, 2429 KiB

Open AccessArticle

Oleanolic Acid’s Semisynthetic Derivatives HIMOXOL and Br-HIMOLID Show Proautophagic Potential and Inhibit Migration of HER2-Positive Breast Cancer Cells In Vitro

by Natalia Magdalena Lisiak, Izabela Lewicka, Mariusz Kaczmarek, Jacek Kujawski, Barbara Bednarczyk-Cwynar, Lucjusz Zaprutko and Blazej Rubis

Int. J. Mol. Sci. 2021, 22(20), 11273; https://doi.org/10.3390/ijms222011273 - 19 Oct 2021

Cited by 8 | Viewed by 2616

Abstract

Approximately 20–30% of the diagnosed breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). This type of cancer is associated with a more aggressive phenotype; thus, there is a need for the discovery of new compounds that would improve the survival [...] Read more.

Approximately 20–30% of the diagnosed breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). This type of cancer is associated with a more aggressive phenotype; thus, there is a need for the discovery of new compounds that would improve the survival in HER2-positive breast cancer patients. It seems that one of the most promising therapeutic cancer strategies could be based on the biological activity of pentacyclic triterpenes’ derivatives and the best-known representative of this group, oleanolic acid (OA). The biological activity of oleanolic acid and its two semisynthetic derivatives, methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate (HIMOXOL) and 12α-bromo-3-hydroxyimonoolean-28→13-olide (Br-HIMOLID), was assessed in SK-BR-3 breast cancer cells (HER2-positive). Viability tests, cell cycle assessment, evaluation of apoptosis, autophagy, and adhesion/migration processes were performed using MTT, clonogenic, cytofluorometry, Western blot, and qPCR. Both derivatives revealed higher cytotoxicity in studied breast cancer cells than the maternal compound, OA. They also decreased cell viability, induced autophagy, and (when applied in sub-cytotoxic concentrations) decreased the migration of SK-BR-3 cells.This study is the first to report the cytostatic, proautophagic (mTOR/LC3/SQSTM/BECN1 pathway), and anti-migratory (integrin β1/FAK/paxillin pathway) activities of HIMOXOL and Br-HIMOLID in HER2-positive breast cancer cells. Full article

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13 pages, 758 KiB

Open AccessReview

Head-to-Head Comparison of Fibroblast Activation Protein Inhibitors (FAPI) Radiotracers versus [¹⁸F]F-FDG in Oncology: A Systematic Review

by Giorgio Treglia, Barbara Muoio, Hessamoddin Roustaei, Zahra Kiamanesh, Kamran Aryana and Ramin Sadeghi

Int. J. Mol. Sci. 2021, 22(20), 11192; https://doi.org/10.3390/ijms222011192 - 17 Oct 2021

Cited by 36 | Viewed by 4407

Abstract

Several recent studies comparing radiolabeled fibroblast activation protein inhibitors (FAPI) and fluorine-18 fluorodeoxyglucose ([¹⁸F]F-FDG) as positron emission tomography (PET) radiotracers in oncology have been published. The aim of this systematic review is to perform an updated evidence-based summary about the comparison [...] Read more.

Several recent studies comparing radiolabeled fibroblast activation protein inhibitors (FAPI) and fluorine-18 fluorodeoxyglucose ([¹⁸F]F-FDG) as positron emission tomography (PET) radiotracers in oncology have been published. The aim of this systematic review is to perform an updated evidence-based summary about the comparison of these PET radiotracers in oncology to better address further research in this setting. Studies or subsets of studies comparing radiolabeled FAPI and [¹⁸F]F-FDG as PET radiotracers in oncology were eligible for inclusion in this systematic review. A systematic literature search of PubMed/MEDLINE and Cochrane library databases was performed until August 2021. Literature data about the comparison of [¹⁸F]F-FDG and radiolabeled FAPI are rapidly increasing. Overall, taking into account radiotracer uptake and tumor-to-background uptake ratio, compared to [¹⁸F]F-FDG PET, an equal or higher detection of primary tumors and/or metastatic lesions was usually demonstrated by using radiolabeled FAPI PET. In particular, the cancer entities with better detection rate of tumor lesions by using radiolabeled FAPI PET, compared to [¹⁸F]F-FDG PET, were gastrointestinal tumors, liver tumors, breast cancer and nasopharyngeal carcinoma. Further comparison studies are needed to better evaluate the best field of application of radiolabeled FAPI PET. Full article

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18 pages, 2863 KiB

Open AccessReview

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Alport Syndrome: A Primer for Clinicians

by Raquel Martínez-Pulleiro, María García-Murias, Manuel Fidalgo-Díaz and Miguel Ángel García-González

Int. J. Mol. Sci. 2021, 22(20), 11063; https://doi.org/10.3390/ijms222011063 - 14 Oct 2021

Cited by 7 | Viewed by 12429

Abstract

Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes COL4A3, COL4A4 and COL4A5, that affects the glomerular basement membrane of the kidney. It is a rare disease with an underestimated prevalence. Genetic analysis [...] Read more.

Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes COL4A3, COL4A4 and COL4A5, that affects the glomerular basement membrane of the kidney. It is a rare disease with an underestimated prevalence. Genetic analysis of population cohorts has revealed that it is the second most common inherited kidney disease after polycystic kidney disease. Renal involvement is the main manifestation, although it may have associated extrarenal manifestations such as hearing loss or ocular problems. The degree of expression of the disease changes according to the gene affected and other factors, known or yet to be known. The pathophysiology is not yet fully understood, although some receptors, pathways or molecules are known to be linked to the disease. There is also no specific treatment for Alport syndrome; the most commonly used are renin–angiotensin–aldosterone system inhibitors. In recent years, diagnosis has come a long way, thanks to advances in DNA sequencing technologies such as next-generation sequencing (NGS). Further research at the genetic and molecular levels in the future will complete the partial vision of the pathophysiological mechanism that we have, and will allow us to better understand what is happening and how to solve it. Full article

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19 pages, 34746 KiB

Open AccessArticle

miR-542-3p Attenuates Bone Loss and Marrow Adiposity Following Methotrexate Treatment by Targeting sFRP-1 and Smurf2

by Ya-Li Zhang, Liang Liu, Yu-Wen Su and Cory J. Xian

Int. J. Mol. Sci. 2021, 22(20), 10988; https://doi.org/10.3390/ijms222010988 - 12 Oct 2021

Cited by 8 | Viewed by 2299

Abstract

Intensive methotrexate (MTX) treatment for childhood malignancies decreases osteogenesis but increases adipogenesis from the bone marrow stromal cells (BMSCs), resulting in bone loss and bone marrow adiposity. However, the underlying mechanisms are unclear. While microRNAs (miRNAs) have emerged as bone homeostasis regulators and [...] Read more.

Intensive methotrexate (MTX) treatment for childhood malignancies decreases osteogenesis but increases adipogenesis from the bone marrow stromal cells (BMSCs), resulting in bone loss and bone marrow adiposity. However, the underlying mechanisms are unclear. While microRNAs (miRNAs) have emerged as bone homeostasis regulators and miR-542-3p was recently shown to regulate osteogenesis in a bone loss context, the role of miR-542-3p in regulating osteogenesis and adipogenesis balance is not clear. Herein, in a rat MTX treatment-induced bone loss model, miR-542-3p was found significantly downregulated during the period of bone loss and marrow adiposity. Following target prediction, network construction, and functional annotation/ enrichment analyses, luciferase assays confirmed sFRP-1 and Smurf2 as the direct targets of miR-542-3p. miRNA-542-3p overexpression suppressed sFRP-1 and Smurf2 expression post-transcriptionally. Using in vitro models, miR-542-3p treatment stimulated osteogenesis but attenuated adipogenesis following MTX treatment. Subsequent signalling analyses revealed that miR-542-3p influences Wnt/β-catenin and TGF-β signalling pathways in osteoblastic cells. Our findings suggest that MTX treatment-induced bone loss and marrow adiposity could be molecularly linked to miR-542-3p pathways. Our results also indicate that miR-542-3p might be a therapeutic target for preserving bone and attenuating marrow fat formation during/after MTX chemotherapy. Full article

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19 pages, 28839 KiB

Open AccessArticle

Effect of Structural Changes Induced by Deletion of ⁵⁴FLRAPSWF⁶¹ Sequence in αB-crystallin on Chaperone Function and Anti-Apoptotic Activity

by Sundararajan Mahalingam, Srabani Karmakar, Puttur Santhoshkumar and Krishna K. Sharma

Int. J. Mol. Sci. 2021, 22(19), 10771; https://doi.org/10.3390/ijms221910771 - 5 Oct 2021

Cited by 2 | Viewed by 2452

Abstract

Previously, we showed that the removal of the 54–61 residues from αB-crystallin (αBΔ54–61) results in a fifty percent reduction in the oligomeric mass and a ten-fold increase in chaperone-like activity. In this study, we investigated the oligomeric organization changes in the deletion mutant [...] Read more.

Previously, we showed that the removal of the 54–61 residues from αB-crystallin (αBΔ54–61) results in a fifty percent reduction in the oligomeric mass and a ten-fold increase in chaperone-like activity. In this study, we investigated the oligomeric organization changes in the deletion mutant contributing to the increased chaperone activity and evaluated the cytoprotection properties of the mutant protein using ARPE-19 cells. Trypsin digestion studies revealed that additional tryptic cleavage sites become susceptible in the deletion mutant than in the wild-type protein, suggesting a different subunit organization in the oligomer of the mutant protein. Static and dynamic light scattering analyses of chaperone–substrate complexes showed that the deletion mutant has more significant interaction with the substrates than wild-type protein, resulting in increased binding of the unfolding proteins. Cytotoxicity studies carried out with ARPE-19 cells showed an enhancement in anti-apoptotic activity in αBΔ54–61 as compared with the wild-type protein. The improved anti-apoptotic activity of the mutant is also supported by reduced caspase activation and normalization of the apoptotic cascade components level in cells treated with the deletion mutant. Our study suggests that altered oligomeric assembly with increased substrate affinity could be the basis for the enhanced chaperone function of the αBΔ54–61 protein. Full article

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18 pages, 4131 KiB

Open AccessArticle

Expression/Activation of PAR-1 in Airway Epithelial Cells of COPD Patients: Ex Vivo/In Vitro Study

by Angela Marina Montalbano, Giuseppina Chiappara, Giusy Daniela Albano, Maria Ferraro, Caterina Di Sano, Patrizio Vitulo, Loredana Pipitone, Fabio Luigi Massimo Ricciardolo, Giulia Anzalone and Mirella Profita

Int. J. Mol. Sci. 2021, 22(19), 10703; https://doi.org/10.3390/ijms221910703 - 2 Oct 2021

Cited by 1 | Viewed by 2420

Abstract

The role of PAR-1 expression and activation was described in epithelial cells from the central and distal airways of COPD patients using an ex vivo/in vitro model. PAR-1 immunoreactivity was studied in epithelial cells from surgical specimens of the central and distal airways [...] Read more.

The role of PAR-1 expression and activation was described in epithelial cells from the central and distal airways of COPD patients using an ex vivo/in vitro model. PAR-1 immunoreactivity was studied in epithelial cells from surgical specimens of the central and distal airways of COPD patients and healthy control (HC). Furthermore, PAR-1 expression and activation were measured in both the human bronchial epithelial cell line (16HBE) and normal human bronchial epithelial cells (NHBEs) exposed to cigarette smoke extract (CSE) (10%) or thrombin. Finally, cell proliferation, apoptosis, and IL-8 release were detected in stimulated NHBEs. We identified higher levels of PAR-1 expression/activation in epithelial cells from the central airways of COPD patients than in HC. Active PAR-1 increased in epithelial cells from central and distal airways of COPD, with higher levels in COPD smokers (correlated with pack-years) than in COPD ex-smokers. 16HBE and NHBEs exposed to CSE or thrombin showed increased levels of active PAR-1 (localized in the cytoplasm) than baseline conditions, while NHBEs treated with thrombin or CSE showed increased levels of IL-8 proteins, with an additional effect when used in combination. Smoking habits generate the upregulation of PAR-1 expression/activation in airway epithelial cells, and promoting IL-8 release might affect the recruitment of infiltrating cells in the airways of COPD patients. Full article

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10 pages, 2413 KiB

Open AccessArticle

IL-33 Enhances IFNγ and TNFα Production by Human MAIT Cells: A New Pro-Th1 Effect of IL-33

by Mourad Azzout, Céline Dietrich, François Machavoine, Pauline Gastineau, Alix Bottier, Guillaume Lezmi and Maria Leite-de-Moraes

Int. J. Mol. Sci. 2021, 22(19), 10602; https://doi.org/10.3390/ijms221910602 - 30 Sep 2021

Cited by 10 | Viewed by 2967

Abstract

Mucosal-associated invariant T (MAIT) cells represent a distinct T cell population restricted by the MHC-class-I-related molecule, MR1, which recognizes microbial-derived vitamin B2 (riboflavin) metabolites. Their abundance in humans, together with their ability to promptly produce distinct cytokines including interferon γ (IFNγ) and tumor [...] Read more.

Mucosal-associated invariant T (MAIT) cells represent a distinct T cell population restricted by the MHC-class-I-related molecule, MR1, which recognizes microbial-derived vitamin B2 (riboflavin) metabolites. Their abundance in humans, together with their ability to promptly produce distinct cytokines including interferon γ (IFNγ) and tumor necrosis factor α (TNFα), are consistent with regulatory functions in innate as well as adaptive immunity. Here, we tested whether the alarmin interleukin 33 (IL-33), which is secreted following inflammation or cell damage, could activate human MAIT cells. We found that MAIT cells stimulated with IL-33 produced high levels of IFNγ, TNFα and Granzyme B (GrzB). The action of IL-33 required IL-12 but was independent of T cell receptor (TCR) cross-linking. MAIT cells expressed the IL-33 receptor ST2 (suppression of tumorigenicity 2) and upregulated Tbet (T-box expressed in T cells) in response to IL-12 or IL-33. Electronically sorted MAIT cells also upregulated the expression of CCL3 (Chemokine C-C motif ligand 3), CD40L (CD40 Ligand), CSF-1 (Colony Stimulating Factor 1), LTA (Lymphotoxin-alpha) and IL-2RA (IL-2 receptor alpha chain) mRNAs in response to IL-33 plus IL-12. In conclusion, IL-33 combined with IL-12 can directly target MAIT cells to induce their activation and cytokine production. This novel mechanism of IL-33 activation provides insight into the mode of action by which human MAIT cells can promote inflammatory responses in a TCR-independent manner. Full article

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18 pages, 4778 KiB

Open AccessArticle

N6-Isopentenyladenosine Hinders the Vasculogenic Mimicry in Human Glioblastoma Cells through Src-120 Catenin Pathway Modulation and RhoA Activity Inhibition

by Cristina Pagano, Giovanna Navarra, Olga Pastorino, Giorgio Avilia, Laura Coppola, Rosa Della Monica, Lorenzo Chiariotti, Tullio Florio, Alessandro Corsaro, Giovanni Torelli, Pasquale Caiazzo, Patrizia Gazzerro, Maurizio Bifulco and Chiara Laezza

Int. J. Mol. Sci. 2021, 22(19), 10530; https://doi.org/10.3390/ijms221910530 - 29 Sep 2021

Cited by 7 | Viewed by 3300

Abstract

Background: Vasculogenic mimicry (VM) is a functional microcirculation pattern formed by aggressive tumor cells. Thus far, no effective drugs have been developed to target VM. Glioblastoma (GBM) is the most malignant form of brain cancer and is a highly vascularized tumor. Vasculogenic mimicry [...] Read more.

Background: Vasculogenic mimicry (VM) is a functional microcirculation pattern formed by aggressive tumor cells. Thus far, no effective drugs have been developed to target VM. Glioblastoma (GBM) is the most malignant form of brain cancer and is a highly vascularized tumor. Vasculogenic mimicry represents a means whereby GBM can escape anti-angiogenic therapies. Methods: Here, using an in vitro tube formation assay on Matrigel, we evaluated the ability of N6-isopentenyladenosine (iPA) to interfere with vasculogenic mimicry (VM). RhoA activity was assessed using a pull-down assay, while the modulation of the adherens junctions proteins was analyzed by Western blot analysis. Results: We found that iPA at sublethal doses inhibited the formation of capillary-like structures suppressing cell migration and invasion of U87MG, U343MG, and U251MG cells, of patient-derived human GBM cells and GBM stem cells. iPA reduces the vascular endothelial cadherin (VE-cadherin) expression levels in a dose-dependent manner, impairs the vasculogenic mimicry network by modulation of the Src/p120-catenin pathway and inhibition of RhoA-GTPase activity. Conclusions: Taken together, our results revealed iPA as a promising novel anti-VM drug in GBM clinical therapeutics. Full article

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15 pages, 1274 KiB

Open AccessReview

Human Pluripotent Stem Cell-Derived Hepatocyte-Like Cells and Organoids for Liver Disease and Therapy

by Yang Li, Xia Yang, Richie Plummer, Yoshihito Hayashi, Xiao-Shan Deng, Yun-Zhong Nie and Hideki Taniguchi

Int. J. Mol. Sci. 2021, 22(19), 10471; https://doi.org/10.3390/ijms221910471 - 28 Sep 2021

Cited by 11 | Viewed by 3986

Abstract

Liver disease is a global health issue that has caused an economic burden worldwide. Organ transplantation is the only effective therapy for end-stage liver disease; however, it has been hampered by a shortage of donors. Human pluripotent stem cells (hPSCs) have been widely [...] Read more.

Liver disease is a global health issue that has caused an economic burden worldwide. Organ transplantation is the only effective therapy for end-stage liver disease; however, it has been hampered by a shortage of donors. Human pluripotent stem cells (hPSCs) have been widely used for studying liver biology and pathology as well as facilitating the development of alternative therapies. hPSCs can differentiate into multiple types of cells, which enables the generation of various models that can be applied to investigate and recapitulate a range of biological activities in vitro. Here, we summarize the recent development of hPSC-derived hepatocytes and their applications in disease modeling, cell therapy, and drug discovery. We also discuss the advantages and limitations of these applications and critical challenges for further development. Full article

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20 pages, 1541 KiB

Open AccessReview

Role of Neutrophils on the Ocular Surface

by Yongseok Mun, Jin Sun Hwang and Young Joo Shin

Int. J. Mol. Sci. 2021, 22(19), 10386; https://doi.org/10.3390/ijms221910386 - 27 Sep 2021

Cited by 18 | Viewed by 4040

Abstract

The ocular surface is a gateway that contacts the outside and receives stimulation from the outside. The corneal innate immune system is composed of many types of cells, including epithelial cells, fibroblasts, natural killer cells, macrophages, neutrophils, dendritic cells, mast cells, basophils, eosinophils, [...] Read more.

The ocular surface is a gateway that contacts the outside and receives stimulation from the outside. The corneal innate immune system is composed of many types of cells, including epithelial cells, fibroblasts, natural killer cells, macrophages, neutrophils, dendritic cells, mast cells, basophils, eosinophils, mucin, and lysozyme. Neutrophil infiltration and degranulation occur on the ocular surface. Degranulation, neutrophil extracellular traps formation, called NETosis, and autophagy in neutrophils are involved in the pathogenesis of ocular surface diseases. It is necessary to understand the role of neutrophils on the ocular surface. Furthermore, there is a need for research on therapeutic agents targeting neutrophils and neutrophil extracellular trap formation for ocular surface diseases. Full article

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14 pages, 4005 KiB

Open AccessArticle

Structure-Based Understanding of ABCA3 Variants

by Marion Onnée, Pascale Fanen, Isabelle Callebaut and Alix de Becdelièvre

Int. J. Mol. Sci. 2021, 22(19), 10282; https://doi.org/10.3390/ijms221910282 - 24 Sep 2021

Cited by 8 | Viewed by 2924

Abstract

ABCA3 is a crucial protein of pulmonary surfactant biosynthesis, associated with recessive pulmonary disorders such as neonatal respiratory distress and interstitial lung disease. Mutations are mostly private, and accurate interpretation of variants is mandatory for genetic counseling and patient care. We used 3D [...] Read more.

ABCA3 is a crucial protein of pulmonary surfactant biosynthesis, associated with recessive pulmonary disorders such as neonatal respiratory distress and interstitial lung disease. Mutations are mostly private, and accurate interpretation of variants is mandatory for genetic counseling and patient care. We used 3D structure information to complete the set of available bioinformatics tools dedicated to medical decision. Using the experimental structure of human ABCA4, we modeled at atomic resolution the human ABCA3 3D structure including transmembrane domains (TMDs), nucleotide-binding domains (NBDs), and regulatory domains (RDs) in an ATP-bound conformation. We focused and mapped known pathogenic missense variants on this model. We pinpointed amino-acids within the NBDs, the RDs and within the interfaces between the NBDs and TMDs intracellular helices (IHs), which are predicted to play key roles in the structure and/or the function of the ABCA3 transporter. This theoretical study also highlighted the possible impact of ABCA3 variants in the cytosolic part of the protein, such as the well-known p.Glu292Val and p.Arg288Lys variants. Full article

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18 pages, 1926 KiB

Open AccessReview

Dark Side of Cancer Therapy: Cancer Treatment-Induced Cardiopulmonary Inflammation, Fibrosis, and Immune Modulation

by Ettickan Boopathi and Chellappagounder Thangavel

Int. J. Mol. Sci. 2021, 22(18), 10126; https://doi.org/10.3390/ijms221810126 - 19 Sep 2021

Cited by 13 | Viewed by 6173

Abstract

Advancements in cancer therapy increased the cancer free survival rates and reduced the malignant related deaths. Therapeutic options for patients with thoracic cancers include surgical intervention and the application of chemotherapy with ionizing radiation. Despite these advances, cancer therapy-related cardiopulmonary dysfunction (CTRCPD) is [...] Read more.

Advancements in cancer therapy increased the cancer free survival rates and reduced the malignant related deaths. Therapeutic options for patients with thoracic cancers include surgical intervention and the application of chemotherapy with ionizing radiation. Despite these advances, cancer therapy-related cardiopulmonary dysfunction (CTRCPD) is one of the most undesirable side effects of cancer therapy and leads to limitations to cancer treatment. Chemoradiation therapy or immunotherapy promote acute and chronic cardiopulmonary damage by inducing reactive oxygen species, DNA damage, inflammation, fibrosis, deregulation of cellular immunity, cardiopulmonary failure, and non-malignant related deaths among cancer-free patients who received cancer therapy. CTRCPD is a complex entity with multiple factors involved in this pathogenesis. Although the mechanisms of cancer therapy-induced toxicities are multifactorial, damage to the cardiac and pulmonary tissue as well as subsequent fibrosis and organ failure seem to be the underlying events. The available biomarkers and treatment options are not sufficient and efficient to detect cancer therapy-induced early asymptomatic cell fate cardiopulmonary toxicity. Therefore, application of cutting-edge multi-omics technology, such us whole-exome sequencing, DNA methylation, whole-genome sequencing, metabolomics, protein mass spectrometry and single cell transcriptomics, and 10 X spatial genomics, are warranted to identify early and late toxicity, inflammation-induced carcinogenesis response biomarkers, and cancer relapse response biomarkers. In this review, we summarize the current state of knowledge on cancer therapy-induced cardiopulmonary complications and our current understanding of the pathological and molecular consequences of cancer therapy-induced cardiopulmonary fibrosis, inflammation, immune suppression, and tumor recurrence, and possible treatment options for cancer therapy-induced cardiopulmonary toxicity. Full article

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11 pages, 1983 KiB

Open AccessArticle

Inhibition of BMI-1 Induces Apoptosis through Downregulation of DUB3-Mediated Mcl-1 Stabilization

by Kaixin Wu, Seon-Min Woo, Seung-Un Seo and Taeg-Kyu Kwon

Int. J. Mol. Sci. 2021, 22(18), 10107; https://doi.org/10.3390/ijms221810107 - 18 Sep 2021

Cited by 8 | Viewed by 2641

Abstract

BMI-1, a polycomb ring finger oncogene, is highly expressed in multiple cancer cells and is involved in cancer cell proliferation, invasion, and apoptosis. BMI-1 represents a cancer stemness marker that is associated with the regulation of stem cell self-renewal. In this study, pharmacological [...] Read more.

BMI-1, a polycomb ring finger oncogene, is highly expressed in multiple cancer cells and is involved in cancer cell proliferation, invasion, and apoptosis. BMI-1 represents a cancer stemness marker that is associated with the regulation of stem cell self-renewal. In this study, pharmacological inhibition (PTC596) or knockdown (siRNA) of BMI-1 reduced cancer stem-like cells and enhanced cancer cell death. Mechanistically, the inhibition of BMI-1 induced the downregulation of Mcl-1 protein, but not Mcl-1 mRNA. PTC596 downregulated Mcl-1 protein expression at the post-translational level through the proteasome-ubiquitin system. PTC596 and BMI-1 siRNA induced downregulation of DUB3 deubiquitinase, which was strongly linked to Mcl-1 destabilization. Furthermore, overexpression of Mcl-1 or DUB3 inhibited apoptosis by PTC596. Taken together, our findings reveal that the inhibition of BMI-1 induces Mcl-1 destabilization through downregulation of DUB3, resulting in the induction of cancer cell death. Full article

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17 pages, 723 KiB

Open AccessReview

Is Multiple System Atrophy a Prion-like Disorder?

by Kurt A. Jellinger, Gregor K. Wenning and Nadia Stefanova

Int. J. Mol. Sci. 2021, 22(18), 10093; https://doi.org/10.3390/ijms221810093 - 18 Sep 2021

Cited by 13 | Viewed by 4234

Abstract

Multiple system atrophy (MSA) is a rapidly progressive, fatal neurodegenerative disease of uncertain aetiology that belongs to the family of α-synucleinopathies. It clinically presents with parkinsonism, cerebellar, autonomic, and motor impairment in variable combinations. Pathological hallmarks are fibrillary α-synuclein (αSyn)-rich glial cytoplasmic inclusions [...] Read more.

Multiple system atrophy (MSA) is a rapidly progressive, fatal neurodegenerative disease of uncertain aetiology that belongs to the family of α-synucleinopathies. It clinically presents with parkinsonism, cerebellar, autonomic, and motor impairment in variable combinations. Pathological hallmarks are fibrillary α-synuclein (αSyn)-rich glial cytoplasmic inclusions (GCIs) mainly involving oligodendroglia and to a lesser extent neurons, inducing a multisystem neurodegeneration, glial activation, and widespread demyelinization. The neuronal αSyn pathology of MSA has molecular properties different from Lewy bodies in Parkinson’s disease (PD), both of which could serve as a pool of αSyn (prion) seeds that could initiate and drive the pathogenesis of synucleinopathies. The molecular cascade leading to the “prion-like” transfer of “strains” of aggregated αSyn contributing to the progression of the disease is poorly understood, while some presented evidence that MSA is a prion disease. However, this hypothesis is difficult to reconcile with postmortem analysis of human brains and the fact that MSA-like pathology was induced by intracerebral inoculation of human MSA brain homogenates only in homozygous mutant 53T mice, without production of disease-specific GCIs, or with replication of MSA prions in primary astrocyte cultures from transgenic mice expressing human αSyn. Whereas recent intrastriatal injection of Lewy body-derived or synthetic human αSyn fibrils induced PD-like pathology including neuronal αSyn aggregates in macaques, no such transmission of αSyn pathology in non-human primates by MSA brain lysate has been reported until now. Given the similarities between αSyn and prions, there is a considerable debate whether they should be referred to as “prions”, “prion-like”, “prionoids”, or something else. Here, the findings supporting the proposed nature of αSyn as a prion and its self-propagation through seeding as well as the transmissibility of neurodegenerative disorders are discussed. The proof of disease causation rests on the concordance of scientific evidence, none of which has provided convincing evidence for the classification of MSA as a prion disease or its human transmission until now. Full article

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21 pages, 30468 KiB

Open AccessArticle

Neuroprotective Effect of 1,4-Naphthoquinones in an In Vitro Model of Paraquat and 6-OHDA-Induced Neurotoxicity

by Ekaterina Menchinskaya, Ekaterina Chingizova, Evgeny Pislyagin, Galina Likhatskaya, Yuri Sabutski, Dmitry Pelageev, Sergei Polonik and Dmitry Aminin

Int. J. Mol. Sci. 2021, 22(18), 9933; https://doi.org/10.3390/ijms22189933 - 14 Sep 2021

Cited by 10 | Viewed by 2459

Abstract

Targeted screening using the MTT cell viability test with a mini-library of natural and synthetic 1,4-naphthoquinones and their derivatives was performed in order to increase the survival of Neuro-2a neuroblastoma cells in in vitro paraquat and 6-hydroxydopamine models of Parkinson’s disease. As a [...] Read more.

Targeted screening using the MTT cell viability test with a mini-library of natural and synthetic 1,4-naphthoquinones and their derivatives was performed in order to increase the survival of Neuro-2a neuroblastoma cells in in vitro paraquat and 6-hydroxydopamine models of Parkinson’s disease. As a result, 10 compounds were selected that could protect neuronal cells from the cytotoxic effects of both paraquat and 6-hydroxydopamine. The five most active compounds at low concentrations were found to significantly protect the activity of nonspecific esterase from the inhibitory effects of neurotoxins, defend cell biomembranes from lytic destruction in the presence of paraquat and 6-hydroxydopamine, and normalize the cell cycle. The protective effects of these compounds are associated with the suppression of oxidative stress, decreased expression of reactive oxygen species and nitric oxide formation in cells and normalization of mitochondrial function, and restoration of the mitochondrial membrane potential altered by neurotoxins. It was suggested that the neuroprotective activity of the studied 1,4-NQs is attributable to their pronounced antioxidant and free radical scavenging activity and their ability to reduce the amount of reactive oxygen species formed by paraquat and 6-hydroxydopamine action on neuronal cells. The significant correlation between the neuroprotective properties of 1,4-naphthoquinones and Quantitative Structure–Activity Relationship descriptors describing the physicochemical properties of these compounds means that the hydrophobicity, polarity, charge, and shape of the molecules can be of decisive importance in determining the biological activity of studied substances. Full article

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15 pages, 1076 KiB

Open AccessReview

Genetic and Epigenetic Factors of Takotsubo Syndrome: A Systematic Review

by Valentina Ferradini, Davide Vacca, Beatrice Belmonte, Ruggiero Mango, Letizia Scola, Giuseppe Novelli, Carmela Rita Balistreri and Federica Sangiuolo

Int. J. Mol. Sci. 2021, 22(18), 9875; https://doi.org/10.3390/ijms22189875 - 13 Sep 2021

Cited by 17 | Viewed by 3395

Abstract

Takotsubo syndrome (TTS), recognized as stress’s cardiomyopathy, or as left ventricular apical balloon syndrome in recent years, is a rare pathology, described for the first time by Japanese researchers in 1990. TTS is characterized by an interindividual heterogeneity in onset and progression, and [...] Read more.

Takotsubo syndrome (TTS), recognized as stress’s cardiomyopathy, or as left ventricular apical balloon syndrome in recent years, is a rare pathology, described for the first time by Japanese researchers in 1990. TTS is characterized by an interindividual heterogeneity in onset and progression, and by strong predominance in postmenopausal women. The clear causes of these TTS features are uncertain, given the limited understanding of this intriguing syndrome until now. However, the increasing frequency of TTS cases in recent years, and particularly correlated to the SARS-CoV-2 pandemic, leads us to the imperative necessity both of a complete knowledge of TTS pathophysiology for identifying biomarkers facilitating its management, and of targets for specific and effective treatments. The suspect of a genetic basis in TTS pathogenesis has been evidenced. Accordingly, familial forms of TTS have been described. However, a systematic and comprehensive characterization of the genetic or epigenetic factors significantly associated with TTS is lacking. Thus, we here conducted a systematic review of the literature before June 2021, to contribute to the identification of potential genetic and epigenetic factors associated with TTS. Interesting data were evidenced, but few in number and with diverse limitations. Consequently, we concluded that further work is needed to address the gaps discussed, and clear evidence may arrive by using multi-omics investigations. Full article

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15 pages, 22181 KiB

Open AccessArticle

Activation of Coronary Arteriolar PKCβ2 Impairs Endothelial NO-Mediated Vasodilation: Role of JNK/Rho Kinase Signaling and Xanthine Oxidase Activation

by Naris Thengchaisri, Travis W. Hein, Yi Ren and Lih Kuo

Int. J. Mol. Sci. 2021, 22(18), 9763; https://doi.org/10.3390/ijms22189763 - 9 Sep 2021

Cited by 5 | Viewed by 2616

Abstract

Protein kinase C (PKC) activation can evoke vasoconstriction and contribute to coronary disease. However, it is unclear whether PKC activation, without activating the contractile machinery, can lead to coronary arteriolar dysfunction. The vasoconstriction induced by the PKC activator phorbol 12,13-dibutyrate (PDBu) was examined [...] Read more.

Protein kinase C (PKC) activation can evoke vasoconstriction and contribute to coronary disease. However, it is unclear whether PKC activation, without activating the contractile machinery, can lead to coronary arteriolar dysfunction. The vasoconstriction induced by the PKC activator phorbol 12,13-dibutyrate (PDBu) was examined in isolated porcine coronary arterioles. The PDBu-evoked vasoconstriction was sensitive to a broad-spectrum PKC inhibitor but not affected by inhibiting PKCβ2 or Rho kinase. After exposure of the vessels to a sub-vasomotor concentration of PDBu (1 nmol/L, 60 min), the endothelium-dependent nitric oxide (NO)-mediated dilations in response to serotonin and adenosine were compromised but the dilation induced by the NO donor sodium nitroprusside was unaltered. PDBu elevated superoxide production, which was blocked by the superoxide scavenger Tempol. The impaired NO-mediated vasodilations were reversed by Tempol or inhibition of PKCβ2, xanthine oxidase, c-Jun N-terminal kinase (JNK) and Rho kinase but were not affected by a hydrogen peroxide scavenger or inhibitors of NAD(P)H oxidase and p38 kinase. The PKCβ2 protein was detected in the arteriolar wall and co-localized with endothelial NO synthase. In conclusion, activation of PKCβ2 appears to compromise NO-mediated vasodilation via Rho kinase-mediated JNK signaling and superoxide production from xanthine oxidase, independent of the activation of the smooth muscle contractile machinery. Full article

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14 pages, 3334 KiB

Open AccessArticle

Methotrexate Ameliorates Systemic Inflammation and Septic Associated-Lung Damage in a Cecal Ligation and Puncture Septic Rat Model

by Josep Bringué, Raquel Guillamat-Prats, Maria Luisa Martinez, Eva Torrents, Marta Camprubí-Rimblas, Lluís Blanch and Antonio Artigas

Int. J. Mol. Sci. 2021, 22(17), 9612; https://doi.org/10.3390/ijms22179612 - 4 Sep 2021

Cited by 11 | Viewed by 3176

Abstract

Background: Sepsis is a serious, heterogeneous clinical entity produced by a severe and systemic host inflammatory response to infection. Methotrexate (MTX) is a folate-antagonist that induces the generation of adenosine and also inhibits JAK/STAT pathway; MTX it is widely used as an anti-inflammatory [...] Read more.

Background: Sepsis is a serious, heterogeneous clinical entity produced by a severe and systemic host inflammatory response to infection. Methotrexate (MTX) is a folate-antagonist that induces the generation of adenosine and also inhibits JAK/STAT pathway; MTX it is widely used as an anti-inflammatory drug to control the immune system. Objective: The aim of this study was to assess the beneficial effects of a single and low dose of MTX in the systemic response and acute lung injury (ALI) induced by sepsis. As in the clinics, we treated our animals with antibiotics and fluids and performed the source control to mimic the current clinic treatment. Methods and main results: Sepsis was induced in rats by a cecal ligation puncture (CLP) procedure. Six hours after induction of sepsis, we proceeded to the source control; fluids and antibiotics were administered at 6 h and 24 h after CLP. MTX (2.5 mg/Kg) was administered 6 h after the first surgery in one CLP experimental group and to one Sham group. A protective effect of MTX was observed through a significant reduction of pro-inflammatory cytokines and a decrease infiltration of inflammatory cells in the lung. In addition, we found a regulation in adenosine receptor A2aR and the metalloproteinases by MTX. Conclusion: A single, low dose of MTX attenuates sepsis lung-associated damage by decreasing pro-inflammatory response, infiltration of pro-inflammatory cells and avoiding defective tissue lung remodeling. Full article

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16 pages, 1188 KiB

Open AccessReview

Links between Infections, Lung Cancer, and the Immune System

by Liviuta Budisan, Oana Zanoaga, Cornelia Braicu, Radu Pirlog, Bogdan Covaliu, Victor Esanu, Schuyler S. Korban and Ioana Berindan-Neagoe

Int. J. Mol. Sci. 2021, 22(17), 9394; https://doi.org/10.3390/ijms22179394 - 30 Aug 2021

Cited by 46 | Viewed by 9466

Abstract

Lung cancer is the leading disease of cancer-related deaths worldwide. Since the beginning of the 20th century, various infectious agents associated with lung cancer have been identified. The mechanisms that include systemic inflammatory pathways as effect of microbial persistence in the lung can [...] Read more.

Lung cancer is the leading disease of cancer-related deaths worldwide. Since the beginning of the 20th century, various infectious agents associated with lung cancer have been identified. The mechanisms that include systemic inflammatory pathways as effect of microbial persistence in the lung can secondarily promote the development of lung carcinogenesis. Chronic inflammation associated with lung-cancer infections is known to precede tumor development, and it has a strong effect on the response(s) to therapy. In fact, both viral and bacterial infections can activate inflammatory cells and inflammatory signaling pathways. In this review, an overview of critical findings of recent studies investigating associations between each of viral and bacterial pathogens and lung carcinoma is provided, with particular emphasis on how infectious organisms can interfere with oncogenic processes and all the way through immunity. Moreover, a discussion of the direct crosstalk between lung tumor development and inflammatory processes is also presented. Full article

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10 pages, 9217 KiB

Open AccessBrief Report

Insulin Receptor Isoforms Differently Regulate Cell Proliferation and Apoptosis in the Ligand-Occupied and Unoccupied State

by Michele Massimino, Laura Sciacca, Nunziatina Laura Parrinello, Nunzio Massimo Scalisi, Antonino Belfiore, Riccardo Vigneri and Paolo Vigneri

Int. J. Mol. Sci. 2021, 22(16), 8729; https://doi.org/10.3390/ijms22168729 - 13 Aug 2021

Cited by 6 | Viewed by 2638

Abstract

The insulin receptor (IR) presents two isoforms (IR-A and IR-B) that differ for the α-subunit C-terminal. Both isoforms are expressed in all human cells albeit in different proportions, yet their functional properties-when bound or unbound to insulin-are not well characterized. From a cell [...] Read more.

The insulin receptor (IR) presents two isoforms (IR-A and IR-B) that differ for the α-subunit C-terminal. Both isoforms are expressed in all human cells albeit in different proportions, yet their functional properties-when bound or unbound to insulin-are not well characterized. From a cell model deprived of the Insulin-like Growth Factor 1 Receptor (IGF1-R) we therefore generated cells exhibiting no IR (R-shIR cells), or only human IR-A (R-shIR-A), or exclusively human IR-B (R-shIR-B) and we studied the specific effect of the two isoforms on cell proliferation and cell apoptosis. In the absence of insulin both IR-A and IR-B similarly inhibited proliferation but IR-B was 2–3 fold more effective than IR-A in reducing resistance to etoposide-induced DNA damage. In the presence of insulin, IR-A and IR-B promoted proliferation with the former significantly more effective than the latter at increasing insulin concentrations. Moreover, only insulin-bound IR-A, but not IR-B, protected cells from etoposide-induced cytotoxicity. In conclusion, IR isoforms have different effects on cell proliferation and survival. When unoccupied, IR-A, which is predominantly expressed in undifferentiated and neoplastic cells, is less effective than IR-B in protecting cells from DNA damage. In the presence of insulin, particularly when present at high levels, IR-A provides a selective growth advantage. Full article

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17 pages, 2371 KiB

Open AccessArticle

RT-qPCR Diagnostics: The “Drosten” SARS-CoV-2 Assay Paradigm

by Stephen Bustin, Sara Kirvell, Jim F. Huggett and Tania Nolan

Int. J. Mol. Sci. 2021, 22(16), 8702; https://doi.org/10.3390/ijms22168702 - 13 Aug 2021

Cited by 4 | Viewed by 6453

Abstract

The reverse transcription quantitative polymerase chain reaction (RT-qPCR) is an established tool for the diagnosis of RNA pathogens. Its potential for automation has caused it to be used as a presence/absence diagnostic tool even when RNA quantification is not required. This technology has [...] Read more.

The reverse transcription quantitative polymerase chain reaction (RT-qPCR) is an established tool for the diagnosis of RNA pathogens. Its potential for automation has caused it to be used as a presence/absence diagnostic tool even when RNA quantification is not required. This technology has been pushed to the forefront of public awareness by the COVID-19 pandemic, as its global application has enabled rapid and analytically sensitive mass testing, with the first assays targeting three viral genes published within days of the publication of the SARS-CoV-2 genomic sequence. One of those, targeting the RNA-dependent RNA polymerase gene, has been heavily criticised for supposed scientific flaws at the molecular and methodological level, and this criticism has been extrapolated to doubts about the validity of RT-qPCR for COVID-19 testing in general. We have analysed this assay in detail, and our findings reveal some limitations but also highlight the robustness of the RT-qPCR methodology for SARS-CoV-2 detection. Nevertheless, whilst our data show that some errors can be tolerated, it is always prudent to confirm that the primer and probe sequences complement their intended target, since, when errors do occur, they may result in a reduction in the analytical sensitivity. However, in this case, it is unlikely that a mismatch will result in poor specificity or a significant number of false-positive SARS-CoV-2 diagnoses, especially as this is routinely checked by diagnostic laboratories as part of their quality assurance. Full article

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23 pages, 7365 KiB

Open AccessArticle

A Time-Course Study of the Expression Level of Synaptic Plasticity-Associated Genes in Un-Lesioned Spinal Cord and Brain Areas in a Rat Model of Spinal Cord Injury: A Bioinformatic Approach

by Vito Antonio Baldassarro, Marco Sanna, Andrea Bighinati, Michele Sannia, Marco Gusciglio, Luciana Giardino, Luca Lorenzini and Laura Calzà

Int. J. Mol. Sci. 2021, 22(16), 8606; https://doi.org/10.3390/ijms22168606 - 10 Aug 2021

Cited by 8 | Viewed by 3470

Abstract

“Neuroplasticity” is often evoked to explain adaptation and compensation after acute lesions of the Central Nervous System (CNS). In this study, we investigated the modification of 80 genes involved in synaptic plasticity at different times (24 h, 8 and 45 days) from the [...] Read more.

“Neuroplasticity” is often evoked to explain adaptation and compensation after acute lesions of the Central Nervous System (CNS). In this study, we investigated the modification of 80 genes involved in synaptic plasticity at different times (24 h, 8 and 45 days) from the traumatic spinal cord injury (SCI), adopting a bioinformatic analysis. mRNA expression levels were analyzed in the motor cortex, basal ganglia, cerebellum and in the spinal segments rostral and caudal to the lesion. The main results are: (i) a different gene expression regulation is observed in the Spinal Cord (SC) segments rostral and caudal to the lesion; (ii) long lasting changes in the SC includes the extracellular matrix (ECM) enzymes Timp1, transcription regulators (Egr, Nr4a1), second messenger associated proteins (Gna1, Ywhaq); (iii) long-lasting changes in the Motor Cortex includes transcription regulators (Cebpd), neurotransmitters/neuromodulators and receptors (Cnr1, Gria1, Nos1), growth factors and related receptors (Igf1, Ntf3, Ntrk2), second messenger associated proteins (Mapk1); long lasting changes in Basal Ganglia and Cerebellum include ECM protein (Reln), growth factors (Ngf, Bdnf), transcription regulators (Egr, Cebpd), neurotransmitter receptors (Grin2c). These data suggest the molecular mapping as a useful tool to investigate the brain and SC reorganization after SCI. Full article

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14 pages, 2576 KiB

Open AccessArticle

A Novel Oxygen Carrier (M101) Attenuates Ischemia-Reperfusion Injuries during Static Cold Storage in Steatotic Livers

by Njikem Asong-Fontem, Arnau Panisello-Rosello, Alexandre Lopez, Katsunori Imai, Franck Zal, Eric Delpy, Joan Rosello-Catafau and René Adam

Int. J. Mol. Sci. 2021, 22(16), 8542; https://doi.org/10.3390/ijms22168542 - 9 Aug 2021

Cited by 13 | Viewed by 2916

Abstract

The combined impact of an increasing demand for liver transplantation and a growing incidence of nonalcoholic liver disease has provided the impetus for the development of innovative strategies to preserve steatotic livers. A natural oxygen carrier, HEMO2life^®, which contains M101 that [...] Read more.

The combined impact of an increasing demand for liver transplantation and a growing incidence of nonalcoholic liver disease has provided the impetus for the development of innovative strategies to preserve steatotic livers. A natural oxygen carrier, HEMO2life^®, which contains M101 that is extracted from a marine invertebrate, has been used for static cold storage (SCS) and has shown superior results in organ preservation. A total of 36 livers were procured from obese Zucker rats and randomly divided into three groups, i.e., control, SCS-24H and SCS-24H + M101 (M101 at 1 g/L), mimicking the gold standard of organ preservation. Ex situ machine perfusion for 2 h was used to evaluate the quality of the livers. Perfusates were sampled for functional assessment, biochemical analysis and subsequent biopsies were performed for assessment of ischemia-reperfusion markers. Transaminases, GDH and lactate levels at the end of reperfusion were significantly lower in the group preserved with M101 (p < 0.05). Protection from reactive oxygen species (low MDA and higher production of NO2-NO3) and less inflammation (HMGB1) were also observed in this group (p < 0.05). Bcl-1 and caspase-3 were higher in the SCS-24H group (p < 0.05) and presented more histological damage than those preserved with HEMO2life^®. These data demonstrate, for the first time, that the addition of HEMO2life^® to the preservation solution significantly protects steatotic livers during SCS by decreasing reperfusion injury and improving graft function. Full article

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12 pages, 2778 KiB

Open AccessArticle

Melatonin and Glycine Reduce Uterus Ischemia/Reperfusion Injury in a Rat Model of Warm Ischemia

by Viktorija Zitkute, Mindaugas Kvietkauskas, Vygante Maskoliunaite, Bettina Leber, Diana Ramasauskaite, Kestutis Strupas, Philipp Stiegler and Peter Schemmer

Int. J. Mol. Sci. 2021, 22(16), 8373; https://doi.org/10.3390/ijms22168373 - 4 Aug 2021

Cited by 5 | Viewed by 2252

Abstract

Ischemia/reperfusion injury (IRI) remains a significant problem to be solved in uterus transplantation (UTx). Melatonin and glycine have been shown to possess direct cytoprotective activities, mainly due to their antioxidative and anti-inflammatory properties. The aim of this study was to investigate the protective [...] Read more.

Ischemia/reperfusion injury (IRI) remains a significant problem to be solved in uterus transplantation (UTx). Melatonin and glycine have been shown to possess direct cytoprotective activities, mainly due to their antioxidative and anti-inflammatory properties. The aim of this study was to investigate the protective effects of melatonin and glycine and their combination on IRI in a rat model of warm ischemia. In this study, Sprague-Dawley rats were assigned to eight groups, including sham and IRI (n = 80). Melatonin and glycine alone or their combination were administered prior to 1 h of uterus ischemia followed by 1 h of reperfusion. Melatonin (50 mg/kg) was administered via gavage 2 h before IRI and glycine in an enriched diet for 5 days prior to intervention. Uterus IRI was estimated by histology, including immunohistochemistry, and biochemical tissue analyses. Histology revealed that uterus IRI was significantly attenuated by pretreatment with melatonin (p = 0.019) and glycine (p = 0.044) alone as well as their combination (p = 0.003). Uterus IRI led to increased myeloperoxidase expression, which was significantly reduced by melatonin (p = 0.004), glycine (p < 0.001) or their combination (p < 0.001). The decline in superoxide dismutase activity was significantly reduced in the melatonin (p = 0.027), glycine (p = 0.038) and combined treatment groups (p = 0.015) when compared to the IRI control group. In conclusion, melatonin, glycine and their combination significantly reduced oxidative stress-induced cell damage after IRI in a small animal warm ischemia model, and, therefore, clinical studies are required to evaluate the protective effects of these well-characterized substances in uterus IRI. Full article

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15 pages, 2608 KiB

Open AccessArticle

Cigarette Smoke Condensate Exposure Induces Receptor for Advanced Glycation End-Products (RAGE)-Dependent Sterile Inflammation in Amniotic Epithelial Cells

by Helena Choltus, Régine Minet-Quinard, Corinne Belville, Julie Durif, Denis Gallot, Loic Blanchon and Vincent Sapin

Int. J. Mol. Sci. 2021, 22(15), 8345; https://doi.org/10.3390/ijms22158345 - 3 Aug 2021

Cited by 8 | Viewed by 4278

Abstract

Maternal smoking is a risk factor of preterm prelabor rupture of the fetal membranes (pPROM), which is responsible for 30% of preterm births worldwide. Cigarettes induce oxidative stress and inflammation, mechanisms both implicated in fetal membranes (FM) weakening. We hypothesized that the receptor [...] Read more.

Maternal smoking is a risk factor of preterm prelabor rupture of the fetal membranes (pPROM), which is responsible for 30% of preterm births worldwide. Cigarettes induce oxidative stress and inflammation, mechanisms both implicated in fetal membranes (FM) weakening. We hypothesized that the receptor for advanced glycation end-products (RAGE) and its ligands can result in cigarette-dependent inflammation. FM explants and amniotic epithelial cells (AECs) were treated with cigarette smoke condensate (CSC), combined or not with RAGE antagonist peptide (RAP), an inhibitor of RAGE. Cell suffering was evaluated by measuring lactate dehydrogenase (LDH) medium-release. Extracellular HMGB1 (a RAGE ligand) release by amnion and choriodecidua explants were checked by western blot. NF-κB pathway induction was determined by a luciferase gene reporter assay, and inflammation was evaluated by cytokine RT-qPCR and protein quantification. Gelatinase activity was assessed using a specific assay. CSC induced cell suffering and HMGB1 secretion only in the amnion, which is directly associated with a RAGE-dependent response. CSC also affected AECs by inducing inflammation (cytokine release and NFκB activation) and gelatinase activity through RAGE engagement, which was linked to an increase in extracellular matrix degradation. This RAGE dependent CSC-induced inflammation associated with an increase of gelatinase activity could explain a pathological FM weakening directly linked to pPROM. Full article

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10 pages, 4696 KiB

Open AccessArticle

Efficient Generation of Neural Stem Cells from Embryonic Stem Cells Using a Three-Dimensional Differentiation System

by Sang-Hoon Yoon, Mi-Rae Bae, Hyeonwoo La, Hyuk Song, Kwonho Hong and Jeong-Tae Do

Int. J. Mol. Sci. 2021, 22(15), 8322; https://doi.org/10.3390/ijms22158322 - 3 Aug 2021

Cited by 6 | Viewed by 3564

Abstract

Mouse embryonic stem cells (ESCs) are useful tools for studying early embryonic development and tissue formation in mammals. Since neural lineage differentiation is a major subject of organogenesis, the development of efficient techniques to induce neural stem cells (NSCs) from pluripotent stem cells [...] Read more.

Mouse embryonic stem cells (ESCs) are useful tools for studying early embryonic development and tissue formation in mammals. Since neural lineage differentiation is a major subject of organogenesis, the development of efficient techniques to induce neural stem cells (NSCs) from pluripotent stem cells must be preceded. However, the currently available NSC differentiation methods are complicated and time consuming. This study aimed to propose an efficient method for the derivation of NSCs from mouse ESCs; early neural lineage commitment was achieved using a three-dimensional (3D) culture system, followed by a two-dimensional (2D) NSC derivation. To select early neural lineage cell types during differentiation, Sox1-GFP transgenic ESCs were used. They were differentiated into early neural lineage, forming spherical aggregates, which were subsequently picked for the establishment of 2D NSCs. The latter showed a morphology similar to that of brain-derived NSCs and expressed NSC markers, Musashi, Nestin, N-cadherin, and Sox2. Moreover, the NSCs could differentiate into three subtypes of neural lineages, neurons, astrocytes, and oligodendrocytes. The results together suggested that ESCs could efficiently differentiate into tripotent NSCs through specification in 3D culture (for approximately 10 days) followed by 2D culture (for seven days). Full article

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26 pages, 800 KiB

Open AccessReview

Mechanisms of Immunotoxicity: Stressors and Evaluators

by Maroun Bou Zerdan, Sara Moussa, Ali Atoui and Hazem I. Assi

Int. J. Mol. Sci. 2021, 22(15), 8242; https://doi.org/10.3390/ijms22158242 - 31 Jul 2021

Cited by 24 | Viewed by 6497

Abstract

The immune system defends the body against certain tumor cells and against foreign agents such as fungi, parasites, bacteria, and viruses. One of its main roles is to distinguish endogenous components from non-self-components. An unproperly functioning immune system is prone to primary immune [...] Read more.

The immune system defends the body against certain tumor cells and against foreign agents such as fungi, parasites, bacteria, and viruses. One of its main roles is to distinguish endogenous components from non-self-components. An unproperly functioning immune system is prone to primary immune deficiencies caused by either primary immune deficiencies such as genetic defects or secondary immune deficiencies such as physical, chemical, and in some instances, psychological stressors. In the manuscript, we will provide a brief overview of the immune system and immunotoxicology. We will also describe the biochemical mechanisms of immunotoxicants and how to evaluate immunotoxicity. Full article

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23 pages, 1451 KiB

Open AccessReview

Targeting Leukemic Stem Cells in Chronic Myeloid Leukemia: Is It Worth the Effort?

by Simona Soverini, Sara De Santis, Cecilia Monaldi, Samantha Bruno and Manuela Mancini

Int. J. Mol. Sci. 2021, 22(13), 7093; https://doi.org/10.3390/ijms22137093 - 30 Jun 2021

Cited by 23 | Viewed by 6251

Abstract

Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal translocation, that converts it into a leukemic stem cell (LSC). The resulting BCR-ABL1 fusion gene [...] Read more.

Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal translocation, that converts it into a leukemic stem cell (LSC). The resulting BCR-ABL1 fusion gene encodes a deregulated tyrosine kinase that is recognized as the disease driver. Therapy with tyrosine kinase inhibitors (TKIs) eliminates progenitor and more differentiated cells but fails to eradicate quiescent LSCs. Thus, although many patients obtain excellent responses and a proportion of them can even attempt treatment discontinuation (treatment free remission [TFR]) after some years of therapy, LSCs persist, and represent a potentially dangerous reservoir feeding relapse and hampering TFR. Over the past two decades, intensive efforts have been devoted to the characterization of CML LSCs and to the dissection of the cell-intrinsic and -extrinsic mechanisms sustaining their persistence, in an attempt to find druggable targets enabling LSC eradication. Here we provide an overview and an update on these mechanisms, focusing in particular on the most recent acquisitions. Moreover, we provide a critical appraisal of the clinical relevance and feasibility of LSC targeting in CML. Full article

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19 pages, 376 KiB

Open AccessReview

Inositols Depletion and Resistance: Principal Mechanisms and Therapeutic Strategies

by Elisa Lepore, Rosa Lauretta, Marta Bianchini, Marilda Mormando, Cherubino Di Lorenzo and Vittorio Unfer

Int. J. Mol. Sci. 2021, 22(13), 6796; https://doi.org/10.3390/ijms22136796 - 24 Jun 2021

Cited by 29 | Viewed by 7229

Abstract

Inositols are natural molecules involved in several biochemical and metabolic functions in different organs and tissues. The term “inositols” refers to five natural stereoisomers, among which myo-Inositol (myo-Ins) is the most abundant one. Several mechanisms contribute to regulate cellular and tissue homeostasis of [...] Read more.

Inositols are natural molecules involved in several biochemical and metabolic functions in different organs and tissues. The term “inositols” refers to five natural stereoisomers, among which myo-Inositol (myo-Ins) is the most abundant one. Several mechanisms contribute to regulate cellular and tissue homeostasis of myo-Ins levels, including its endogenous synthesis and catabolism, transmembrane transport, intestinal adsorption and renal excretion. Alterations in these mechanisms can lead to a reduction of inositols levels, exposing patient to several pathological conditions, such as Polycystic Ovary Syndrome (PCOS), hypothyroidism, hormonal and metabolic imbalances, like weight gain, hyperinsulinemia, dyslipidemia, and metabolic syndrome. Indeed, myo-Ins is involved in different physiological processes as a key player in signal pathways, including reproductive, hormonal, and metabolic modulation. Genetic mutations in genes codifying for proteins of myo-Ins synthesis and transport, competitive processes with structurally similar molecules, and the administration of specific drugs that cause a central depletion of myo-Ins as a therapeutic outcome, can lead to a reduction of inositols levels. A deeper knowledge of the main mechanisms involved in cellular inositols depletion may add new insights for developing tailored therapeutic approaches and shaping the dosages and the route of administration, with the aim to develop efficacious and safe approaches counteracting inositols depletion-induced pathological events. Full article

25 pages, 7582 KiB

Open AccessArticle

LRP5 Regulates HIF-1α Stability via Interaction with PHD2 in Ischemic Myocardium

by Sujin Ju, Leejin Lim, Kwanhwan Wi, Changwon Park, Young-Jae Ki, Dong-Hyun Choi and Heesang Song

Int. J. Mol. Sci. 2021, 22(12), 6581; https://doi.org/10.3390/ijms22126581 - 19 Jun 2021

Cited by 5 | Viewed by 2723

Abstract

Low-density lipoprotein receptor-related protein 5 (LRP5) has been studied as a co-receptor for Wnt/β-catenin signaling. However, its role in the ischemic myocardium is largely unknown. Here, we show that LRP5 may act as a negative regulator of ischemic heart injury via its interaction [...] Read more.

Low-density lipoprotein receptor-related protein 5 (LRP5) has been studied as a co-receptor for Wnt/β-catenin signaling. However, its role in the ischemic myocardium is largely unknown. Here, we show that LRP5 may act as a negative regulator of ischemic heart injury via its interaction with prolyl hydroxylase 2 (PHD2), resulting in hypoxia-inducible factor-1α (HIF-1α) degradation. Overexpression of LRP5 in cardiomyocytes promoted hypoxia-induced apoptotic cell death, whereas LRP5-silenced cardiomyocytes were protected from hypoxic insult. Gene expression analysis (mRNA-seq) demonstrated that overexpression of LRP5 limited the expression of HIF-1α target genes. LRP5 promoted HIF-1α degradation, as evidenced by the increased hydroxylation and shorter stability of HIF-1α under hypoxic conditions through the interaction between LRP5 and PHD2. Moreover, the specific phosphorylation of LRP5 at T1492 and S1503 is responsible for enhancing the hydroxylation activity of PHD2, resulting in HIF-1α degradation, which is independent of Wnt/β-catenin signaling. Importantly, direct myocardial delivery of adenoviral constructs, silencing LRP5 in vivo, significantly improved cardiac function in infarcted rat hearts, suggesting the potential value of LRP5 as a new target for ischemic injury treatment. Full article

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12 pages, 4054 KiB

Open AccessArticle

Empagliflozin Improves Metabolic and Hepatic Outcomes in a Non-Diabetic Obese Biopsy-Proven Mouse Model of Advanced NASH

by Nikolaos Perakakis, Pavlina Chrysafi, Michael Feigh, Sanne Skovgard Veidal and Christos S. Mantzoros

Int. J. Mol. Sci. 2021, 22(12), 6332; https://doi.org/10.3390/ijms22126332 - 13 Jun 2021

Cited by 21 | Viewed by 4165

Abstract

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on [...] Read more.

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions. Full article

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10 pages, 1705 KiB

Open AccessCommunication

[β-Glu²]TRH Is a Functional Antagonist of Thyrotropin-Releasing Hormone (TRH) in the Rodent Brain

by Katalin Prokai-Tatrai, Vien Nguyen and Laszlo Prokai

Int. J. Mol. Sci. 2021, 22(12), 6230; https://doi.org/10.3390/ijms22126230 - 9 Jun 2021

Cited by 2 | Viewed by 2808

Abstract

Selective antagonists of thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH₂), in order to enable a better understanding of this peptide’s central functions, have not been identified. Using pGlu-Glu-Pro-NH₂ ([Glu²]TRH) as a lead peptide and with modification at its central residue, our [...] Read more.

Selective antagonists of thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH₂), in order to enable a better understanding of this peptide’s central functions, have not been identified. Using pGlu-Glu-Pro-NH₂ ([Glu²]TRH) as a lead peptide and with modification at its central residue, our studies focused on some of its analogues synthesized as potential functional antagonists of TRH in the rodent brain. Among the peptides studied, the novel isomeric analogue [β-Glu²]TRH was found to suppress the analeptic and antidepressant-like pharmacological activities of TRH without eliciting intrinsic effects in these paradigms. [β-Glu²]TRH also completely reversed TRH’s stimulation of acetylcholine turnover in the rat hippocampus without a cholinergic activity of its own, which was demonstrated through in vivo microdialysis experiments. Altogether, [β-Glu²]TRH emerged as the first selective functional antagonist of TRH’s prominent cholinergic actions, by which this endogenous peptide elicits a vast array of central effects. Full article

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Graphical abstract

13 pages, 1476 KiB

Open AccessArticle

3′ Tth Endonuclease Cleavage Polymerase Chain Reaction (3TEC-PCR) Technology for Single-Base-Specific Multiplex Pathogen Detection using a Two-Oligonucleotide System

by Owen Higgins and Terry J. Smith

Int. J. Mol. Sci. 2021, 22(11), 6061; https://doi.org/10.3390/ijms22116061 - 4 Jun 2021

Cited by 2 | Viewed by 2988

Abstract

Polymerase chain reaction (PCR) is the standard in nucleic acid amplification technology for infectious disease pathogen detection and has been the primary diagnostic tool employed during the global COVID-19 pandemic. Various PCR technology adaptations, typically using two-oligonucleotide dye-binding methods or three-oligonucleotide hydrolysis probe [...] Read more.

Polymerase chain reaction (PCR) is the standard in nucleic acid amplification technology for infectious disease pathogen detection and has been the primary diagnostic tool employed during the global COVID-19 pandemic. Various PCR technology adaptations, typically using two-oligonucleotide dye-binding methods or three-oligonucleotide hydrolysis probe systems, enable real-time multiplex target detection or single-base specificity for the identification of single-nucleotide polymorphisms (SNPs). A small number of two-oligonucleotide PCR systems facilitating both multiplex detection and SNP identification have been reported; however, these methods often have limitations in terms of target specificity, production of variable or false-positive results, and the requirement for extensive optimisation or post-amplification analysis. This study introduces 3′ Tth endonuclease cleavage PCR (3TEC-PCR), a two-oligonucleotide PCR system incorporating a modified primer/probe and a thermostable cleavage enzyme, Tth endonuclease IV, for real-time multiplex detection and SNP identification. Complete analytical specificity, low limits of detection, single-base specificity, and simultaneous multiple target detection have been demonstrated in this study using 3TEC-PCR to identify bacterial meningitis associated pathogens. This is the first report of a two-oligonucleotide, real-time multiplex PCR technology with single-base specificity using Tth endonuclease IV. Full article

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16 pages, 26645 KiB

Open AccessArticle

Polycystin-1 Enhances Stemmness Potential of Umbilical Cord Blood-Derived Mesenchymal Stem Cells

by Se-Hwa Jung, Ji-Eun You, Soon-Won Choi, Kyung-Sun Kang, Je-Yeol Cho, Jungmook Lyu and Pyung-Hwan Kim

Int. J. Mol. Sci. 2021, 22(9), 4868; https://doi.org/10.3390/ijms22094868 - 4 May 2021

Cited by 3 | Viewed by 2587

Abstract

Polycystic Kidney Disease (PKD) is a disorder that affects the kidneys and other organs, and its major forms are encoded by polycystin-1 (PC1) and polycystin-2 (PC2), as PKD1 and PKD2. It is located sandwiched inside and outside [...] Read more.

Polycystic Kidney Disease (PKD) is a disorder that affects the kidneys and other organs, and its major forms are encoded by polycystin-1 (PC1) and polycystin-2 (PC2), as PKD1 and PKD2. It is located sandwiched inside and outside cell membranes and interacts with other cells. This protein is most active in kidney cells before birth, and PC1 and PC2 work together to help regulate cell proliferation, cell migration, and interactions with other cells. The molecular relationship and the function between PKD1 and cancer is well known, such as increased or decreased cell proliferation and promoting or suppressing cell migration depending on the cancer cell type specifically. However, its function in stem cells has not been revealed. Therefore, in this study, we investigated the biological function of PC1 and umbilical cord blood-derived mesenchymal stem cell (UCB-MSC). Furthermore, we assessed how it affects cell migration, proliferation, and the viability of cells when expressed in the PKD1 gene. In addition, we confirmed in an ex vivo artificial tooth model generated by the three-dimension printing technique that the ability to differentiate into osteocytes improved according to the expression level of the stemness markers when PKD1 was expressed. This study is the first report to examine the biological function of PKD1 in UCB-MSC. This gene may be capable of enhancing differentiation ability and maintaining long-term stemness for the therapeutic use of stem cells. Full article

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17 pages, 6186 KiB

Open AccessArticle

Distinct Expression Patterns of Cxcl12 in Mesenchymal Stem Cell Niches of Intact and Injured Rodent Teeth

by Pierfrancesco Pagella, César Nombela-Arrieta and Thimios A. Mitsiadis

Int. J. Mol. Sci. 2021, 22(6), 3024; https://doi.org/10.3390/ijms22063024 - 16 Mar 2021

Cited by 9 | Viewed by 3823

Abstract

Specific stem cell populations within dental mesenchymal tissues guarantee tooth homeostasis and regeneration throughout life. The decision between renewal and differentiation of stem cells is greatly influenced by interactions with stromal cells and extracellular matrix molecules that form the tissue specific stem cell [...] Read more.

Specific stem cell populations within dental mesenchymal tissues guarantee tooth homeostasis and regeneration throughout life. The decision between renewal and differentiation of stem cells is greatly influenced by interactions with stromal cells and extracellular matrix molecules that form the tissue specific stem cell niches. The Cxcl12 chemokine is a general marker of stromal cells and plays fundamental roles in the maintenance, mobilization and migration of stem cells. The aim of this study was to exploit Cxcl12-GFP transgenic mice to study the expression patterns of Cxcl12 in putative dental niches of intact and injured teeth. We showed that endothelial and stromal cells expressed Cxcl12 in the dental pulp tissue of both intact molars and incisors. Isolated non-endothelial Cxcl12⁺ dental pulp cells cultured in different conditions in vitro exhibited expression of both adipogenic and osteogenic markers, thus suggesting that these cells possess multipotent fates. Taken together, our results show that Cxcl12 is widely expressed in intact and injured teeth and highlight its importance as a key component of the various dental mesenchymal stem cell niches. Full article

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