Biomedicines

17 pages, 7588 KiB

Open AccessArticle

Inactivation of Yes-Associated Protein Mediates Trophoblast Dysfunction: A New Mechanism of Pregnancy Loss Associated with Anti-Phospholipid Antibodies?

by Zengshu Huang, Zhijing Tang, Haiyun Guan, Wingting Leung, Lu Wang, Hexia Xia and Wei Zhang

Biomedicines 2022, 10(12), 3296; https://doi.org/10.3390/biomedicines10123296 - 19 Dec 2022

Cited by 2 | Viewed by 2037

Abstract

Pregnancy morbidity induced by anti-phospholipid antibodies (aPL+/PM+) is mainly thought to arise from placental abnormalities. We attempted to investigate the effect of aPL on the activity of Yes-associated protein (YAP) in the trophoblast and how YAP regulated human trophoblasts function. Thus, HTR-8 cells [...] Read more.

Pregnancy morbidity induced by anti-phospholipid antibodies (aPL+/PM+) is mainly thought to arise from placental abnormalities. We attempted to investigate the effect of aPL on the activity of Yes-associated protein (YAP) in the trophoblast and how YAP regulated human trophoblasts function. Thus, HTR-8 cells were treated with IgG purified from aPL+/PM+ women or normal controls. We found that aPL+/PM+ IgG impacted YAP activity via abrogating YAP expression. Further investigation of the anti-β2GPI-IgG/β2GPI complex showed an inhibition of nuclear YAP level and translocation in a dose-dependent manner, which might be rescued by progesterone in HTR-8 cells. YAP overexpression or knockdown HTR-8 cells were established for the evaluation of cell function and related gene expression in vitro. Loss of YAP arrested cell cycles in the G2/M phase, accelerated cell apoptosis by increasing the ratio of Bax/Bcl2, and disrupted MMP2/9-mediated cell migration and angiogenesis tube formation by VEGF. These findings support a new mechanism of PM associated with aPL through which YAP inactivation induced by aPL perturbs the trophoblast cell cycle, apoptosis, migration, and angiogenesis, finally developing into pregnancy failure. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines-Immunopathogenesis of Autoimmune Diseases)

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15 pages, 2642 KiB

Open AccessArticle

Re-Analysis of Single-Nucleus Transcriptomics Reveals Diverse Dorsal Root Ganglia Macrophage Responses Following Peripheral Nerve Injury

by Nea Korvenlaita and Lauri Louhivuori

Biomedicines 2022, 10(12), 3295; https://doi.org/10.3390/biomedicines10123295 - 19 Dec 2022

Cited by 2 | Viewed by 1849

Abstract

An increasing amount of evidence points to an important role of macrophages in peripheral nerve injury (PNI) and associated pain. Peripheral nerve macrophages facilitate the regeneration, while dorsal root ganglia (DRG) macrophages might propagate the injury after a PNI. These differences might be [...] Read more.

An increasing amount of evidence points to an important role of macrophages in peripheral nerve injury (PNI) and associated pain. Peripheral nerve macrophages facilitate the regeneration, while dorsal root ganglia (DRG) macrophages might propagate the injury after a PNI. These differences might be explained by various in vivo models of PNIs or non-uniform methodologies to phenotype the macrophages. Unbiased methods to phenotype macrophages using single whole cell or nucleus transcriptomics have been rarely applied on PNIs outside the nerves themselves. Here, we compare the effects of the transection or crush of the sciatic nerve and spinal nerve transection on the DRG macrophage phenotypes utilizing a publicly available single-nucleus transcriptomic DRG dataset. Our results demonstrate that unique and time-dependent DRG macrophage gene expression profiles were produced by the three PNI models with particular macrophage clusters being enriched that were dependent on the severity of the neuronal injury score. PNI associated DRG macrophages were not purely anti- or pro-inflammatory. These results suggest that various functions of DRG macrophage subtypes are carefully orchestrated upon a PNI. These findings open a new avenue for studying the DRG macrophage subtypes in PNIs and encourage further unbiased phenotyping efforts to better understand their relevance in neuropathic pain. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 3.0)

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21 pages, 1470 KiB

Open AccessReview

New Insights into the Use of Empagliflozin—A Comprehensive Review

by Joanna Forycka, Joanna Hajdys, Julia Krzemińska, Piotr Wilczopolski, Magdalena Wronka, Ewelina Młynarska, Jacek Rysz and Beata Franczyk

Biomedicines 2022, 10(12), 3294; https://doi.org/10.3390/biomedicines10123294 - 19 Dec 2022

Cited by 12 | Viewed by 5939

Abstract

Empagliflozin is a relatively new drug that, as an inhibitor of the sodium–glucose cotransporter 2 (SGLT2), causes increased urinary glucose excretion and thus contributes to improved glycemic control, better glucose metabolism, reduced glucotoxicity and insulin resistance. Although its original use was to induce [...] Read more.

Empagliflozin is a relatively new drug that, as an inhibitor of the sodium–glucose cotransporter 2 (SGLT2), causes increased urinary glucose excretion and thus contributes to improved glycemic control, better glucose metabolism, reduced glucotoxicity and insulin resistance. Although its original use was to induce a hypoglycemic effect in patients with type 2 diabetes mellitus (T2DM), empagliflozin has also shown a number of other beneficial effects by demonstrating a nephroprotective effect, and it has proven to be a breakthrough in the treatment of heart failure (HF). Empagliflozin has been shown to reduce hospitalizations for HF and the number of deaths from cardiovascular causes. Empagliflozin treatment also reduces the incidence of renal events, including death from renal causes, as well as the risk of end-stage renal failure. Empagliflozin appears to be a fairly well-tolerated and safe drug. In patients with inadequate glycemic control, empagliflozin used in monotherapy or as an adjunct to therapy effectively lowers fasting blood glucose, postprandial blood glucose, average daily glucose levels, glycated hemoglobin A_1C (HbA_1C) and also leads to significant weight reduction in patients with T2DM. Unfortunately, there are some limitations, e.g., severe hypersensitivity reaction to the drug and a glomerular filtration rate (GFR) < 30 mL/min/1.73 m². As with any drug, empagliflozin is also characterized by several side effects among which symptomatic hypotension, troublesome genital fungal infections, urinary tract infections and rare ketoacidosis are characteristic. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Advances in New Pharmacological Therapies)

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13 pages, 4032 KiB

Open AccessArticle

Arsenic Trioxide Triggers Apoptosis of Metastatic Oral Squamous Cells Carcinoma with Concomitant Downregulation of GLI1 in Hedgehog Signaling

by Raphael Luís Rocha Nogueira, Taís Bacelar Sacramento de Araújo, Ludmila Faro Valverde, Viviane Aline Oliveira Silva, Bruno Raphael Ribeiro Cavalcante, Erik Aranha Rossi, Kyan James Allahdadi, Mitermayer Galvão dos Reis, Thiago Almeida Pereira, Ricardo D. Coletta, Daniel Pereira Bezerra, Bruno Solano de Freitas Souza, Rosane Borges Dias and Clarissa A. Gurgel Rocha

Biomedicines 2022, 10(12), 3293; https://doi.org/10.3390/biomedicines10123293 - 19 Dec 2022

Cited by 4 | Viewed by 2357

Abstract

Given the lack of advances in Oral Squamous Cell Carcinoma (OSCC) therapy in recent years, pharmacological strategies to block OSCC-related signaling pathways have gained prominence. The present study aimed to evaluate the therapeutic potential of Arsenic Trioxide (ATO) concerning its antitumoral effects and [...] Read more.

Given the lack of advances in Oral Squamous Cell Carcinoma (OSCC) therapy in recent years, pharmacological strategies to block OSCC-related signaling pathways have gained prominence. The present study aimed to evaluate the therapeutic potential of Arsenic Trioxide (ATO) concerning its antitumoral effects and the inhibition of the Hedgehog (HH) pathway in OSCC. Initially, ATO cytotoxicity was assessed in a panel of cell lines. Cell viability, cell cycle, death patterns, and cell morphology were analyzed, as well as the effect of ATO on the expression of HH pathway components. After the cytotoxic assay, HSC3 cells were chosen for all in vitro assays. ATO increased apoptotic cell death and nuclear fragmentation in the sub-G1 cell cycle phase and promoted changes in cell morphology. In addition, the reduced expression of GLI1 indicated that ATO inhibits HH activity. The present study provides evidence of ATO as an effective cytotoxic drug for oral cancer treatment in vitro. Full article

(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy 2.0)

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14 pages, 457 KiB

Open AccessReview

What Are the Roles of Proprotein Convertases in the Immune Escape of Tumors?

by Elham Mehranzadeh, Olatz Crende, Iker Badiola and Patricia Garcia-Gallastegi

Biomedicines 2022, 10(12), 3292; https://doi.org/10.3390/biomedicines10123292 - 19 Dec 2022

Cited by 6 | Viewed by 2298

Abstract

Protein convertases (PCs) play a significant role in post-translational procedures by transforming inactive precursor proteins into their active forms. The role of PCs is crucial for cellular homeostasis because they are involved in cell signaling. They have also been described in many diseases [...] Read more.

Protein convertases (PCs) play a significant role in post-translational procedures by transforming inactive precursor proteins into their active forms. The role of PCs is crucial for cellular homeostasis because they are involved in cell signaling. They have also been described in many diseases such as Alzheimer’s and cancer. Cancer cells are secretory cells that send signals to the tumor microenvironment (TME), remodeling the surrounding space for their own benefits. One of the most important components of the TME is the immune system of the tumor. In this review, we describe recent discoveries that link PCs to the immune escape of tumors. Among PCs, many findings have determined the role of Furin (PC3) as a paramount enzyme causing the TME to induce tumor immune evasion. The overexpression of various cytokines and proteins, for instance, IL10 and TGF-B, moves the TME towards the presence of Tregs and, consequently, immune tolerance. Furthermore, Furin is implicated in the regulation of macrophage activity that contributes to the increased impairment of DCs (dendritic cells) and T effector cells. Moreover, Furin interferes in the MHC Class_1 proteolytic cleavage in the trans-Golgi network. In tumors, the T cytotoxic lymphocytes (CTLs) response is impeded by the PD1 receptor (PD1-R) located on CTLs and its ligand, PDL1, located on cancer cells. The inhibition of Furin is a subtle means of enhancing the antitumor response by repressing PD-1 expression in tumors or macrophage cells. The impacts of other PCs in tumor immune escape have not yet been clarified to the extent that Furin has. Accordingly, the influence of other types of PCs in tumor immune escape is a promising topic for further consideration. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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12 pages, 504 KiB

Open AccessArticle

Delphi-Based Consensus on Interstitial Lung Disease Screening in Patients with Connective Tissue Diseases (Croatian National-Based Study)

by Mislav Radić, Srđan Novak, Marko Barešić, Ana Hećimović, Dijana Perković, Jasna Tekavec-Trkanjec, Miroslav Mayer, Višnja Prus, Jadranka Morović-Vergles, Daniela Marasović Krstulović, Mislav Cerovec, Ljiljana Bulat Kardum, Miroslav Samaržija and Branimir Anić

Biomedicines 2022, 10(12), 3291; https://doi.org/10.3390/biomedicines10123291 - 19 Dec 2022

Cited by 8 | Viewed by 3109

Abstract

The aim of this study was to develop a Croatian Delphi-based expert consensus for screening interstitial lung disease (ILD) associated with connective tissue disease (CTD). A systematic literature review was conducted on risk factors for the development of ILD, prevalence and incidence of [...] Read more.

The aim of this study was to develop a Croatian Delphi-based expert consensus for screening interstitial lung disease (ILD) associated with connective tissue disease (CTD). A systematic literature review was conducted on risk factors for the development of ILD, prevalence and incidence of ILD, diagnostic and screening methods for ILD, and prognosis of ILD in idiopathic inflammatory myopathy (IIM), mixed connective tissue disease (MCTD), primary Sjögren’s syndrome (pSS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) were performed. Based on the evidence found, experts developed questionnaires for screening and monitoring ILD in each CTD, which were provided via an online survey. Following the electronic survey, two screening algorithms were developed based on the consensus opinions. The detection strategy for ILD included high-resolution computed tomography (HRCT) in addition to pulmonary function testing for IIM, MCTD, and SSc. and pulmonary function testing for newly diagnosed pSS, RA and SLE. However, in patients with identified risk factors for ILD HRCT, these tests should also be performed. A screening strategy for early identification of patients with various CTD-ILD was first developed by a multidisciplinary team of rheumatologists, pulmonologists, and radiologists to identify early CTD patients at risk of ILD, a severe extra-articular manifestation of CTD. Full article

(This article belongs to the Special Issue Frontiers of Targeted Therapy and Predictors of Treatment Response in Systemic Sclerosis)

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24 pages, 2468 KiB

Open AccessReview

A Bio-Social Model during the First 1000 Days Optimizes Healthcare for Children with Developmental Disabilities

by Mark S. Scher

Biomedicines 2022, 10(12), 3290; https://doi.org/10.3390/biomedicines10123290 - 19 Dec 2022

Cited by 13 | Viewed by 3252

Abstract

Most children with developmental disabilities (DD) live in resource-limited countries (LMIC) or high-income country medical deserts (HICMD). A social contract between healthcare providers and families advocates for accurate diagnoses and effective interventions to treat diseases and toxic stressors. This bio-social model emphasizes reproductive [...] Read more.

Most children with developmental disabilities (DD) live in resource-limited countries (LMIC) or high-income country medical deserts (HICMD). A social contract between healthcare providers and families advocates for accurate diagnoses and effective interventions to treat diseases and toxic stressors. This bio-social model emphasizes reproductive health of women with trimester-specific maternal and pediatric healthcare interactions. Lifelong neuronal connectivity is more likely established across 80% of brain circuitries during the first 1000 days. Maladaptive gene-environment (G x E) interactions begin before conception later presenting as maternal-placental-fetal (MPF) triad, neonatal, or childhood neurologic disorders. Synergy between obstetrical and pediatric healthcare providers can reduce neurologic morbidities. Partnerships between healthcare providers and families should begin during the first 1000 days to address diseases more effectively to moderate maternal and childhood adverse effects. This bio-social model lowers the incidence and lessens the severity of sequalae such as DD. Access to genetic-metabolomic, neurophysiologic and neuroimaging evaluations enhances clinical decision-making for more effective interventions before full expression of neurologic dysfunction. Diagnostic accuracy facilitates developmental interventions for effective preschool planning. A description of a mother-child pair in a HIC emphasizes the time-sensitive importance for early interventions that influenced brain health throughout childhood. Partnership by her parents with healthcare providers and educators provided effective healthcare and lessened adverse effects. Effective educational interventions were later offered through her high school graduation. Healthcare disparities in LMIC and HICMD require that this bio-social model of care begin before the first 1000 days to effectively treat the most vulnerable women and children. Prioritizing family planning followed by prenatal, neonatal and child healthcare improves wellness and brain health. Familiarity with educational neuroscience for teachers applies neurologic diagnoses for effective individual educational plans. Integrating diversity and inclusion into medical and educational services cross socioeconomic, ethnic, racial, and cultural barriers with life-course benefits. Families require knowledge to recognize risks for their children and motivation to sustain relationships with providers and educators for optimal outcomes. The WHO sustainable development goals promote brain health before conception through the first 1000 days. Improved education, employment, and social engagement for all persons will have intergenerational and transgenerational benefits for communities and nations. Full article

(This article belongs to the Special Issue Neurodevelopmental Disabilities)

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11 pages, 857 KiB

Open AccessArticle

Cytokine Profiles Differentiate Symptomatic from Asymptomatic PTSD in Service Members and Veterans with Chronic Traumatic Brain Injury

by Ethan G. Smith, James Hentig, Carina Martin, Chelsea Wagner, Vivian A. Guedes, Katie A. Edwards, Christina Devoto, Kerri Dunbar, Michael J. Roy and Jessica M. Gill

Biomedicines 2022, 10(12), 3289; https://doi.org/10.3390/biomedicines10123289 - 19 Dec 2022

Cited by 1 | Viewed by 1923

Abstract

Traumatic brain injuries (TBI) and posttraumatic stress disorder (PTSD) are commonly observed comorbid occurrences among military service members and veterans (SMVs). In this cross-sectional study, SMVs with a history of TBI were stratified into symptomatic and asymptomatic PTSD groups based on posttraumatic stress [...] Read more.

Traumatic brain injuries (TBI) and posttraumatic stress disorder (PTSD) are commonly observed comorbid occurrences among military service members and veterans (SMVs). In this cross-sectional study, SMVs with a history of TBI were stratified into symptomatic and asymptomatic PTSD groups based on posttraumatic stress checklist-civilian (PCL-C) total scores. Blood-based biomarkers were assessed, and significant differential markers were associated with scores from multiple neurobehavioral self-report assessments. PCL-C cutoffs were total scores >50 (PTSD symptomatic) and <25 (asymptomatic). Cytokines IL6, IL8, TNFα, and IL10 were significantly elevated (p < 0.05–0.001) in the TBI+/PTSD symptomatic group compared to the TBI+/asymptomatic group. Cytokine levels of IL8, TNFα, and IL10 were strongly associated with PCL-C scores (0.356 < r > 0.624 for all, p < 0.01 for all), while TNFα and IL10 were additionally associated with NSI totals (r = 0.285 and r = 0.270, p < 0.05, respectively). This is the first study focused on PTSD symptom severity to report levels of circulating pro-inflammatory IL8, specifically in SMVs with TBI. These data suggest that within the military TBI population, there are unique cytokine profiles that relate to neurobehavioral outcomes associated with TBI and PTSD. Full article

(This article belongs to the Special Issue Molecular Research of Neurodegenerative and Psychiatric Diseases)

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14 pages, 1066 KiB

Open AccessSystematic Review

Prognostic and Predictive Biomarkers in Head and Neck Squamous Cell Carcinoma Treated with Radiotherapy—A Systematic Review

by Daniel H. Schanne, Alexander Koch, Olgun Elicin, Roland Giger, Michaela Medová, Yitzhak Zimmer and Daniel M. Aebersold

Biomedicines 2022, 10(12), 3288; https://doi.org/10.3390/biomedicines10123288 - 19 Dec 2022

Cited by 3 | Viewed by 2504

Abstract

Background: Radiotherapy is a mainstay in head and neck squamous cell carcinoma (HNSCC) treatment but is mostly applied without stratification by molecular diagnostics. Development of reliable biomarkers may have the potential to improve radiotherapy (RT) efficacy and reduce toxicity. We conducted a [...] Read more.

Background: Radiotherapy is a mainstay in head and neck squamous cell carcinoma (HNSCC) treatment but is mostly applied without stratification by molecular diagnostics. Development of reliable biomarkers may have the potential to improve radiotherapy (RT) efficacy and reduce toxicity. We conducted a systematic review to summarize the field of biomarkers in HNSCC treated by RT. Methods: Pubmed and EMBASE were searched independently by two researchers following pre-defined inclusion and exclusion criteria. Z curves were generated to investigate publication bias. OncoKB was used for identification of druggable targets. Results: 134 manuscripts remained for data extraction. 12% of tumors were AJCC/UICC stage I–II and 82% were stage III–IV. The most common biomarkers were proteins (39%), DNA (14%) and mRNA (9%). Limiting analysis to prospective data and statistically significant results, we found three potentially druggable targets: ERCC2, PTCH1 and EGFR. Regarding data quality, AJCC/UICC stage was missing in 32% of manuscripts. 73% of studies were retrospective and only 7% were based on prospective randomized trials. Z-curves indicated the presence of publication bias. Conclusion: An abundance of potential biomarkers in HNSCC is available but data quality is limited by retrospective collection, lack of validation and publication bias. Improved study design and reporting quality might accelerate successful development of personalized treatments in HNSCC. Full article

(This article belongs to the Special Issue Head and Neck Cancers: Diagnosis, Therapy, Molecular and Cellular Mechanisms)

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15 pages, 1801 KiB

Open AccessArticle

Investigating the Antibacterial Properties of Prospective Scabicides

by Sara Taylor, Deonne Walther, Deepani D. Fernando, Pearl Swe-Kay and Katja Fischer

Biomedicines 2022, 10(12), 3287; https://doi.org/10.3390/biomedicines10123287 - 19 Dec 2022

Cited by 2 | Viewed by 2882

Abstract

Scabies is a dermatological disease found worldwide. Mainly in tropical regions, it is also the cause of significant morbidity and mortality due to its association with potentially severe secondary bacterial infections. Current treatment strategies for scabies do not consider the role of opportunistic [...] Read more.

Scabies is a dermatological disease found worldwide. Mainly in tropical regions, it is also the cause of significant morbidity and mortality due to its association with potentially severe secondary bacterial infections. Current treatment strategies for scabies do not consider the role of opportunistic bacteria, and here we investigate whether current and emerging scabicides can offer any anti-bacterial protection. Using the broth microdilution method, we examined antimicrobial potential of the current scabicide ivermectin and emerging scabies treatments: abametapir, mānuka oil, and its individual β-triketones. Our results demonstrate that the two novel scabicides abametapir and mānuka oil have antimicrobial properties against common scabies-associated bacteria, specifically Staphylococcus aureus, Streptococcus pyogenes, Streptococcus dysgalactiae subsp. equisimilis and Acinetobacter baumannii. The current scabicide ivermectin offers some antimicrobial activity and is capable of inhibiting the growth aforementioned bacteria. This research is important as it could help to inform future best treatment options of scabies, and scabies-related impetigo. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Host-Bacterial Pathogen Interactions: Novel Promising Drug Targets)

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13 pages, 2626 KiB

Open AccessArticle

Hypoxia-Induced Downregulation of miR-29 in Renal Tumor Cells Affects Collagen IV Subunit Expression through Multiple Sites

by Chuncheng Liu, Linan Liu, Jinlai Bo, Xian Lu, Donghui Qu, Gehui Liu, Zhiyan Jiang and Lu Cai

Biomedicines 2022, 10(12), 3286; https://doi.org/10.3390/biomedicines10123286 - 19 Dec 2022

Cited by 1 | Viewed by 1752

Abstract

Multiple tumor exacerbations and treatment procedures, such as extracellular matrix remodeling, metabolic reprogramming, immunological evasion, and resistance to chemotherapy and radiotherapy, are influenced by intratumoral hypoxia. It is becoming increasingly clear how hypoxia interacts with the extracellular matrix and how this affects the [...] Read more.

Multiple tumor exacerbations and treatment procedures, such as extracellular matrix remodeling, metabolic reprogramming, immunological evasion, and resistance to chemotherapy and radiotherapy, are influenced by intratumoral hypoxia. It is becoming increasingly clear how hypoxia interacts with the extracellular matrix and how this affects the growth of cancer. We analyzed the published sequencing results of hypoxia-stressed mouse kidney tumor cells and found that the expression of miR-29b was significantly downregulated. There are several sites that are complementary to the miR-29 seed sequence in the 3’ non-coding regions (3’UTRs) of various extracellular matrix-related genes, including collagen IV. We analyzed the sequences of the 3’UTRs of different subunits of collagen IV in different species and constructed the corresponding phylogenetic trees. We found that the 3’UTRs of Col4a1 and Col4a4 may have been subjected to particular evolutionary pressures. By cloning the 3’UTRs of collagen IV subunits into the psiCHECK^TM-2 vector, we found that seven of the eight sites in the Col4a3–Col4a6 gene complementary to miR-29 were significantly repressed by miR-29a, b (except for the 7774–7781 of Col4a3 gene). The inhibitory efficiency of miR-29a, b on these seven sites was between 27% and 57%. The research on the regulation of miR-29 and extracellular matrix by hypoxia can provide a theoretical basis for tumor and fibrosis research and treatment. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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23 pages, 7651 KiB

Open AccessArticle

Synbiotic Intervention Ameliorates Oxidative Stress and Gut Permeability in an In Vitro and In Vivo Model of Ethanol-Induced Intestinal Dysbiosis

by Dhara Patel, Chirayu Desai, Deepmala Singh, Virupakshi Soppina, Kirti Parwani, Farhin Patel and Palash Mandal

Biomedicines 2022, 10(12), 3285; https://doi.org/10.3390/biomedicines10123285 - 19 Dec 2022

Cited by 6 | Viewed by 2537

Abstract

Alcoholic liver disease (ALD) alters gut microbiota and tight junctions, causing bacterial components to enter the portal vein and induce oxidative stress-induced inflammation in the liver. Only corticosteroids and liver transplants are treatment options for severe alcoholic hepatitis. ALD’s pathophysiology is unknown. However, [...] Read more.

Alcoholic liver disease (ALD) alters gut microbiota and tight junctions, causing bacterial components to enter the portal vein and induce oxidative stress-induced inflammation in the liver. Only corticosteroids and liver transplants are treatment options for severe alcoholic hepatitis. ALD’s pathophysiology is unknown. However, acetaldehyde’s toxic effects cause oxidative stress and intestinal permeability. This study investigates the influence of a synbiotic (a combination of aged garlic extract (AGE) and Lactobacillus rhamnosus MTCC1423) on colonic oxidative stress and inflammation in ALD male Wistar rats and Caco2 cells. MDA measurement by HPLC in CaCo2 cells, blood serum, and colon tissue demonstrated that synbiotic treatment in the ALD model reduces oxidative stress. Further, fecal high-throughput 16S rRNA gene sequencing revealed the microbiome’s shift towards Firmicutes in the synbiotic group compared to ethanol. In addition, DCFDA labeling and H/E staining demonstrate that the synbiotic is beneficial in inhibiting the development of ALD. In the colon, the synbiotic reduces the activation of CYP2E1 and the inflammatory markers TNF-a and IL-6 while elevating the mRNA expression of ZO-1, occludin, and IL-10. Synbiotics colonize Lactobacillus to restore barrier function and microbiota and reduce colon oxidative stress. Thus, a synbiotic combination can be used in ALD treatment. Full article

(This article belongs to the Special Issue Gut Dysbiosis: Molecular Mechanisms and Therapies 2.0)

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18 pages, 2321 KiB

Open AccessArticle

Ivermectin Affects Neutrophil-Induced Inflammation through Inhibition of Hydroxylysine but Stimulation of Cathepsin G and Phenylalanine Secretion

by Svetlana I. Galkina, Ekaterina A. Golenkina, Marina V. Serebryakova, Natalia V. Fedorova, Alexander L. Ksenofontov, Vladimir I. Stadnichuk and Galina F. Sud’ina

Biomedicines 2022, 10(12), 3284; https://doi.org/10.3390/biomedicines10123284 - 19 Dec 2022

Cited by 3 | Viewed by 3668

Abstract

The invasion and integrin-dependent adhesion of neutrophils to lung tissues and their secretion lead to the development of pneumonia in various pulmonary pathologies, including acute respiratory distress syndrome in coronavirus disease. We studied the effect of ivermectin, a possible therapeutic agent for inflammation [...] Read more.

The invasion and integrin-dependent adhesion of neutrophils to lung tissues and their secretion lead to the development of pneumonia in various pulmonary pathologies, including acute respiratory distress syndrome in coronavirus disease. We studied the effect of ivermectin, a possible therapeutic agent for inflammation and cancer, on integrin-dependent neutrophil adhesion to fibronectin and the concomitant secretion. Ivermectin did not affect the attachment of neutrophils to the substrate and the reactive oxygen species production but sharply inhibited the adhesion-induced release of hydroxylysine and stimulated the release of phenylalanine and cathepsin G. Hydroxylysine is a product of lysyl hydroxylase, which is overexpressed in tumor cells with an increased ability to invade and metastasize. The inhibition of hydroxylysine release by ivermectin, by analogy, may indicate the suppression of neutrophil invasion into tissue. The increase in the release of phenylalanine in our experiments coincided with the secretion of cathepsin G, which indicates the possible role of this enzyme in the cleavage of phenylalanine. What is the substrate in such a reaction is unknown. We demonstrated that exogenously added angiotensin II (1–8) can serve as a substrate for phenylalanine cleavage. Mass spectrometry revealed the formation of angiotensin II (1–7) in the secretion of neutrophils, which attached to fibronectin in the presence of ivermectin and exogenous angiotensin II (1–8), indicating a possible involvement of ivermectin in the inactivation of angiotensin II. Full article

(This article belongs to the Collection Feature Papers in Immunology and Immunotherapy)

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12 pages, 2430 KiB

Open AccessArticle

EMT and Tumor Turning Point Analysis in 3D Spheroid Culture of HNSCC and Mesenchymal Stem Cells

by Sabine Brylka and Florian Böhrnsen

Biomedicines 2022, 10(12), 3283; https://doi.org/10.3390/biomedicines10123283 - 19 Dec 2022

Cited by 1 | Viewed by 1931

Abstract

The prognosis, metastasis, and behavior of head and neck squamous cancer cells are influenced by numerous factors concerning the tumor microenvironment, intercellular communication, and epithelial-to-mesenchymal transition (EMT). The aim of this study was to examine the codependent interaction of the mesenchymal stroma with [...] Read more.

The prognosis, metastasis, and behavior of head and neck squamous cancer cells are influenced by numerous factors concerning the tumor microenvironment, intercellular communication, and epithelial-to-mesenchymal transition (EMT). The aim of this study was to examine the codependent interaction of the mesenchymal stroma with head and neck squamous cell carcinoma (HNSCC) in a 3D spheroid structure. To simulate stroma-rich and -poor 3D tumor microenvironments, cells of the established cell SCC-040 were cultured with human mesenchymal stromal cells (MSCs), forming 3D stroma-tumor spheroids (STSs). STSs were compared to uniform spheroids of SCC-040 and MSC, respectively. The expressions of CD24, β-catenin, SNAI2, and ZEB2 were analyzed via RT-qPCR. The immunohistochemical expressions of E-cadherin, connexin 43, vimentin, and emmprin were analyzed, and protein expression pathways as well as Akt signaling were assessed via protein analysis. A promotive effect on the expressions of EMT markers ZEB2 (p = 0.0099), SNAI2 (p = 0.0352), and β-catenin (p = 0.0031) was demonstrated in STSs, as was the expression of Akt pathway proteins mTOR (p = 0.007), Erk1/2 (p = 0.0045), and p70 S6 Kinase (p = 0.0016). Our study demonstrated a change in genetic expression patterns early on in tumor development, indicating a tumor turning point. Full article

(This article belongs to the Section Biomedical Engineering and Materials)

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14 pages, 2434 KiB

Open AccessArticle

Bioengineered Ciprofloxacin-Loaded Chitosan Nanoparticles for the Treatment of Bovine Mastitis

by Preeti Yadav, Awadh Bihari Yadav, Preksha Gaur, Vartika Mishra, Zul-I Huma, Neelesh Sharma and Young-Ok Son

Biomedicines 2022, 10(12), 3282; https://doi.org/10.3390/biomedicines10123282 - 19 Dec 2022

Cited by 9 | Viewed by 2382

Abstract

Mastitis is the most devastating economic disease in dairy cattle. Mastitis in dairy cattle frequently occurs during the dry period or during early lactation. Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus)are the main causative agents of mastitis [...] Read more.

Mastitis is the most devastating economic disease in dairy cattle. Mastitis in dairy cattle frequently occurs during the dry period or during early lactation. Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus)are the main causative agents of mastitis in India. S. aureus can form microabscesses in the udder and develop a subclinical form of mastitis. This bacterial property hinders an effective cure during the lactation period. Antimicrobials used for treatments have a short half-life at the site of action because of frequent milking; thereforethey are unable to maintain the desired drug concentration for effective clearance of bacteria. We demonstrated the potential of ciprofloxacin-encapsulated nanocarriersthat can improve the availability of drugs and provide an effective means for mastitis treatment. These drug-loaded nanoparticles show low toxicity and slow clearance from the site of action. Antimicrobial activity against clinical strains of E. coli and S. aureus showed that the zone of inhibition depended on the dose (0.5 mg to 2 mg/mL nanoparticle solution from 11.6 to 14.5 mm and 15 to 18 mm). These nanoparticles showed good antimicrobial activity in broth culture and agar diffusion assay against bacteria. Full article

(This article belongs to the Topic Microfluidics Applied in Nanomedicine and Pharmaceutics)

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16 pages, 1013 KiB

Open AccessReview

Seventy Years of Treating Delusional Disorder with Antipsychotics: A Historical Perspective

by Alexandre González-Rodríguez, José A. Monreal, Mentxu Natividad and Mary V. Seeman

Biomedicines 2022, 10(12), 3281; https://doi.org/10.3390/biomedicines10123281 - 18 Dec 2022

Cited by 8 | Viewed by 8917

Abstract

For many decades, delusional disorder (DD) has been considered a treatment-resistant disorder, with antipsychotics acknowledged as the best, though imperfect, treatment. It is possible that the discovery of the right drug could turn treatment resistance into treatment response. The goal of this narrative [...] Read more.

For many decades, delusional disorder (DD) has been considered a treatment-resistant disorder, with antipsychotics acknowledged as the best, though imperfect, treatment. It is possible that the discovery of the right drug could turn treatment resistance into treatment response. The goal of this narrative review is to provide a historical perspective of the treatment of DD since the introduction of antipsychotics 70 years ago. The following search terms were used to scan the literature: antipsychotics AND “delusional disorder”. Findings were that therapy for DD symptoms has changed over time. Initial reports suggested that the drug of choice was the antipsychotic pimozide, and that this drug was especially effective for the somatic subtype of DD. Subsequent studies demonstrated that other antipsychotics, for instance, risperidone and olanzapine, were also highly effective. Treatment response may vary according to the presence or absence of specific symptoms, such as cognitive defect and depression. Clozapine, partial D2 agonists, and long-acting injectable drugs may be more effective than other drugs, but the evidence is not yet in. Because of the absence of robust evidence, treatment guidelines for the optimal management of DD are not yet available. Full article

(This article belongs to the Special Issue Antipsychotics: 70 Years)

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16 pages, 1089 KiB

Open AccessArticle

Effectiveness and Safety Profiles of Biological Therapies in Inflammatory Bowel Disease: Real Life Data from an Active Pharmacovigilance Project

by Maria Antonietta Barbieri, Anna Viola, Giuseppe Cicala, Edoardo Spina and Walter Fries

Biomedicines 2022, 10(12), 3280; https://doi.org/10.3390/biomedicines10123280 - 18 Dec 2022

Cited by 7 | Viewed by 2914

Abstract

Post-marketing surveillance is essential to evaluate the risk/benefit profile of drugs; however, pharmacovigilance studies comparing persistence and safety of biologic therapies in patients with inflammatory bowel disease (IBD) are scant. The aim of this study was to prospectively investigate persistence together with safety [...] Read more.

Post-marketing surveillance is essential to evaluate the risk/benefit profile of drugs; however, pharmacovigilance studies comparing persistence and safety of biologic therapies in patients with inflammatory bowel disease (IBD) are scant. The aim of this study was to prospectively investigate persistence together with safety profiles of biologics in a cohort of patients diagnosed with Crohn’s Disease (CD) or ulcerative colitis (UC) followed by the IBD unit of Messina and treated with infliximab (IFX), adalimumab (ADA), golimumab (GOL), vedolizumab (VED), and ustekinumab (UST) from 2017 through 2021. Descriptive and treatment persistence analyses with predictors for discontinuation and occurrence of adverse drug reactions (ADRs) were performed. A total of 675 IBD patients were enrolled. A higher persistence rate was noted for UST and ADA in the first year (83.8% and 83.1%, respectively) and for IFX in the fifth year of treatment (58.1%). GOL, VED, and UST—all used as second/third-line therapies—seemed to have a higher risk of non-persistence than IFX (in order HR: 2.19; CI 95%: 1.33–3.61, 1.45; 1.04–2.04, 2.25; 1.25–4.07) as well as switchers and those who had at least one ADR (18.1; 13.22–24.68 and 1.55; 1.20–1.99, respectively). The reported ADRs, which were generally mild–moderate, were largely known. However, real-world data should be implemented to further study undetected safety concerns, including risk of malignancy. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches in Inflammatory Bowel Diseases 3.0)

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17 pages, 2317 KiB

Open AccessArticle

Transposons Acting as Competitive Endogenous RNAs: In-Silico Evidence from Datasets Characterised by L1 Overexpression

by Mauro Esposito, Nicolò Gualandi, Giovanni Spirito, Federico Ansaloni, Stefano Gustincich and Remo Sanges

Biomedicines 2022, 10(12), 3279; https://doi.org/10.3390/biomedicines10123279 - 17 Dec 2022

Cited by 1 | Viewed by 2054

Abstract

LINE L1 are transposable elements that can replicate within the genome by passing through RNA intermediates. The vast majority of these element copies in the human genome are inactive and just between 100 and 150 copies are still able to mobilize. During evolution, [...] Read more.

LINE L1 are transposable elements that can replicate within the genome by passing through RNA intermediates. The vast majority of these element copies in the human genome are inactive and just between 100 and 150 copies are still able to mobilize. During evolution, they could have been positively selected for beneficial cellular functions. Nonetheless, L1 deregulation can be detrimental to the cell, causing diseases such as cancer. The activity of miRNAs represents a fundamental mechanism for controlling transcript levels in somatic cells. These are a class of small non-coding RNAs that cause degradation or translational inhibition of their target transcripts. Beyond this, competitive endogenous RNAs (ceRNAs), mostly made by circular and non-coding RNAs, have been seen to compete for the binding of the same set of miRNAs targeting protein coding genes. In this study, we have investigated whether autonomously transcribed L1s may act as ceRNAs by analyzing public dataset in-silico. We observed that genes sharing miRNA target sites with L1 have a tendency to be upregulated when L1 are overexpressed, suggesting the possibility that L1 might act as ceRNAs. This finding will help in the interpretation of transcriptomic responses in contexts characterized by the specific activation of transposons. Full article

(This article belongs to the Special Issue microRNAs in Health and Disease)

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12 pages, 911 KiB

Open AccessArticle

Epidemiological, Clinical, and Genomic Profile in Head and Neck Cancer Patients and Their Families

by Thiago Celestino Chulam, Fernanda Bernardi Bertonha, Rolando André Rios Villacis, João Gonçalves Filho, Luiz Paulo Kowalski and Silvia Regina Rogatto

Biomedicines 2022, 10(12), 3278; https://doi.org/10.3390/biomedicines10123278 - 17 Dec 2022

Cited by 2 | Viewed by 1995

Abstract

Inherited cancer predisposition genes are described as risk factors in head and neck cancer (HNC) families. To explore the clinical and epidemiological data and their association with a family history of cancer, we recruited 74 patients and 164 relatives affected by cancer. The [...] Read more.

Inherited cancer predisposition genes are described as risk factors in head and neck cancer (HNC) families. To explore the clinical and epidemiological data and their association with a family history of cancer, we recruited 74 patients and 164 relatives affected by cancer. The germline copy number alterations were evaluated in 18 patients using array comparative genomic hybridization. Two or more first-degree relatives with HNC, tobacco-associated tumor sites (lung, esophagus, and pancreas), or other related tumors (breast, colon, kidney, bladder, cervix, stomach carcinomas, and melanoma) were reported in 74 families. Ten index patients had no exposure to any known risk factors. Family members presented tumors of 19 topographies (30 head and neck, 26 breast, 21 colon). In first-degree relatives, siblings were frequently affected by cancer (n = 58, 13 had HNC). Breast cancer (n = 21), HNC (n = 19), and uterine carcinoma (n = 15) were commonly found in first-degree relatives and HNC in second-degree relatives (n = 11). Nineteen germline genomic imbalances were detected in 13 patients; three presented gains of WRD genes. The number of HNC patients, the degree of kinship, and the tumor types detected in each relative support the role of heredity in these families. Germline alterations may potentially contribute to cancer development. Full article

(This article belongs to the Special Issue Head and Neck Tumors 2.0)

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26 pages, 1417 KiB

Open AccessReview

Markers of Bronchiolitis Obliterans Syndrome after Lung Transplant: Between Old Knowledge and Future Perspective

by Dalila Cavallaro, Marco Guerrieri, Stefano Cattelan, Gaia Fabbri, Sara Croce, Martina Armati, David Bennett, Antonella Fossi, Luca Voltolini, Luca Luzzi, Alberto Salvicchi, Piero Paladini, Adriano Peris, Miriana d’Alessandro, Paolo Cameli, Elena Bargagli, Tuscany Transplant Group and Laura Bergantini

Biomedicines 2022, 10(12), 3277; https://doi.org/10.3390/biomedicines10123277 - 17 Dec 2022

Cited by 6 | Viewed by 3126

Abstract

Bronchiolitis obliterans syndrome (BOS) is the most common form of CLAD and is characterized by airflow limitation and an obstructive spirometric pattern without high-resolution computed tomography (HRCT) evidence of parenchymal opacities. Computed tomography and microCT analysis show abundant small airway obstruction, starting from [...] Read more.

Bronchiolitis obliterans syndrome (BOS) is the most common form of CLAD and is characterized by airflow limitation and an obstructive spirometric pattern without high-resolution computed tomography (HRCT) evidence of parenchymal opacities. Computed tomography and microCT analysis show abundant small airway obstruction, starting from the fifth generation of airway branching and affecting up to 40–70% of airways. The pathogenesis of BOS remains unclear. It is a multifactorial syndrome that leads to pathological tissue changes and clinical manifestations. Because BOS is associated with the worst long-term survival in LTx patients, many studies are focused on the early identification of BOS. Markers may be useful for diagnosis and for understanding the molecular and immunological mechanisms involved in the onset of BOS. Diagnostic and predictive markers of BOS have also been investigated in various biological materials, such as blood, BAL, lung tissue and extracellular vesicles. The aim of this review was to evaluate the scientific literature on markers of BOS after lung transplant. We performed a systematic review to find all available data on potential prognostic and diagnostic markers of BOS. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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32 pages, 5394 KiB

Open AccessReview

Amyloid Disassembly: What Can We Learn from Chaperones?

by Zaida L. Almeida and Rui M. M. Brito

Biomedicines 2022, 10(12), 3276; https://doi.org/10.3390/biomedicines10123276 - 17 Dec 2022

Cited by 10 | Viewed by 2926

Abstract

Protein aggregation and subsequent accumulation of insoluble amyloid fibrils with cross-β structure is an intrinsic characteristic of amyloid diseases, i.e., amyloidoses. Amyloid formation involves a series of on-pathway and off-pathway protein aggregation events, leading to mature insoluble fibrils that eventually accumulate in multiple [...] Read more.

Protein aggregation and subsequent accumulation of insoluble amyloid fibrils with cross-β structure is an intrinsic characteristic of amyloid diseases, i.e., amyloidoses. Amyloid formation involves a series of on-pathway and off-pathway protein aggregation events, leading to mature insoluble fibrils that eventually accumulate in multiple tissues. In this cascade of events, soluble oligomeric species are formed, which are among the most cytotoxic molecular entities along the amyloid cascade. The direct or indirect action of these amyloid soluble oligomers and amyloid protofibrils and fibrils in several tissues and organs lead to cell death in some cases and organ disfunction in general. There are dozens of different proteins and peptides causing multiple amyloid pathologies, chief among them Alzheimer’s, Parkinson’s, Huntington’s, and several other neurodegenerative diseases. Amyloid fibril disassembly is among the disease-modifying therapeutic strategies being pursued to overcome amyloid pathologies. The clearance of preformed amyloids and consequently the arresting of the progression of organ deterioration may increase patient survival and quality of life. In this review, we compiled from the literature many examples of chemical and biochemical agents able to disaggregate preformed amyloids, which have been classified as molecular chaperones, chemical chaperones, and pharmacological chaperones. We focused on their mode of action, chemical structure, interactions with the fibrillar structures, morphology and toxicity of the disaggregation products, and the potential use of disaggregation agents as a treatment option in amyloidosis. Full article

(This article belongs to the Special Issue Protein Aggregation: Molecular Mechanisms, Determinants and Therapeutic Approaches)

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11 pages, 536 KiB

Open AccessArticle

by Francesca Barbin, Michele Ghidini, Alessandra Panichi, Gianluca Tomasello, Claudia Bareggi, Barbara Galassi, Nerina Denaro, Fiorella Ruatta, Carolina Cauchi, Maria Grazia Rossino and Ornella Garrone

Biomedicines 2022, 10(12), 3275; https://doi.org/10.3390/biomedicines10123275 - 17 Dec 2022

Cited by 4 | Viewed by 3288

Abstract

Oxaliplatin-based chemotherapy is extensively used for the treatment of gastrointestinal tumors and other malignancies. Oxaliplatin-related hypersensitivity reactions (HSRs) are common during antitumor treatment. Several studies have been conducted to identify predictive risk factors for oxaliplatin-related HSRs, but findings remain controversial. No definitive approach [...] Read more.

Oxaliplatin-based chemotherapy is extensively used for the treatment of gastrointestinal tumors and other malignancies. Oxaliplatin-related hypersensitivity reactions (HSRs) are common during antitumor treatment. Several studies have been conducted to identify predictive risk factors for oxaliplatin-related HSRs, but findings remain controversial. No definitive approach has been identified to reduce the risk of developing HSRs. The aim of this article is to provide an overview of oxaliplatin-related HSRs, and to report our institution’s experience. With our work, we reviewed available data from the literature and described our case series. A total of 153 patients were treated with oxaliplatin and 17 developed an HSR. On the whole, 70.6% of reactions were Grade 3, mostly with respiratory and cutaneous symptoms. Steroids and antihistamines were administered to reduce hypersensitivity symptoms and prevent further reactions. A stronger premedication and prolonged time of infusion resulted in milder reactions or absence of subsequent reactions. We did not find any clear predictive factor for the development of HSRs. Although it is not possible to cancel the risk of oxaliplatin-based HSRs, strategies to reduce the risk of occurrence could be stronger premedication and prolonged time of infusion. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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16 pages, 3632 KiB

Open AccessArticle

Development and Characterization of Phage-Display-Derived Novel Human Monoclonal Antibodies against the Receptor Binding Domain of SARS-CoV-2

by Ji Woong Kim, Sung Won Min, Jichul Lee, Ha Gyeong Shin, Hye Lim Choi, Ha Rim Yang, Ji Hyun Lee, Yea Bin Cho, Hyunbo Shim and Sukmook Lee

Biomedicines 2022, 10(12), 3274; https://doi.org/10.3390/biomedicines10123274 - 17 Dec 2022

Cited by 5 | Viewed by 5581

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in an ongoing global pandemic crisis, caused by the life-threatening illness coronavirus disease 2019 (COVID-19). Thus, the rapid development of monoclonal antibodies (mAbs) to cope with COVID-19 is urgently necessary. In this study, we used [...] Read more.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in an ongoing global pandemic crisis, caused by the life-threatening illness coronavirus disease 2019 (COVID-19). Thus, the rapid development of monoclonal antibodies (mAbs) to cope with COVID-19 is urgently necessary. In this study, we used phage display to develop four human mAbs specific to the receptor-binding domain (RBD) of SARS-CoV-2. Our intensive in vitro functional analyses demonstrated that K102.1, an anti-SARS-CoV-2 RBD-specific mAb, exerted potent neutralizing activity against pseudoviral and live viral infection and the interaction between SARS-CoV-2 RBD and human angiotensin-converting enzyme 2. Monotherapy with K102.1 also revealed the therapeutic potential against SARS-CoV-2 infection in vivo. Further, this study developed a sandwich enzyme-linked immunosorbent assay with a non-competing mAb pair, K102.1 and K102.2, that accurately detected the RBDs of SARS-CoV-2 wild-type and variants with high sensitivity in the picomolar range. These findings suggest that the phage-display-based mAb selection from an established antibody library may be an effective strategy for the rapid development of mAbs against the constantly evolving SARS-CoV-2. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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18 pages, 1940 KiB

Open AccessReview

Management of Familial Hypercholesterolemia with Special Emphasis on Evinacumab

by Julia Krzemińska, Ewelina Młynarska, Ewa Radzioch, Magdalena Wronka, Jacek Rysz and Beata Franczyk

Biomedicines 2022, 10(12), 3273; https://doi.org/10.3390/biomedicines10123273 - 16 Dec 2022

Cited by 2 | Viewed by 2691

Abstract

Familial hypercholesterolemia (FH) is an underdiagnosed disease that contributes to a significant number of cardiovascular incidents through high serum Low-Density Lipoprotein Cholesterol (LDL-C) values. Its treatment primarily requires healthy lifestyle and therapy based on statins, ezetimibe and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9); [...] Read more.

Familial hypercholesterolemia (FH) is an underdiagnosed disease that contributes to a significant number of cardiovascular incidents through high serum Low-Density Lipoprotein Cholesterol (LDL-C) values. Its treatment primarily requires healthy lifestyle and therapy based on statins, ezetimibe and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9); however, there are also new treatment options that can be used in patients who do not respond to therapy, among which we highlight evinacumab. Elevated LDL-C values, together with clinical manifestations associated with cholesterol deposition (e.g., tendon xanthomas, xanthelasma and arcus cornealis) and family history are the main elements in the diagnosis of FH. Pathognomonic signs of FH include extensor tendon xanthomas; however, their absence does not exclude the diagnosis. Elevated LDL-C levels lead to premature Atherosclerotic Cardiovascular Disease (ASCVD), which is why early diagnosis and treatment of FH is essential. Evinacumab, a novelty in pharmacological practice, having a complex mechanism of action, causes desirable changes in lipid parameters in patients with homozygous form of familial hypercholesterolemia (HoFH). This review collects and summarizes the most important aspects of the new drug, especially being a discovery in the treatment of HoFH, giving these patients hope for a longer and more comfortable life. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Genetics of Cholesterol in Cardiovascular Disease: From Basics to Clinics)

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14 pages, 9520 KiB

Open AccessArticle

Ruminococcaceae_UCG-013 Promotes Obesity Resistance in Mice

by Jinlian Feng, Hongliang Ma, Yiting Huang, Jiangchao Li and Weidong Li

Biomedicines 2022, 10(12), 3272; https://doi.org/10.3390/biomedicines10123272 - 16 Dec 2022

Cited by 18 | Viewed by 2289

Abstract

Alterations in the gut microbiome have been linked to obesity and type 2 diabetes, in epidemiologic studies and studies of fecal transfer effects in germ-free mice. Here, we aimed to identify the effects of specific gut microbes on the phenotype of mice fed [...] Read more.

Alterations in the gut microbiome have been linked to obesity and type 2 diabetes, in epidemiologic studies and studies of fecal transfer effects in germ-free mice. Here, we aimed to identify the effects of specific gut microbes on the phenotype of mice fed a high-fat diet (HFD). After eight weeks of HFD feeding, male C57BL/6J mice in the HFD group ranking in the upper and lower quartiles for body weight gain were considered obese prone and obese resistant, respectively. 16S rRNA gene sequencing was used to determine the composition of the intestinal microbiota, and fecal transplantation (FMT) was conducted to determine whether the microbiota plays a causal role in phenotypic variation. Ruminococcaceae_UCG-013 was more abundant in the gut microbes of mice with a lean phenotype than in those with an obese phenotype. Ruminococcaceae_UCG-013 was identified as the most significant biomarker for alleviating obesity by random forest analysis. In a correlation analysis of serum parameters and body weight, Ruminococcaceae_UCG-013 was positively associated with serum HDL-C levels and negatively associated with serum TC, TG, and LDL-C levels. To conclude, Ruminococcaceae_UCG-013 was identified as a novel microbiome biomarker for obesity resistance, which may serve as a basis for understanding the critical gut microbes responsible for obesity resistance. Ruminococcaceae_UCG-013 may serve as a target for microbiome-based diagnoses and treatments in the future. Full article

(This article belongs to the Special Issue The Interplay of Gut Dysbiosis with Metabolic Syndrome)

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18 pages, 3321 KiB

Open AccessArticle

Differential Regulation of MMPs, Apoptosis and Cell Proliferation by the Cannabinoid Receptors CB1 and CB2 in Vascular Smooth Muscle Cells and Cardiac Myocytes

by Bettina Greiner, Manuela Sommerfeld, Ulrich Kintscher, Thomas Unger, Kai Kappert and Elena Kaschina

Biomedicines 2022, 10(12), 3271; https://doi.org/10.3390/biomedicines10123271 - 16 Dec 2022

Cited by 4 | Viewed by 2023

Abstract

Cannabinoids (CB) are implicated in cardiovascular diseases via the two main receptor subtypes CB₁R and CB₂R. This study investigated whether cannabinoids regulate the activity of matrix metalloproteases (MMP-2, MMP-9) in vascular smooth muscle cells (VSMCs) and in cells of [...] Read more.

Cannabinoids (CB) are implicated in cardiovascular diseases via the two main receptor subtypes CB₁R and CB₂R. This study investigated whether cannabinoids regulate the activity of matrix metalloproteases (MMP-2, MMP-9) in vascular smooth muscle cells (VSMCs) and in cells of cardiac origin (H9c2 cell line). The influence of CB₁- and CB₂ receptor stimulation or inhibition on cell proliferation, apoptosis and glucose uptake was also evaluated. We used four compounds that activate or block CB receptors: arachidonyl-2-chloroethylamide (ACEA)—CB₁R agonist, rimonabant—CB₁R antagonist, John W. Huffman (JWH133)—CB₂R agonist and CB₂R antagonist—6-Iodopravadoline (AM630). Treatment of cells with the CB₂R agonist JWH133 decreased cytokine activated secretion of proMMP-2, MMP-2 and MMP-9, reduced Fas ligand and caspase-3-mediated apoptosis, normalized the expression of TGF-beta1 and prevented cytokine-induced increase in glucose uptake into the cell. CB₁R inhibition with rimonabant showed similar protective properties as the CB₂R agonist JWH133, but to a lesser extent. In conclusion, CB₁R and CB₂R exert opposite effects on cell glucose uptake, proteolysis and apoptosis in both VSMCs and H9c2 cells. The CB₂R agonist JWH133 demonstrated the highest protective properties. These findings may pave the way to a new treatment of cardiovascular diseases, especially those associated with extracellular matrix degradation. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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21 pages, 5564 KiB

Open AccessArticle

A Cyclopentanone Compound Attenuates the Over-Accumulation of Extracellular Matrix and Fibrosis in Diabetic Nephropathy via Downregulating the TGF-β/p38MAPK Axis

by Chunyin Tang, Meng Wang, Jieting Liu, Chunlei Zhang, Luxin Li, Yan Wu, Yanhui Chu, Dan Wu, Haifeng Liu and Xiaohuan Yuan

Biomedicines 2022, 10(12), 3270; https://doi.org/10.3390/biomedicines10123270 - 16 Dec 2022

Cited by 6 | Viewed by 1695

Abstract

Excessive accumulation of the extracellular matrix (ECM) is a crucial pathological process in chronic kidney diseases, such as diabetic nephropathy, etc. The underlying mechanisms of how to decrease ECM deposition to improve diabetic nephropathy remain elusive. The present study investigated whether cyclopentanone compound [...] Read more.

Excessive accumulation of the extracellular matrix (ECM) is a crucial pathological process in chronic kidney diseases, such as diabetic nephropathy, etc. The underlying mechanisms of how to decrease ECM deposition to improve diabetic nephropathy remain elusive. The present study investigated whether cyclopentanone compound H8 alleviated ECM over-deposition and fibrosis to prevent and treat diabetic nephropathy. HK-2 cell viability after treatment with H8 was measured by an MTT assay. ECM alterations and renal fibrosis were identified in vitro and in vivo. A pharmacological antagonist was used to detect associations between H8 and the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. H8 binding was identified through computer simulation methods. Studies conducted on high glucose and transforming growth factor β1 (TGF-β1)-stimulated HK-2 cells revealed that the p38MAPK inhibitor SB 202190 and H8 had similar pharmacological effects. In addition, excessive ECM accumulation and fibrosis in diabetic nephropathy were remarkably improved after H8 administration in vivo and in vitro. Finally, the two molecular docking models further proved that H8 is a specific p38MAPK inhibitor that forms a hydrogen bond with the LYS-53 residue of p38MAPK. The cyclopentanone compound H8 alleviated the over-deposition of ECM and the development of fibrosis in diabetic nephropathy by suppressing the TGF-β/p38MAPK axis. Full article

(This article belongs to the Special Issue Pathological Mechanisms of Diabetic Nephropathy)

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12 pages, 1217 KiB

Open AccessReview

Current Application of iPS Cells in the Dental Tissue Regeneration

by Sayuri Hamano, Risa Sugiura, Daiki Yamashita, Atsushi Tomokiyo, Daigaku Hasegawa and Hidefumi Maeda

Biomedicines 2022, 10(12), 3269; https://doi.org/10.3390/biomedicines10123269 - 16 Dec 2022

Cited by 3 | Viewed by 2799

Abstract

When teeth and periodontal tissues are severely damaged by severe caries, trauma, and periodontal disease, such cases may be subject to tooth extraction. As tooth loss leads to the deterioration of quality of life, the development of regenerative medicine for tooth and periodontal [...] Read more.

When teeth and periodontal tissues are severely damaged by severe caries, trauma, and periodontal disease, such cases may be subject to tooth extraction. As tooth loss leads to the deterioration of quality of life, the development of regenerative medicine for tooth and periodontal tissue is desired. Induced pluripotent stem cells (iPS cells) are promising cell resources for dental tissue regeneration because they offer high self-renewal and pluripotency, along with fewer ethical issues than embryonic stem cells. As iPS cells retain the epigenetic memory of donor cells, they have been established from various dental tissues for dental tissue regeneration. This review describes the regeneration of dental tissue using iPS cells. It is important to mimic the process of tooth development in dental tissue regeneration using iPS cells. Although iPS cells had safety issues in clinical applications, they have been overcome in recent years. Dental tissue regeneration using iPS cells has not yet been established, but it is expected in the future. Full article

(This article belongs to the Special Issue Cell Biology in Dentistry)

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12 pages, 730 KiB

Open AccessArticle

Ten Years of KPC-Kp Bloodstream Infections Experience: Impact of Early Appropriate Empirical Therapy on Mortality

by Silvia Corcione, Ilaria De Benedetto, Nour Shbaklo, Fabio Ranzani, Simone Mornese Pinna, Anna Castiglione, Silvia Scabini, Gabriele Bianco, Rossana Cavallo, Stefano Mirabella, Renato Romagnoli and Francesco Giuseppe De Rosa

Biomedicines 2022, 10(12), 3268; https://doi.org/10.3390/biomedicines10123268 - 16 Dec 2022

Cited by 7 | Viewed by 1687

Abstract

Background. In K. pneumoniae KPC (KPC-Kp) bloodstream infections (BSI), INCREMENT CPE score >7, Charlson Comorbidity Index (CCI) ≥3 and septic shock are recognized predictors of mortality, with a possible beneficial effect of combination therapy in seriously ill patients. Materials and Methods. We conducted [...] Read more.

Background. In K. pneumoniae KPC (KPC-Kp) bloodstream infections (BSI), INCREMENT CPE score >7, Charlson Comorbidity Index (CCI) ≥3 and septic shock are recognized predictors of mortality, with a possible beneficial effect of combination therapy in seriously ill patients. Materials and Methods. We conducted a ten-year retrospective study including all KPC-Kp BSI in patients ≥18 years of age with the aim to evaluate the characteristics and impact of appropriate empirical therapy, either monotherapy or combination therapy, and targeted therapy on mortality. Appropriate therapy was defined as at least one active antimicrobial agent with in vitro activity against KPC-kp demonstrated by susceptibility testing, administered within 48 h from blood culture collection. Results. The median age of the 435 analyzed patients was 66.09 years (IQR 54.87–73.98). The median CCI was 4. KPC-Kp colonization was present in 324 patients (74.48%). The probable origin of the KPC-Kp BSI was not identified in 136 patients (31.26%), whereas in 120 (27.59%) patients, it was CVC-related, and in 118 (27.13%), it was respiratory. Source control was achieved in 87 patients (72.5%) with CVC-related KPC-Kp BSI. The twenty-eight-day survival was 70.45% for empirical monotherapy, 63.88% for empirical combination therapy and 57.05% for targeted therapy (p = 0.0399). A probable source of KPC-Kp BSI other than urinary, CVC or abdominal [aHR 1.64 (IC 1.15–2.34) p = 0.006] and deferred targeted therapy [HR 1.67 (IC 1.12–2.51), p= 0.013] emerged as predictors of mortality, whereas source control [HR 0.62 (IC 0.44–0.86), p = 0.005] and ceftazidime/avibactam administration in empirical therapy [aHR 0.37 (IC 0.20–0.68) p = 0.002] appeared as protective factors. Discussion. These data underline the importance of source control together with timing appropriateness in the early start of empirical therapy over the choice of monotherapy or combination therapy and the use of ceftazidime/avibactam against KPC-Kp BSI. Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

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11 pages, 1124 KiB

Open AccessArticle

Clinical Significance of Serum Elafin in Children with Inflammatory Bowel Disease

by Paulina Krawiec and Elżbieta Pac-Kożuchowska

Biomedicines 2022, 10(12), 3267; https://doi.org/10.3390/biomedicines10123267 - 16 Dec 2022

Cited by 4 | Viewed by 1727

Abstract

Background: The role of elafin in the pathophysiology of inflammatory bowel disease (IBD) has not been not elucidated. We aimed to evaluate serum elafin in children with IBD and assess its relationship with disease activity. Methods: We enrolled children with IBD in the [...] Read more.

Background: The role of elafin in the pathophysiology of inflammatory bowel disease (IBD) has not been not elucidated. We aimed to evaluate serum elafin in children with IBD and assess its relationship with disease activity. Methods: We enrolled children with IBD in the study group and children with functional abdominal pain in the control group. We evaluated serum elafin using enzyme-linked immunosorbent assay kits. Results: In children with IBD, serum elafin (mean ± SD: 4.192 ± 1.424 ng/mL) was significantly elevated compared with controls (mean ± SD: 3.029 ± 1.366 ng/mL) (p = 0.0005). Elafin was significantly increased in children in the active phase of IBD (mean ± SD: 4.424 ± 1.449 ng/mL) compared with the control group (p = 0.0003). In IBD remission, only children with ulcerative colitis (mean ± SD: 4.054 ± 1.536 ng/mL) had elevated elafin compared with controls (p = 0.004). ROC analysis revealed that the area under the curve (AUC) of serum elafin was 0.809 while discriminating patients with ulcerative colitis from the control group, and the AUC was 0.664 while differentiating patients with Crohn’s disease from the control group. Conclusions: Serum elafin was found to be elevated in our cohort of children with IBD, depending on disease activity. Serum elafin was increased in the active phases of both ulcerative colitis and Crohn’s disease, but only in the remission of ulcerative colitis. Elafin appears to be a potential candidate for a biomarker of ulcerative colitis. Full article

(This article belongs to the Special Issue Antimicrobial Peptides Aka Host Defense Peptides – from Basic Research to Therapy 2.0)

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