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Biomedicines
Volume 10
Issue 5
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Biomedicines, Volume 10, Issue 5 (May 2022) – 286 articles

Cover Story (view full-size image): For the treatment of PTSD, the development of animal models that mimic patients has become necessary, and many methods have been developed for doing so. Physical stressors induce anxiety through direct physical stimulation. The (A) and (B) methods allow rodents to swim in an inescapable maze and expose them to ethers until they lose their minds. The (C) method imprinted PTSD onto rodents with electric shock and sound signals by using metal rods. (E), as a psychological stressor, can cause PTSD by placing rodents in a face-to-face situation directly or indirectly with predators. Rodent models that undergo PTSD may experience dysfunction through increasing the negative feedback of the hypothalamic–pituitary–adrenal (HPA) axis, and may contribute to the occurrence of neuroinflammation due to PTSD. View this paper
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20 pages, 8062 KiB  
Article
Clinical Feasibility Study of Gold Nanoparticles as Theragnostic Agents for Precision Radiotherapy
by José Antonio López-Valverde, Elisa Jiménez-Ortega and Antonio Leal
Biomedicines 2022, 10(5), 1214; https://doi.org/10.3390/biomedicines10051214 - 23 May 2022
Cited by 6 | Viewed by 2783
Abstract
Background: Gold nanoparticles (AuNP) may be useful in precision radiotherapy and disease monitoring as theragnostic agents. In diagnostics, they can be detected by computerized tomography (CT) because of their higher atomic number. AuNP may also improve the treatment results in radiotherapy due to [...] Read more.
Background: Gold nanoparticles (AuNP) may be useful in precision radiotherapy and disease monitoring as theragnostic agents. In diagnostics, they can be detected by computerized tomography (CT) because of their higher atomic number. AuNP may also improve the treatment results in radiotherapy due to a higher cross-section, locally improving the physically absorbed dose. Methods: Key parameters values involved in the use of AuNP were imposed to be optimal in the clinical scenario. Mass concentration of AuNP as an efficient contrast agent in clinical CT was found and implemented in a Monte Carlo simulation method for dose calculation under different proposed therapeutic beams. The radiosensitization effect was determined in irradiated cells with AuNP. Results: an AuNP concentration was found for a proper contrast level and enhanced therapeutic effect under a beam typically used for image-guided therapy and monitoring. This lower energetic proposed beam showed potential use for treatment monitoring in addition to absorbed dose enhancement and higher radiosensitization at the cellular level. Conclusion: the results obtained show the use of AuNP concentration around 20 mg Au·mL−1 as an efficient tool for diagnosis, treatment planning, and monitoring treatment. Simultaneously, the delivered prescription dose provides a higher radiobiological effect on the cancer cell for achieving precision radiotherapy. Full article
(This article belongs to the Special Issue Advances in Nanomedicine for Disease Treatment and Diagnosis)
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12 pages, 2633 KiB  
Article
Administration Routes as Modulators of the Intrahepatic Distribution and Anti-Anemic Activity of Salicylic Acid/Fe3O4 Nanoparticles
by Bogdan Mîndrilă, Sandra-Alice Buteică, Ion Mîndrilă, Dan-Eduard Mihaiescu, Marina-Daniela Mănescu and Ion Rogoveanu
Biomedicines 2022, 10(5), 1213; https://doi.org/10.3390/biomedicines10051213 - 23 May 2022
Cited by 5 | Viewed by 2127
Abstract
The liver is a key organ in the pharmacokinetics of iron oxide nanoparticles (IONPs). This paper examined how the intravenous (IV) or intragastric (IG) route of administration influenced the intrahepatic distribution or therapeutic effects of IONPs. Wistar rats, some with bleeding-induced anemia, and [...] Read more.
The liver is a key organ in the pharmacokinetics of iron oxide nanoparticles (IONPs). This paper examined how the intravenous (IV) or intragastric (IG) route of administration influenced the intrahepatic distribution or therapeutic effects of IONPs. Wistar rats, some with bleeding-induced anemia, and iron oxide nanoparticles functionalized with salicylic acid (SaIONPs), with an average hydrodynamic diameter of 73 nm, compatible with rat sinusoid fenestrations, were used in this study. Light microscopy and multispectral camera analysis of Prussian blue labeled SaIONPs allowed mapping of intrahepatic nanoparticle deposits and revealed intrahepatic distribution patterns specific to each route of administration: loading of Kupffer cells and periportal hepatocytes when the IV route was used and predominant loading of hepatocytes when the IG route was used. Reducing the time to return to baseline values for hemoglobin (HGB) in rats with bleeding-induced anemia with IV or IG therapy has proven the therapeutic potential of SaIONPs in such anemias. The long-term follow-up showed that IV therapy resulted in higher HGB values. Proper use of the administration routes may modulate intrahepatic distribution and therapeutic effects of nanoparticles. These results may be beneficial in theragnosis of liver disease. Full article
(This article belongs to the Special Issue Advances in Nanomedicine for Disease Treatment and Diagnosis)
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23 pages, 2421 KiB  
Review
Stressing the Regulatory Role of Long Non-Coding RNA in the Cellular Stress Response during Cancer Progression and Therapy
by Yi-Zhen Wu, Yong-Han Su and Ching-Ying Kuo
Biomedicines 2022, 10(5), 1212; https://doi.org/10.3390/biomedicines10051212 - 23 May 2022
Cited by 5 | Viewed by 3039
Abstract
Cellular stress response is an important adaptive mechanism for regulating cell fate decision when cells confront with stress. During tumorigenesis, tumor progression and the course of treatment, cellular stress signaling can activate subsequent response to deal with stress. Therefore, cellular stress response has [...] Read more.
Cellular stress response is an important adaptive mechanism for regulating cell fate decision when cells confront with stress. During tumorigenesis, tumor progression and the course of treatment, cellular stress signaling can activate subsequent response to deal with stress. Therefore, cellular stress response has impacts on the fate of tumor cells and tumor responsiveness relative to therapeutic agents. In recent years, attention has been drawn to long non-coding RNAs (lncRNAs), a novel class of RNA molecules with more than 200 nucleotides in length, which has little protein-coding potential and possesses various functions in multiple biological processes. Accumulating evidence has shown that lncRNAs are also engaged in the regulation of cellular stress response, particularly in cancers. Here, we summarize lncRNAs that have been reported in the adaptive response to major types of cellular stress including genotoxic, hypoxic, oxidative, metabolic and endoplasmic reticulum stress, all of which are often encountered by cancer cells. Specifically, the molecular mechanisms of how lncRNAs regulate cellular stress response during tumor progression or the development of therapy resistance are emphasized. The potential clinical applications of stress-responsive lncRNAs as biomarkers will also be discussed. Full article
(This article belongs to the Special Issue Non-coding RNA as Promising Biomarker for Disease Diagnosis and Prognosis)
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10 pages, 541 KiB  
Article
Safety of FOLFIRI + Durvalumab +/− Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59
by Camille Evrard, Thomas Aparicio, Emilie Soularue, Karine Le Malicot, Jérôme Desramé, Damien Botsen, Farid El Hajbi, Daniel Gonzalez, Come Lepage, Olivier Bouché, David Tougeron and on behalf of the DURIGAST—PRODIGE 59 Investigators/Collaborators
Biomedicines 2022, 10(5), 1211; https://doi.org/10.3390/biomedicines10051211 - 23 May 2022
Cited by 4 | Viewed by 2549
Abstract
Efficacy of immune checkpoint inhibitors (ICI) as monotherapy in 2nd line treatment for gastric or gastro-oesophageal junction (GEJ) adenocarcinoma is low, with no evaluation of efficacy and safety of ICI combined with chemotherapy. The DURIGAST PRODIGE 59 study is a randomised, multicentre, phase [...] Read more.
Efficacy of immune checkpoint inhibitors (ICI) as monotherapy in 2nd line treatment for gastric or gastro-oesophageal junction (GEJ) adenocarcinoma is low, with no evaluation of efficacy and safety of ICI combined with chemotherapy. The DURIGAST PRODIGE 59 study is a randomised, multicentre, phase II study designed to assess the efficacy and safety of the combination of FOLFIRI + Durvalumab +/− Tremelimumab as 2nd line treatment of patients with advanced gastric/GEJ adenocarcinoma. Here, we report data from the safety run-in phase with FOLFIRI Durvalumab (arm A) or FOLFIRI Durvalumab and Tremelimumab (arm B). Among the 11 patients included, 63.6% experienced at least one grade 3–4 adverse events (AEs) related to the treatment, most frequently neutropenia (36.4%). There was only one immune-related AE (grade 2 hyperthyroidism). Ten serious AEs were described among six patients, but only two were related to the treatment, due to the chemotherapy. One seizure epilepsy related to a brain metastasis was observed, but was not related by the investigator to the treatment. However, the Independent Data Monitoring Committee recommended brain imaging at inclusion. This safety run-in phase demonstrates an expected safety profile of FOLFIRI with Durvalumab +/− Tremelimumab combination allowing the randomised phase II. Full article
(This article belongs to the Special Issue Oncoimmunity and Immunotherapy in Solid Tumors)
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14 pages, 1151 KiB  
Article
A Prognostic and Carboplatin Response Predictive Model in Ovarian Cancer: A Mono-Institutional Retrospective Study Based on Clinics and Pharmacogenomics
by Nicoletta Staropoli, Mariamena Arbitrio, Angela Salvino, Francesca Scionti, Domenico Ciliberto, Rossana Ingargiola, Caterina Labanca, Giuseppe Agapito, Eleonora Iuliano, Vito Barbieri, Maria Cucè, Valeria Zuccalà, Mario Cannataro, Pierfrancesco Tassone and Pierosandro Tagliaferri
Biomedicines 2022, 10(5), 1210; https://doi.org/10.3390/biomedicines10051210 - 23 May 2022
Cited by 2 | Viewed by 2269
Abstract
Carboplatin is the cornerstone of ovarian cancer (OC) treatment, while platinum-response, dependent on interindividual variability, is the major prognostic factor for long-term outcomes. This retrospective study was focused on explorative search of genetic polymorphisms in the Absorption, Distribution, Metabolism, Excretion (ADME) genes for [...] Read more.
Carboplatin is the cornerstone of ovarian cancer (OC) treatment, while platinum-response, dependent on interindividual variability, is the major prognostic factor for long-term outcomes. This retrospective study was focused on explorative search of genetic polymorphisms in the Absorption, Distribution, Metabolism, Excretion (ADME) genes for the identification of biomarkers prognostic/predictive of platinum-response in OC patients. Ninety-two advanced OC patients treated with carboplatin-based therapy were enrolled at our institution. Of these, we showed that 72% of patients were platinum-sensitive, with a significant benefit in terms of OS (p = 0.001). We identified an inflammatory-score with a longer OS in patients with lower scores as compared to patients with the maximum score (p = 0.001). Thirty-two patients were genotyped for 1931 single nucleotide polymorphisms (SNPs) and five copy number variations (CNVs) by the DMET Plus array platform. Among prognostic polymorphisms, we found a potential role of UGT2A1 both as a predictor of platinum-response (p = 0.01) and as prognostic of survival (p = 0.05). Finally, we identified 24 SNPs related to OS. UGT2A1 correlates to an “inflammatory-score” and retains a potential prognostic role in advanced OC. These data provide a proof of concept that warrants further validation in follow-up studies for the definition of novel biomarkers in this aggressive disease. Full article
(This article belongs to the Topic Molecular Profiling and Identification of Molecular Signatures Associated with Tissue Development, Tumorigenesis, and Anticancer Agents’ Action)
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13 pages, 1393 KiB  
Article
Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism
by Dino Šisl, Darja Flegar, Maša Filipović, Petra Turčić, Pavao Planinić, Alan Šućur, Nataša Kovačić, Danka Grčević and Tomislav Kelava
Biomedicines 2022, 10(5), 1209; https://doi.org/10.3390/biomedicines10051209 - 23 May 2022
Cited by 4 | Viewed by 2797
Abstract
The available treatments for cholestatic liver fibrosis are limited, and the disease often progresses to liver cirrhosis. Tamoxifen is a selective modulator of estrogen receptors, commonly used in breast cancer therapy. A recent in vitro study showed that tamoxifen deactivates hepatic stellate cells, [...] Read more.
The available treatments for cholestatic liver fibrosis are limited, and the disease often progresses to liver cirrhosis. Tamoxifen is a selective modulator of estrogen receptors, commonly used in breast cancer therapy. A recent in vitro study showed that tamoxifen deactivates hepatic stellate cells, suggesting its potential as an antifibrotic therapeutic, but its effects in vivo remain poorly investigated. In the present study, we show that tamoxifen protects against the cholestatic fibrosis induced by a diet supplemented with 0.025% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Mice fed with a DDC-supplemented diet for four weeks and treated with tamoxifen developed a significantly milder degree of liver fibrosis than vehicle-treated mice, as evidenced by a lower percentage of Sirius red-stained area (60.4% decrease in stained area in male and 42% decrease in female mice, p < 0.001 and p < 0.01, respectively) and by lower hydroxyproline content. The finding was further confirmed by qPCR analysis, which showed a lower expression of genes for Col1a1, Acta2, Sox9, Pdgf, and Krt19, indicating the inhibitory effect on hepatic stellate cells, collagen production, and biliary duct proliferation. The degree of protection was similar in male and female mice. Tamoxifen per se, injected into standard-diet-fed mice, increased the expression of genes for Il6 (p < 0.01 and p < 0.001 in male and female mice, respectively) and Tgfβ (p < 0.01 for both sexes), and had no adverse effects. We showed that tamoxifen sex-independently protects against cholestatic DDC-induced liver fibrosis. The increased expression of Il6 and Tgfβ seems to be a plausible protective mechanism that should be the primary focus of further research. Full article
(This article belongs to the Section Drug Discovery, Development and Delivery)
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13 pages, 2176 KiB  
Article
OncoPan®: An NGS-Based Screening Methodology to Identify Molecular Markers for Therapy and Risk Assessment in Pancreatic Ductal Adenocarcinoma
by Maria Grazia Tibiletti, Ileana Carnevali, Valeria Pensotti, Anna Maria Chiaravalli, Sofia Facchi, Sara Volorio, Frederique Mariette, Paolo Mariani, Stefano Fortuzzi, Marco Alessandro Pierotti and Fausto Sessa
Biomedicines 2022, 10(5), 1208; https://doi.org/10.3390/biomedicines10051208 - 23 May 2022
Cited by 4 | Viewed by 2330
Abstract
Pancreatic cancer has a high morbidity and mortality with the majority being PC ductal adenocarcinomas (PDAC). Whole genome sequencing provides a wide description of genomic events involved in pancreatic carcinogenesis and identifies putative biomarkers for new therapeutic approaches. However, currently, there are no [...] Read more.
Pancreatic cancer has a high morbidity and mortality with the majority being PC ductal adenocarcinomas (PDAC). Whole genome sequencing provides a wide description of genomic events involved in pancreatic carcinogenesis and identifies putative biomarkers for new therapeutic approaches. However, currently, there are no approved treatments targeting driver mutations in PDAC that could produce clinical benefit for PDAC patients. A proportion of 5–10% of PDAC have a hereditary origin involving germline variants of homologous recombination genes, such as Mismatch Repair (MMR), STK11 and CDKN2A genes. Very recently, BRCA genes have been demonstrated as a useful biomarker for PARP-inhibitor (PARPi) treatments. In this study, a series of 21 FFPE PDACs were analyzed using OncoPan®, a strategic next-generation sequencing (NGS) panel of 37 genes, useful for identification of therapeutic targets and inherited cancer syndromes. Interestingly, this approach, successful also on minute pancreatic specimens, identified biomarkers for personalized therapy in five PDAC patients, including two cases with HER2 amplification and three cases with mutations in HR genes (BRCA1, BRCA2 and FANCM) and potentially eligible to PARPi therapy. Molecular analysis on normal tissue identified one PDAC patient as a carrier of a germline BRCA1 pathogenetic variant and, noteworthy, this patient was a member of a family affected by inherited breast and ovarian cancer conditions. This study demonstrates that the OncoPan® NGS-based panel constitutes an efficient methodology for the molecular profiling of PDAC, suitable for identifying molecular markers both for therapy and risk assessment. Our data demonstrate the feasibility and utility of these NGS analysis in the routine setting of PDAC molecular characterization. Full article
(This article belongs to the Collection Hereditary Gastrointestinal Cancer Syndromes: Molecular Basis of Onset and Progression, Molecular Diagnosis, and Precision Therapy)
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19 pages, 3347 KiB  
Article
Solid Magnetoliposomes as Multi-Stimuli-Responsive Systems for Controlled Release of Doxorubicin: Assessment of Lipid Formulations
by Beatriz D. Cardoso, Vanessa F. Cardoso, Senetxu Lanceros-Méndez and Elisabete M. S. Castanheira
Biomedicines 2022, 10(5), 1207; https://doi.org/10.3390/biomedicines10051207 - 23 May 2022
Cited by 8 | Viewed by 3053
Abstract
Stimuli-responsive liposomes are a class of nanocarriers whose drug release occurs, preferentially, when exposed to a specific biological environment, to an external stimulus, or both. This work is focused on the design of solid magnetoliposomes (SMLs) as lipid-based nanosystems aiming to obtain multi-stimuli-responsive [...] Read more.
Stimuli-responsive liposomes are a class of nanocarriers whose drug release occurs, preferentially, when exposed to a specific biological environment, to an external stimulus, or both. This work is focused on the design of solid magnetoliposomes (SMLs) as lipid-based nanosystems aiming to obtain multi-stimuli-responsive vesicles for doxorubicin (DOX) controlled release in pathological areas under the action of thermal, magnetic, and pH stimuli. The effect of lipid combinations on structural, colloidal stability, and thermodynamic parameters were evaluated. The results confirmed the reproducibility for SMLs synthesis based on nine lipid formulations (combining DPPC, DSPC, CHEMS, DOPE and/or DSPE-PEG), with structural and colloidal properties suitable for biological applications. A loss of stability and thermosensitivity was observed for formulations containing dioleoylphosphatidylethanolamine (DOPE) lipid. SMLs PEGylation is an essential step to enhance both their long-term storage stability and stealth properties. DOX encapsulation (encapsulation efficiency ranging between 87% and 96%) in the bilayers lowered its pKa, which favors the displacement of DOX from the acyl chains to the surface when changing from alkaline to acidic pH. The release profiles demonstrated a preferential release at acidic pH, more pronounced under mimetic mild-hyperthermia conditions (42 °C). Release kinetics varied with the lipid formulation, generally demonstrating hyperthermia temperatures and acidic pH as determining factors in DOX release; PEGylation was shown to act as a diffusion barrier on the SMLs surface. The integrated assessment and characterization of SMLs allows tuning lipid formulations that best respond to the needs for specific controlled release profiles of stimuli-responsive nanosystems as a multi-functional approach to cancer targeting and therapy. Full article
(This article belongs to the Special Issue Advances in Nanomaterials for Drug Delivery)
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38 pages, 953 KiB  
Review
TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications
by Jian Luo
Biomedicines 2022, 10(5), 1206; https://doi.org/10.3390/biomedicines10051206 - 23 May 2022
Cited by 40 | Viewed by 6098
Abstract
Astrocytes are essential for normal brain development and functioning. They respond to brain injury and disease through a process referred to as reactive astrogliosis, where the reactivity is highly heterogenous and context-dependent. Reactive astrocytes are active contributors to brain pathology and can exert [...] Read more.
Astrocytes are essential for normal brain development and functioning. They respond to brain injury and disease through a process referred to as reactive astrogliosis, where the reactivity is highly heterogenous and context-dependent. Reactive astrocytes are active contributors to brain pathology and can exert beneficial, detrimental, or mixed effects following brain insults. Transforming growth factor-β (TGF-β) has been identified as one of the key factors regulating astrocyte reactivity. The genetic and pharmacological manipulation of the TGF-β signaling pathway in animal models of central nervous system (CNS) injury and disease alters pathological and functional outcomes. This review aims to provide recent understanding regarding astrocyte reactivity and TGF-β signaling in brain injury, aging, and neurodegeneration. Further, it explores how TGF-β signaling modulates astrocyte reactivity and function in the context of CNS disease and injury. Full article
(This article belongs to the Special Issue Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach 2.0)
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17 pages, 3237 KiB  
Article
Docosahexaenoic Acid and Melatonin Prevent Impaired Oligodendrogenesis Induced by Intrauterine Growth Restriction (IUGR)
by Britta Anna Kühne, Paula Vázquez-Aristizabal, Mercè Fuentes-Amell, Laura Pla, Carla Loreiro, Jesús Gómez-Catalán, Eduard Gratacós, Miriam Illa and Marta Barenys
Biomedicines 2022, 10(5), 1205; https://doi.org/10.3390/biomedicines10051205 - 23 May 2022
Cited by 3 | Viewed by 2539
Abstract
In this study, our aims were to characterize oligodendrogenesis alterations in fetuses with intrauterine growth restriction (IUGR) and to find therapeutic strategies to prevent/treat them using a novel rabbit in vitro neurosphere culture. IUGR was surgically induced in one uterine horn of pregnant [...] Read more.
In this study, our aims were to characterize oligodendrogenesis alterations in fetuses with intrauterine growth restriction (IUGR) and to find therapeutic strategies to prevent/treat them using a novel rabbit in vitro neurosphere culture. IUGR was surgically induced in one uterine horn of pregnant rabbits, while the contralateral horn served as a control. Neural progenitor cells (NPCs) were obtained from pup’s whole brain and cultured as neurospheres mimicking the basic processes of brain development including migration and cell differentiation. Five substances, chosen based on evidence provided in the literature, were screened in vitro in neurospheres from untreated rabbits: Docosahexaenoic acid (DHA), melatonin (MEL), zinc, 3,3′,5-Triiodo-L-thyronine (T3), and lactoferrin (LF) or its metabolite sialic acid (SA). DHA, MEL and LF were further selected for in vivo administration and subsequent evaluation in the Neurosphere Assay. In the IUGR culture, we observed a significantly reduced percentage of oligodendrocytes (OLs) which correlated with clinical findings indicating white matter injury in IUGR infants. We identified DHA and MEL as the most effective therapies. In all cases, our in vitro rabbit neurosphere assay predicted the outcome of the in vivo administration of the therapies and confirmed the reliability of the model, making it a powerful and consistent tool to select new neuroprotective therapies. Full article
(This article belongs to the Special Issue Advanced Research in Neurogenesis)
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18 pages, 4125 KiB  
Article
Generation of hiPSC-Derived Skeletal Muscle Cells: Exploiting the Potential of Skeletal Muscle-Derived hiPSCs
by Eric Metzler, Helena Escobar, Daniele Yumi Sunaga-Franze, Sascha Sauer, Sebastian Diecke and Simone Spuler
Biomedicines 2022, 10(5), 1204; https://doi.org/10.3390/biomedicines10051204 - 23 May 2022
Cited by 4 | Viewed by 2835
Abstract
Cell therapies for muscle wasting disorders are on the verge of becoming a realistic clinical perspective. Muscle precursor cells derived from human induced pluripotent stem cells (hiPSCs) represent the key to unrestricted cell numbers indispensable for the treatment of generalized muscle wasting such [...] Read more.
Cell therapies for muscle wasting disorders are on the verge of becoming a realistic clinical perspective. Muscle precursor cells derived from human induced pluripotent stem cells (hiPSCs) represent the key to unrestricted cell numbers indispensable for the treatment of generalized muscle wasting such as cachexia or intensive care unit (ICU)-acquired weakness. We asked how the cell of origin influences efficacy and molecular properties of hiPSC-derived muscle progenitor cells. We generated hiPSCs from primary muscle stem cells and from peripheral blood mononuclear cells (PBMCs) of the same donors (n = 4) and compared their molecular profiles, myogenic differentiation potential, and ability to generate new muscle fibers in vivo. We show that reprogramming into hiPSCs from primary muscle stem cells was faster and 35 times more efficient than from blood cells. Global transcriptome comparison revealed significant differences, but differentiation into induced myogenic cells using a directed transgene-free approach could be achieved with muscle- and PBMC-derived hiPSCs, and both cell types generated new muscle fibers in vivo. Differences in myogenic differentiation efficiency were identified with hiPSCs generated from individual donors. The generation of muscle-stem-cell-derived hiPSCs is a fast and economic method to obtain unrestricted cell numbers for cell-based therapies in muscle wasting disorders, and in this aspect are superior to blood-derived hiPSCs. Full article
(This article belongs to the Special Issue The Promise of Induced Pluripotent Stem Cells in the Biomedical Research)
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35 pages, 1367 KiB  
Review
Current Development of Nano-Drug Delivery to Target Macrophages
by Donglin Cai, Wendong Gao, Zhelun Li, Yufeng Zhang, Lan Xiao and Yin Xiao
Biomedicines 2022, 10(5), 1203; https://doi.org/10.3390/biomedicines10051203 - 23 May 2022
Cited by 27 | Viewed by 6186
Abstract
Macrophages are the most important innate immune cells that participate in various inflammation-related diseases. Therefore, macrophage-related pathological processes are essential targets in the diagnosis and treatment of diseases. Since nanoparticles (NPs) can be preferentially taken up by macrophages, NPs have attracted most attention [...] Read more.
Macrophages are the most important innate immune cells that participate in various inflammation-related diseases. Therefore, macrophage-related pathological processes are essential targets in the diagnosis and treatment of diseases. Since nanoparticles (NPs) can be preferentially taken up by macrophages, NPs have attracted most attention for specific macrophage-targeting. In this review, the interactions between NPs and the immune system are introduced to help understand the pharmacokinetics and biodistribution of NPs in immune cells. The current design and strategy of NPs modification for specific macrophage-targeting are investigated and summarized. Full article
(This article belongs to the Special Issue Advances in Nanomaterials for Drug Delivery)
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14 pages, 8195 KiB  
Article
The Four-Feature Prognostic Models for Cancer-Specific and Overall Survival after Surgery for Localized Clear Cell Renal Cancer: Is There a Place for Inflammatory Markers?
by Łukasz Zapała, Aleksander Ślusarczyk, Rafał Wolański, Paweł Kurzyna, Karolina Garbas, Piotr Zapała and Piotr Radziszewski
Biomedicines 2022, 10(5), 1202; https://doi.org/10.3390/biomedicines10051202 - 23 May 2022
Cited by 4 | Viewed by 2048
Abstract
We aimed at a determination of the relevance of comorbidities and selected inflammatory markers to the survival of patients with primary non-metastatic localized clear cell renal cancer (RCC). We retrospectively analyzed data from a single tertiary center on 294 patients who underwent a [...] Read more.
We aimed at a determination of the relevance of comorbidities and selected inflammatory markers to the survival of patients with primary non-metastatic localized clear cell renal cancer (RCC). We retrospectively analyzed data from a single tertiary center on 294 patients who underwent a partial or radical nephrectomy in the years 2012–2018. The following parameters were incorporated in the risk score: tumor stage, grade, size, selected hematological markers (SIRI—systemic inflammatory response index; SII—systemic immune-inflammation index) and a comorbidities assessment tool (CCI—Charlson Comorbidity Index). For further analysis we compared our model with existing prognostic tools. In a multivariate analysis, tumor stage (p = 0.01), tumor grade (p = 0.03), tumor size (p = 0.006) and SII (p = 0.02) were significant predictors of CSS, while tumor grade (p = 0.02), CCI (p = 0.02), tumor size (p = 0.01) and SIRI (p = 0.03) were significant predictors of OS. We demonstrated that our model was characterized by higher accuracy in terms of OS prediction compared to the Leibovich and GRANT models and outperformed the GRANT model in terms of CSS prediction, while non-inferiority to the VENUSS model was revealed. Four different features were included in the predictive models for CSS (grade, size, stage and SII) and OS (grade, size, CCI and SIRI) and were characterized by adequate or even superior accuracy when compared with existing prognostic tools. Full article
(This article belongs to the Special Issue Advances in the Treatment of Kidney and Upper Urinary Tract Cancers)
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18 pages, 2934 KiB  
Review
Phospholipid Membrane Transport and Associated Diseases
by Raúl Ventura, Inma Martínez-Ruiz and María Isabel Hernández-Alvarez
Biomedicines 2022, 10(5), 1201; https://doi.org/10.3390/biomedicines10051201 - 23 May 2022
Cited by 16 | Viewed by 5838
Abstract
Phospholipids are the basic structure block of eukaryotic membranes, in both the outer and inner membranes, which delimit cell organelles. Phospholipids can also be damaged by oxidative stress produced by mitochondria, for instance, becoming oxidized phospholipids. These damaged phospholipids have been related to [...] Read more.
Phospholipids are the basic structure block of eukaryotic membranes, in both the outer and inner membranes, which delimit cell organelles. Phospholipids can also be damaged by oxidative stress produced by mitochondria, for instance, becoming oxidized phospholipids. These damaged phospholipids have been related to prevalent diseases such as atherosclerosis or non-alcoholic steatohepatitis (NASH) because they alter gene expression and induce cellular stress and apoptosis. One of the main sites of phospholipid synthesis is the endoplasmic reticulum (ER). ER association with other organelles through membrane contact sites (MCS) provides a close apposition for lipid transport. Additionally, an important advance in this small cytosolic gap are lipid transfer proteins (LTPs), which accelerate and modulate the distribution of phospholipids in other organelles. In this regard, LTPs can be established as an essential point within phospholipid circulation, as relevant data show impaired phospholipid transport when LTPs are defected. This review will focus on phospholipid function, metabolism, non-vesicular transport, and associated diseases. Full article
(This article belongs to the Special Issue The Lipid Metabolism in Health and Diseases)
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14 pages, 1699 KiB  
Article
Point-of-Care Wound Blotting with Alcian Blue Grading versus Fluorescence Imaging for Biofilm Detection and Predicting 90-Day Healing Outcomes
by Yu-Feng Wu, Yu-Chen Lin, Hung-Wei Yang, Nai-Chen Cheng and Chao-Min Cheng
Biomedicines 2022, 10(5), 1200; https://doi.org/10.3390/biomedicines10051200 - 22 May 2022
Cited by 2 | Viewed by 3512
Abstract
Biofilm infection has been identified as a crucial factor of the pathogenesis of chronic wound, but wound biofilm diagnosis remains as an unmet clinical need. We previously proposed a modified wound blotting technique using Alcian blue staining for biofilm detection that was characterized [...] Read more.
Biofilm infection has been identified as a crucial factor of the pathogenesis of chronic wound, but wound biofilm diagnosis remains as an unmet clinical need. We previously proposed a modified wound blotting technique using Alcian blue staining for biofilm detection that was characterized as being non-invasive, time-saving, non-expansive, and informative for biofilm distribution. In this study, we adapted a novel Alcian blue grading method as the severity of biofilm infection for the wound blotting technique and compared its biofilm detection efficacy with MolecuLight i:X- a point-of-care florescence imaging device to detect bacteria and biofilm in wounds. Moreover, their predictive value of complete wound healing at 90 days was analyzed. When validated with wound culture results in the 53 enrolled subjects with chronic wounds, the modified wound blotting method showed a strong association with wound culture, while MolecuLight i:X only exhibited a weak association. In predicting 90-day wound outcomes, the modified wound blotting method showed a strong association (Kendall’s tau value = 0.563, p < 0.001), and the wound culture showed a moderate association (Spearman’s rho = 0.535, p < 0.001), but MolecuLight i:X exhibited no significant association (p = 0.184). In this study, modified wound blotting with the Alcian blue grading method showed superior value to MolecuLight i:X both in biofilm detection and predictive validity in 90-day wound-healing outcomes. Full article
(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)
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14 pages, 1184 KiB  
Article
Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies
by Rafael Franco and Joan Serrano-Marín
Biomedicines 2022, 10(5), 1199; https://doi.org/10.3390/biomedicines10051199 - 22 May 2022
Cited by 3 | Viewed by 2973
Abstract
The Krebs cycle in cells that contain mitochondria is necessary for both energy production and anabolic processes. In given cell/condition, the Krebs cycle is dynamic but remains at a steady state. In this article, we first aimed at comparing the properties of a [...] Read more.
The Krebs cycle in cells that contain mitochondria is necessary for both energy production and anabolic processes. In given cell/condition, the Krebs cycle is dynamic but remains at a steady state. In this article, we first aimed at comparing the properties of a closed cycle versus the same metabolism in a linear array. The main finding is that, unlike a linear metabolism, the closed cycle can reach a steady state (SS) regardless of the nature and magnitude of the disturbance. When the cycle is modeled with input and output reactions, the “open” cycle is robust and reaches a steady state but with exceptions that lead to sustained accumulation of intermediate metabolites, i.e., conditions at which no SS can be achieved. The modeling of the cycle in cancer, trying to obtain marked reductions in flux, shows that these reductions are limited and therefore the Warburg effect is moderate at most. In general, our results of modeling the cycle in different conditions and looking for the achievement, or not, of SS, suggest that the cycle may have a regulation, not yet discovered, to go from an open cycle to a closed one. Said regulation could allow for reaching the steady state, thus avoiding the unwanted effects derived from the aberrant accumulation of metabolites in the mitochondria. The information in this paper might be useful to evaluate metabolism-modifying medicines. Full article
(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Mitochondrial Biology)
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13 pages, 2994 KiB  
Article
A Single Oral Dose of Diclofenac Causes Transition of Experimental Subclinical Acute Kidney Injury to Chronic Kidney Disease
by Johanna Störmer, Wilfried Gwinner, Katja Derlin, Stephan Immenschuh, Song Rong, Mi-Sun Jang, Nelli Shushakova, Hermann Haller, Faikah Gueler and Robert Greite
Biomedicines 2022, 10(5), 1198; https://doi.org/10.3390/biomedicines10051198 - 22 May 2022
Cited by 4 | Viewed by 8938
Abstract
Nephrotoxic drugs can cause acute kidney injury (AKI) and analgesic nephropathy. Diclofenac is potentially nephrotoxic and frequently prescribed for pain control. In this study, we investigated the effects of single and repetitive oral doses of diclofenac in the setting of pre-existing subclinical AKI [...] Read more.
Nephrotoxic drugs can cause acute kidney injury (AKI) and analgesic nephropathy. Diclofenac is potentially nephrotoxic and frequently prescribed for pain control. In this study, we investigated the effects of single and repetitive oral doses of diclofenac in the setting of pre-existing subclinical AKI on the further course of AKI and on long-term renal consequences. Unilateral renal ischemia–reperfusion injury (IRI) for 15 min was performed in male CD1 mice to induce subclinical AKI. Immediately after surgery, single oral doses (100 mg or 200 mg) of diclofenac were administered. In a separate experimental series, repetitive treatment with 100 mg diclofenac over three days was performed after IRI and sham surgery. Renal morphology and pro-fibrotic markers were investigated 24 h and two weeks after the single dose and three days after the repetitive dose of diclofenac treatment using histology, immunofluorescence, and qPCR. Renal function was studied in a bilateral renal IRI model. A single oral dose of 200 mg, but not 100 mg, of diclofenac after IRI aggravated acute tubular injury after 24 h and caused interstitial fibrosis and tubular atrophy two weeks later. Repetitive treatment with 100 mg diclofenac over three days aggravated renal injury and caused upregulation of the pro-fibrotic marker fibronectin in the setting of subclinical AKI, but not in sham control kidneys. In conclusion, diclofenac aggravated renal injury in pre-existing subclinical AKI in a dose and time-dependent manner and already a single dose can cause progression to chronic kidney disease (CKD) in this model. Full article
(This article belongs to the Special Issue Acute Kidney Injury to Chronic Kidney Disease: Pathophysiology and Therapy Targets)
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10 pages, 1758 KiB  
Article
Clinical, Histopathologic, and Immunohistochemical Features of Patients with IgG/IgA Pemphigus
by Yung-Tsu Cho, Ko-Ting Fu, Kai-Lung Chen, Yih-Leong Chang and Chia-Yu Chu
Biomedicines 2022, 10(5), 1197; https://doi.org/10.3390/biomedicines10051197 - 22 May 2022
Cited by 2 | Viewed by 5058
Abstract
Pemphigus is an autoantibody-mediated blistering disease. In addition to conventional pemphigus vulgaris and pemphigus foliaceus, several other types have been reported. Among them, IgG/IgA pemphigus is less well defined and seldom reported. To characterize the clinical, histopathologic, and immunohistochemical presentation of IgG/IgA pemphigus, [...] Read more.
Pemphigus is an autoantibody-mediated blistering disease. In addition to conventional pemphigus vulgaris and pemphigus foliaceus, several other types have been reported. Among them, IgG/IgA pemphigus is less well defined and seldom reported. To characterize the clinical, histopathologic, and immunohistochemical presentation of IgG/IgA pemphigus, we retrospectively identified 22 patients with the disease at a referral center in Taiwan. These patients showed two types of skin lesion: annular or arciform erythemas with blisters or erosions (45.5%) and discrete erosions or blisters such as those in conventional pemphigus (54.5%). Mucosal involvement was found in 40.9%. Histopathologic analysis identified acantholysis (77.3%) and intra-epidermal aggregates of neutrophils (40.9%) and eosinophils (31.8%). Direct immunofluorescence studies showed IgG/IgA (100%) and C3 (81.8%) depositions in the intercellular space of the epidermis. In immunohistochemical staining, patients with IgG/IgA pemphigus demonstrated significantly higher levels of epidermal expression of interleukin-8 and matrix metalloproteinase-9 than those with conventional pemphigus (p < 0.05). In conclusion, although IgG/IgA pemphigus is heterogeneous in presentation, it shows characteristic features that are different from other forms of pemphigus and should be considered a distinct type of pemphigus. Full article
(This article belongs to the Special Issue Autoimmune Blistering Diseases)
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14 pages, 5014 KiB  
Article
Combined Treatment of Nitrated [6,6,6]Tricycles Derivative (SK2)/Ultraviolet C Highly Inhibits Proliferation in Oral Cancer Cells In Vitro
by Sheng-Chieh Wang, Ching-Yu Yen, Jun-Ping Shiau, Meng-Yang Chang, Ming-Feng Hou, Jen-Yang Tang and Hsueh-Wei Chang
Biomedicines 2022, 10(5), 1196; https://doi.org/10.3390/biomedicines10051196 - 22 May 2022
Cited by 1 | Viewed by 2069
Abstract
Combined treatment is an effective strategy to improve anticancer therapy, but severe side effects frequently limit this application. Drugs inhibiting the proliferation of cancer cells, but not normal cells, display preferential antiproliferation to cancer cells. It shows the benefits of avoiding side effects [...] Read more.
Combined treatment is an effective strategy to improve anticancer therapy, but severe side effects frequently limit this application. Drugs inhibiting the proliferation of cancer cells, but not normal cells, display preferential antiproliferation to cancer cells. It shows the benefits of avoiding side effects and enhancing antiproliferation for combined treatment. Nitrated [6,6,6]tricycles derivative (SK2), a novel chemical exhibiting benzo-fused dioxabicyclo[3.3.1]nonane core with an n-butyloxy substituent, exhibiting preferential antiproliferation, was chosen to evaluate its potential antioral cancer effect in vitro by combining it with ultraviolet C (UVC) irradiation. Combination treatment (UVC/SK2) caused lower viability in oral cancer cells (Ca9-22 and OC-2) than single treatment (20 J/m2 UVC or 10 μg/mL SK2), i.e., 42.3%/41.1% vs. 81.6%/69.2%, and 89.5%/79.6%, respectively. In contrast, it showed a minor effect on cell viability of normal oral cells (HGF-1), ranging from 82.2 to 90.6%. Moreover, UVC/SK2 caused higher oxidative stress in oral cancer cells than normal cells through the examination of reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane potential. UVC/SK2 also caused subG1 increment associated with apoptosis detections by assessing annexin V; panaspase; and caspases 3, 8, and 9. The antiproliferation and oxidative stress were reverted by N-acetylcysteine, validating the involvement of oxidative stress in antioral cancer cells. UVC/SK2 also caused DNA damage by detecting γH2AX and 8-hydroxy-2′-deoxyguanosine in oral cancer cells. In conclusion, SK2 is an effective enhancer for improving the UVC-caused antiproliferation against oral cancer cells in vitro. UVC/SK2 demonstrated a preferential and synergistic antiproliferation ability towards oral cancer cells with little adverse effects on normal cells. Full article
(This article belongs to the Special Issue Oncogenic Signaling Pathways in Cancer)
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12 pages, 1345 KiB  
Article
In Vitro Evaluation of Acrylic Adhesives in Lymphatic Fluids-Influence of Glue Type and Procedural Parameters
by Daniel Kuetting, Patrick Kupczyk, Tatjana Dell, Julian A. Luetkens, Carsten Meyer, Ulrike I. Attenberger and Claus C. Pieper
Biomedicines 2022, 10(5), 1195; https://doi.org/10.3390/biomedicines10051195 - 21 May 2022
Cited by 2 | Viewed by 1605
Abstract
To evaluate the embolic properties of different acrylic adhesive/iodized oil mixtures for lymphatic interventions. Polymerization of histoacryl (HA) (Bayer Healthcare) and glubran 2 (GL) (GEM) mixed with iodized oil (ratios 1:0–1:7) were investigated in lymphatic fluids with low and high triglyceride (low TG [...] Read more.
To evaluate the embolic properties of different acrylic adhesive/iodized oil mixtures for lymphatic interventions. Polymerization of histoacryl (HA) (Bayer Healthcare) and glubran 2 (GL) (GEM) mixed with iodized oil (ratios 1:0–1:7) were investigated in lymphatic fluids with low and high triglyceride (low TG & high TG) contents. Static polymerization time and dynamic polymerization experiments with different volumes of glucose flush (1, 2 and 5 mL) were performed to simulate thoracic duct embolization. For both glues, static polymerization times were longer when the iodized oil content was increased and when performed in high TG lymphatic fluid. In the dynamic experiments, the prolongation of polymerization due to the oil content and TG levels was less pronounced for both glue types. Increased lymphatic flow rates decreased embolization times for low glue/oil ratios while preventing embolization for high glue/oil ratios. Higher glucose flush volumes increased occlusion times. Polymerization times of acrylic glue in a lymphatic fluid are prolonged by increasing the iodized oil concentration and triglyceride concentration as well as by using larger volumes of glucose flush. Increased lymphatic flow rates decrease embolization times for low glue/oil ratios and may prevent embolization for high glue/oil ratios. Full article
(This article belongs to the Special Issue Vascular Embolization: Present and Future)
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18 pages, 1029 KiB  
Article
Hepatitis B Virus Variants with Multiple Insertions and/or Deletions in the X Open Reading Frame 3′ End: Common Members of Viral Quasispecies in Chronic Hepatitis B Patients
by Selene García-García, Andrea Caballero-Garralda, David Tabernero, Maria Francesca Cortese, Josep Gregori, Francisco Rodriguez-Algarra, Josep Quer, Mar Riveiro-Barciela, Maria Homs, Ariadna Rando-Segura, Beatriz Pacin-Ruiz, Marta Vila, Roser Ferrer-Costa, Tomas Pumarola, Maria Buti and Francisco Rodriguez-Frias
Biomedicines 2022, 10(5), 1194; https://doi.org/10.3390/biomedicines10051194 - 21 May 2022
Cited by 2 | Viewed by 2964
Abstract
Deletions in the 3′ end region of the hepatitis B virus (HBV) X open reading frame (HBX) may affect the core promoter (Cp) and have been frequently associated with hepatocellular carcinoma (HCC). The aim of this study was to investigate the [...] Read more.
Deletions in the 3′ end region of the hepatitis B virus (HBV) X open reading frame (HBX) may affect the core promoter (Cp) and have been frequently associated with hepatocellular carcinoma (HCC). The aim of this study was to investigate the presence of variants with deletions and/or insertions (Indels) in this region in the quasispecies of 50 chronic hepatitis B (CHB) patients without HCC. We identified 103 different Indels in 47 (94%) patients, in a median of 3.4% of their reads (IQR, 1.3–8.4%), and 25% (IQR, 13.1–40.7%) of unique sequences identified in each quasispecies (haplotypes). Of those Indels, 101 (98.1%) caused 44 different altered stop codons, the most commonly observed were at positions 128, 129, 135, and 362 (putative position). Moreover, 39 (37.9%) Indels altered the TATA-like box (TA) sequences of Cp; the most commonly observed caused TA2 + TA3 fusion, creating a new putative canonical TATA box. Four (8%) patients developed negative clinical outcomes after a median follow-up of 9.4 (8.7–12) years. In conclusion, we observed variants with Indels in the HBX 3′ end in the vast majority of our CHB patients, some of them encoding alternative versions of HBx with potential functional roles, and/or alterations in the regulation of transcription. Full article
(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Hepatobiliary Diseases)
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13 pages, 1767 KiB  
Article
Myeloid-Specific Pyruvate-Kinase-Type-M2-Deficient Mice Are Resistant to Acute Lung Injury
by Xinlei Sun, Fujie Shi, Weiran Wang, Yunfei Wu, Shuang Qu, Jing Li, Hongwei Liang and Ke Zen
Biomedicines 2022, 10(5), 1193; https://doi.org/10.3390/biomedicines10051193 - 21 May 2022
Cited by 3 | Viewed by 2247
Abstract
Infiltration of polymorphonuclear neutrophils (PMNs) plays a central role in acute lung injury (ALI). The mechanisms governing PMN inflammatory responses, however, remain incompletely understood. Based on our recent study showing a non-metabolic role of pyruvate kinase type M2 (PKM2) in controlling PMN degranulation [...] Read more.
Infiltration of polymorphonuclear neutrophils (PMNs) plays a central role in acute lung injury (ALI). The mechanisms governing PMN inflammatory responses, however, remain incompletely understood. Based on our recent study showing a non-metabolic role of pyruvate kinase type M2 (PKM2) in controlling PMN degranulation of secondary and tertiary granules and consequent chemotaxis, here we tested a hypothesis that Pkm2-deficient mice may resist ALI due to impaired PMN inflammatory responses. We found that PMN aerobic glycolysis controlled the degranulation of secondary and tertiary granules induced by fMLP and PMA. Compared to WT PMNs, Pkm2-deficient (Pkm2-/-) PMNs displayed significantly less capacity for fMLP- or PMA-induced degranulation of secondary and tertiary granules, ROS production, and transfilter migration. In line with this, myeloid-specific Pkm2-/- mice exhibited impaired zymosan-induced PMN infiltration in the peritoneal cavity. Employing an LPS-induced ALI mouse model, LPS-treated Pkm2-/- mice displayed significantly less infiltration of inflammatory PMNs in the alveolar space and a strong resistance to LPS-induced ALI. Our results thus reveal that PKM2 is required for PMN inflammatory responses and deletion of PKM2 in PMN leads to an impaired PMN function but protection against LPS-induced ALI. Full article
(This article belongs to the Section Cell Biology and Pathology)
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25 pages, 980 KiB  
Review
Alcohol Use Disorder: Neurobiology and Therapeutics
by Waisley Yang, Rohit Singla, Oshin Maheshwari, Christine J. Fontaine and Joana Gil-Mohapel
Biomedicines 2022, 10(5), 1192; https://doi.org/10.3390/biomedicines10051192 - 21 May 2022
Cited by 24 | Viewed by 21264
Abstract
Alcohol use disorder (AUD) encompasses the dysregulation of multiple brain circuits involved in executive function leading to excessive consumption of alcohol, despite negative health and social consequences and feelings of withdrawal when access to alcohol is prevented. Ethanol exerts its toxicity through changes [...] Read more.
Alcohol use disorder (AUD) encompasses the dysregulation of multiple brain circuits involved in executive function leading to excessive consumption of alcohol, despite negative health and social consequences and feelings of withdrawal when access to alcohol is prevented. Ethanol exerts its toxicity through changes to multiple neurotransmitter systems, including serotonin, dopamine, gamma-aminobutyric acid, glutamate, acetylcholine, and opioid systems. These neurotransmitter imbalances result in dysregulation of brain circuits responsible for reward, motivation, decision making, affect, and the stress response. Despite serious health and psychosocial consequences, this disorder still remains one of the leading causes of death globally. Treatment options include both psychological and pharmacological interventions, which are aimed at reducing alcohol consumption and/or promoting abstinence while also addressing dysfunctional behaviours and impaired functioning. However, stigma and social barriers to accessing care continue to impact many individuals. AUD treatment should focus not only on restoring the physiological and neurological impairment directly caused by alcohol toxicity but also on addressing psychosocial factors associated with AUD that often prevent access to treatment. This review summarizes the impact of alcohol toxicity on brain neurocircuitry in the context of AUD and discusses pharmacological and non-pharmacological therapies currently available to treat this addiction disorder. Full article
(This article belongs to the Special Issue Biological Aspects of Drug Addiction)
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20 pages, 2053 KiB  
Article
A Nine-Strain Bacterial Consortium Improves Portal Hypertension and Insulin Signaling and Delays NAFLD Progression In Vivo
by Iris Pinheiro, Aurora Barberá, Imma Raurell, Federico Estrella, Marcel de Leeuw, Selin Bolca, Davide Gottardi, Nigel Horscroft, Sam Possemiers, María Teresa Salcedo, Joan Genescà, María Martell and Salvador Augustin
Biomedicines 2022, 10(5), 1191; https://doi.org/10.3390/biomedicines10051191 - 20 May 2022
Cited by 5 | Viewed by 6213
Abstract
The gut microbiome has a recognized role in Non-alcoholic fatty liver disease (NAFLD) and associated comorbidities such as Type-2 diabetes and obesity. Stool transplantation has been shown to improve disease by restoring endothelial function and insulin signaling. However, more patient-friendly treatments are required. [...] Read more.
The gut microbiome has a recognized role in Non-alcoholic fatty liver disease (NAFLD) and associated comorbidities such as Type-2 diabetes and obesity. Stool transplantation has been shown to improve disease by restoring endothelial function and insulin signaling. However, more patient-friendly treatments are required. The present study aimed to test the effect of a defined bacterial consortium of nine gut commensal strains in two in vivo rodent models of Non-alcoholic steatohepatitis (NASH): a rat model of NASH and portal hypertension (PHT), and the Stelic animal (mouse) model (STAM™). In both studies the consortium was administered orally q.d. after disease induction. In the NASH rats, the consortium was administered for 2 weeks and compared to stool transplant. In the STAM™ study administration was performed for 4 weeks, and the effects compared to vehicle or Telmisartan at the stage of NASH/early fibrosis. A second group of animals was followed for another 3 weeks to assess later-stage fibrosis. In the NASH rats, an improvement in PHT and endothelial function was observed. Gut microbial compositional changes also revealed that the consortium achieved a more defined and richer replacement of the gut microbiome than stool transplantation. Moreover, liver transcriptomics suggested a beneficial modulation of pro-fibrogenic pathways. An improvement in liver fibrosis was then confirmed in the STAM™ study. In this study, the bacterial consortium improved the NAFLD activity score, consistent with a decrease in steatosis and ballooning. Serum cytokeratin-18 levels were also reduced. Therefore, administration of a specific bacterial consortium of defined composition can ameliorate NASH, PHT, and fibrosis, and delay disease progression. Full article
(This article belongs to the Special Issue Metabolic Syndrome and NASH: From Molecular Basis to Therapy)
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25 pages, 1584 KiB  
Article
Expression Profile of mRNAs and miRNAs Related to the Oxidative-Stress Phenomenon in the Ishikawa Cell Line Treated Either Cisplatin or Salinomycin
by Szymon Januszyk, Paweł Mieszczański, Hubert Lurka, Dorota Sagan, Dariusz Boroń and Beniamin Oskar Grabarek
Biomedicines 2022, 10(5), 1190; https://doi.org/10.3390/biomedicines10051190 - 20 May 2022
Cited by 5 | Viewed by 2713
Abstract
The oxidative stress phenomenon is a result of anticancer therapy. The aim of this study was the assessment of gene expression profile changes, and to determine the miRNAs regulating genes’ transcriptional activity in an Ishikawa endometrial cancer culture exposed to cisplatin or salinomycin, [...] Read more.
The oxidative stress phenomenon is a result of anticancer therapy. The aim of this study was the assessment of gene expression profile changes, and to determine the miRNAs regulating genes’ transcriptional activity in an Ishikawa endometrial cancer culture exposed to cisplatin or salinomycin, compared to a control culture. The molecular analysis comprised the microarray technique (mRNAs and micro RNA (miRNA), the real-time quantitative reverse transcription reaction (RTqPCR), enzyme-linked immunosorbent assay (ELISA) reactions, and Western blot. NR4A2, MAP3K8, ICAM1, IL21, CXCL8, CCL7, and SLC7A11 were statistically significantly differentiated depending not only on time, but also on the drug used in the experiment. The conducted assessment indicated that the strongest links were between NR4A2 and hsa-miR-30a-5p and has-miR-302e, MAP3K8 and hsa-miR-144-3p, CXCL8 and hsa-miR-140-3p, and SLC7A11 and hsa-miR-144-3p. The obtained results suggest that four mRNAs—NR4A2, MAP3K8, CXCL8 and SLC7A11—and four miRNAs—hsa-miR-30a-5p, hsa-miR-302e, hsa-miR-144-3p and hsa-miR-140-3—changed their expressions regardless of the chemotherapeutic agent used, which suggests the possibility of their use in monitoring the severity of oxidative stress in endometrial cancer. However, considering the results at both the mRNA and the protein level, it is most likely that the expressions of NR4A2, MAP3K8, CXCL8 and SLC7A11 are regulated by miRNA molecules as well as other epigenetic mechanisms. Full article
(This article belongs to the Special Issue Epigenetic Regulation of the Immune System)
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20 pages, 4635 KiB  
Article
Lipidomics Analysis of Free Fatty Acids in Human Plasma of Healthy and Diabetic Subjects by Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS)
by Maroula G. Kokotou, Christiana Mantzourani, Charikleia S. Batsika, Olga G. Mountanea, Ioanna Eleftheriadou, Ourania Kosta, Nikolaos Tentolouris and George Kokotos
Biomedicines 2022, 10(5), 1189; https://doi.org/10.3390/biomedicines10051189 - 20 May 2022
Cited by 6 | Viewed by 3558
Abstract
Targeted analytical methods for the determination of free fatty acids (FFAs) in human plasma are of high interest because they may help in identifying biomarkers for diseases and in monitoring the progress of a disease. The determination of FFAs is of particular importance [...] Read more.
Targeted analytical methods for the determination of free fatty acids (FFAs) in human plasma are of high interest because they may help in identifying biomarkers for diseases and in monitoring the progress of a disease. The determination of FFAs is of particular importance in the case of metabolic disorders because FFAs have been associated with diabetes. We present a liquid chromatography-high resolution mass spectrometry (LC-HRMS) method, which allows the simultaneous determination of 74 FFAs in human plasma. The method is fast (10-min run) and straightforward, avoiding any derivatization step and tedious sample preparation. A total of 35 standard saturated and unsaturated FFAs, as well as 39 oxygenated (either hydroxy or oxo) saturated FFAs, were simultaneously detected and quantified in plasma samples from 29 subjects with type 2 diabetes mellitus (T2D), 14 with type 1 diabetes mellitus (T1D), and 28 healthy subjects. Alterations in the levels of medium-chain FFAs (C6:0 to C10:0) were observed between the control group and T2D and T1D patients. Full article
(This article belongs to the Special Issue The Lipid Metabolism in Health and Diseases)
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11 pages, 574 KiB  
Article
Distress and Sensitization as Main Mediators of Severity in Women with Fibromyalgia: A Structural Equation Model
by Bernard X. W. Liew, Juan Antonio Valera-Calero, Umut Varol, Jo Nijs, Lars Arendt-Nielsen, Gustavo Plaza-Manzano and César Fernández-de-las-Peñas
Biomedicines 2022, 10(5), 1188; https://doi.org/10.3390/biomedicines10051188 - 20 May 2022
Cited by 9 | Viewed by 2380
Abstract
We aimed to explore a path model identified using a structural equation model (SEM) which best explains the multivariate contributions of sensitization, sensitivity, and emotional variables to clinical severity in women with FMS. Pain features, the Central Sensitization Inventory (CSI), painDETECT, S-LANSS, the [...] Read more.
We aimed to explore a path model identified using a structural equation model (SEM) which best explains the multivariate contributions of sensitization, sensitivity, and emotional variables to clinical severity in women with FMS. Pain features, the Central Sensitization Inventory (CSI), painDETECT, S-LANSS, the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI), the Pain Catastrophizing Scale (PCS), the Pain Vigilance and Awareness Questionnaire (PVAQ), the 11-item Tampa Scale for Kinesiophobia (TSK-11), and pressure pain thresholds (PPTs) were collected from 113 women with FMS. Four latent variables were created: severity (clinical pain features), sensitivity (PPTs), sensitization (S-LANSS, CSI, painDETECT), and distress (HADS-A, HADS-D, PCS, PVAQ, TSK-11). Data fit for the measurement model were considered excellent (RMSEA = 0.043, CFI = 0.966, SRMR = 0.067, and NNFI = 0.960). Distress had a significant relationship with the mediators of sleep (β = 0.452, p = 0.031) and sensitization (β = 0.618, p = 0.001). The only mediator with a significant effect (β = 1.113, p < 0.001) on severity was sensitization. A significant indirect effect of sensitization (β = 0.687, p = 0.001) that explained the relationship between distress and severity was also identified. The proposed model suggests that distress and sensitization, together with poor sleep, have a complex mediating effect on severity in women with FMS. The identified path model can be leveraged in clinical trials investigating treatment approaches for FMS. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Musculoskeletal Conditions)
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30 pages, 2539 KiB  
Review
Nanoparticles Loaded with Docetaxel and Resveratrol as an Advanced Tool for Cancer Therapy
by Magdalena Jurczyk, Janusz Kasperczyk, Dorota Wrześniok, Artur Beberok and Katarzyna Jelonek
Biomedicines 2022, 10(5), 1187; https://doi.org/10.3390/biomedicines10051187 - 20 May 2022
Cited by 33 | Viewed by 4340
Abstract
A growing interest in the use of a combination of chemosensitizers and cytostatics for overcoming cancer resistance to treatment and the development of their delivery systems has been observed. Resveratrol (Res) presents antioxidant, anti-inflammatory and chemopreventive properties but also limits multidrug resistance against [...] Read more.
A growing interest in the use of a combination of chemosensitizers and cytostatics for overcoming cancer resistance to treatment and the development of their delivery systems has been observed. Resveratrol (Res) presents antioxidant, anti-inflammatory and chemopreventive properties but also limits multidrug resistance against docetaxel (Dtx), which is one of the main causes of failure in cancer therapy with this drug. However, the use of both drugs presents challenges, including poor bioavailability, the unfavourable pharmacokinetics and chemical instability of Res and the poor water solubility and dose-limiting toxicity of Dtx. In order to overcome these difficulties, attempts have been made to create different forms of delivery for both agents. This review is focused on the latest developments in nanoparticles for the delivery of Dtx, Res and for the combined delivery of those two drugs. The aim of this review was also to summarize the synergistic mechanism of action of Dtx and Res on cancer cells. According to recent reports, Dtx and Res loaded in a nano-delivery system exhibit better efficiency in cancer treatment compared to free drugs. Also, the co-delivery of Dtx and Res in one actively targeted delivery system providing the simultaneous release of both drugs in cancer cells has a chance to fulfil the requirements of effective anticancer therapy and reduce limitations in therapy caused by multidrug resistance (MDR). Full article
(This article belongs to the Section Nanomedicine and Nanobiology)
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21 pages, 23581 KiB  
Article
Elucidation of the Potential Hair Growth-Promoting Effect of Botryococcus terribilis, Its Novel Compound Methylated-Meijicoccene, and C32 Botryococcene on Cultured Hair Follicle Dermal Papilla Cells Using DNA Microarray Gene Expression Analysis
by Aprill Kee Oliva, Meriem Bejaoui, Atsushi Hirano, Takashi Arimura, Tran Ngoc Linh, Eriko Uchiage, Sachiko Nukaga, Kenichi Tominaga, Hiroyuki Nozaki and Hiroko Isoda
Biomedicines 2022, 10(5), 1186; https://doi.org/10.3390/biomedicines10051186 - 20 May 2022
Cited by 6 | Viewed by 3818
Abstract
A person’s quality of life can be adversely affected by hair loss. Microalgae are widely recognized for their abundance and rich functional components. Here, we evaluated the hair growth effect of a green alga, Botryococcus terribilis (B. terribilis), in vitro using [...] Read more.
A person’s quality of life can be adversely affected by hair loss. Microalgae are widely recognized for their abundance and rich functional components. Here, we evaluated the hair growth effect of a green alga, Botryococcus terribilis (B. terribilis), in vitro using hair follicle dermal papilla cells (HFDPCs). We isolated two types of cells from B. terribilis—green and orange cells, obtained from two different culture conditions. Microarray and real time-PCR results revealed that both cell types stimulated the expression of several pathways and genes associated with different aspect of the hair follicle cycle. Additionally, we demonstrated B. terribilis’ effect on collagen and keratin synthesis and inflammation reduction. We successfully isolated a novel compound, methylated-meijicoccene (me-meijicoccene), and C32 botryococcene from B. terribilis to validate their promising effects. Our study revealed that treatment with the two compounds had no cytotoxic effect on HFDPCs and significantly enhanced the gene expression levels of hair growth markers at low concentrations. Our study provides the first evidence of the underlying hair growth promoting effect of B. terribilis and its novel compound, me-meijicoccene, and C32 botryococcene. Full article
(This article belongs to the Section Gene and Cell Therapy)
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Article
Proinflammatory Endothelial Phenotype in Very Preterm Infants: A Pilot Study
by Giacomo S. Amelio, Livia Provitera, Genny Raffaeli, Ilaria Amodeo, Silvia Gulden, Valeria Cortesi, Francesca Manzoni, Nicola Pesenti, Matteo Tripodi, Valentina Pravatà, Caterina Lonati, Gaia Cervellini, Fabio Mosca and Giacomo Cavallaro
Biomedicines 2022, 10(5), 1185; https://doi.org/10.3390/biomedicines10051185 - 20 May 2022
Cited by 3 | Viewed by 2078
Abstract
Very preterm infants are exposed to prenatal inflammatory processes and early postnatal hemodynamic and respiratory complications, but limited data are available about the endothelial effect of these conditions. The present pilot study investigates the perinatal endothelial phenotype in very preterm infants (VPIs) and [...] Read more.
Very preterm infants are exposed to prenatal inflammatory processes and early postnatal hemodynamic and respiratory complications, but limited data are available about the endothelial effect of these conditions. The present pilot study investigates the perinatal endothelial phenotype in very preterm infants (VPIs) and explores its predictive value on neonatal mortality and hemodynamic and respiratory complications. Angiopoietin 1 (Ang-1), Ang-2, E-selectin, vascular adhesion molecule 1 (VCAM-1), tissue factor (TF), and endothelin 1 (ET-1) concentrations were tested in first (T1), 3rd (T2), and 7–10th (T3) day of life in 20 VPIs using Luminex technology and compared with 14 healthy full-term infants (FTIs). Compared to FTIs, VPIs had lower Ang-1 at T1 and T2; higher Ang-2 at T1, T2, and T3; higher Ang-2/Ang-1 ratio at T1, T2, and T3; lower E-selectin at T1, T2, and T3; higher VCAM-1 at T1; higher TF at T2. No differences in concentrations were found in neonatal deaths. VPIs with hemodynamic or respiratory complications had higher Ang-2 at T3. Perinatal low Ang-1 and high Ang-2 associated with high VCAM-1 and TF in VPIs suggest a proinflammatory endothelial phenotype, resulting from the synergy of a pathological prenatal inheritance and a premature extrauterine transition. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)
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