Molecular and functional resemblance of dexamethasone and quercetin: A paradigm worth exploring in dexamethasone-nonresponsive COVID-19 patients.
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ABSTRACT:
SUBMITTER: Pawar A
PROVIDER: S-EPMC7537236 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although quercetin has numerous biological benefits, including preventing muscle atrophy due to disuse, no reports have been published to date about the preventive effects and molecular mechanisms underlying drug-induced muscle atrophy. Highly soluble and bioavailable quercetin glycosides (QGs) were used to examine the inhibition of dexamethasone (DEX)-induced muscle atrophy in vivo. Male BALB/cCrSlc mice were treated with or without QGs for 7 days ad libitum, followed by addition of DEX to their drinking water for a further 7 days. The weight of gastrocnemius (GM) adjusted by body weight was significantly decreased on day 7 after DEX treatment. DEX-induced decrease of GM weight was improved by QG co-administration on day 7. The mRNA levels of muscle atrophy-related genes in the gastrocnemius were significantly lowered by QGs on day 1. In particular, the expression of myostatin, a master regulator of muscle mass homeostasis, was suppressed to that of the control level. In murine C2C12 myotubes, quercetin elevated the phosphorylation of Akt, which are downstream of the myostatin pathway, as well as expression of atrogenes. We demonstrated the protective effect of QGs in DEX-induced muscle atrophy, which might depend on the suppression of myostatin signaling.
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Project description:Patient-specific pluripotent stem cells (PSCs) can be generated via nuclear reprogramming by transcription factors (i.e., induced pluripotent stem cells, iPSCs) or by somatic cell nuclear transfer (SCNT). However, abnormalities and preclinical application of differentiated cells generated by different reprogramming mechanisms have yet to be evaluated. Here we investigated the molecular and functional features, and drug response of cardiomyocytes (PSC-CMs) and endothelial cells (PSC-ECs) derived from genetically relevant sets of human iPSCs, SCNT-derived embryonic stem cells (nt-ESCs), as well as in vitro fertilization embryo-derived ESCs (IVF-ESCs). We found that differentiated cells derived from isogenic iPSCs and nt-ESCs showed comparable lineage gene expression, cellular heterogeneity, physiological properties, and metabolic functions. Genome-wide transcriptome and DNA methylome analysis indicated that iPSC derivatives (iPSC-CMs and iPSC-ECs) were more similar to isogenic nt-ESC counterparts than those derived from IVF-ESCs. Although iPSCs and nt-ESCs shared the same nuclear DNA and yet carried different sources of mitochondrial DNA, CMs derived from iPSC and nt-ESCs could both recapitulate doxorubicin-induced cardiotoxicity and exhibited insignificant differences on reactive oxygen species generation in response to stress condition. We conclude that molecular and functional characteristics of differentiated cells from human PSCs are primarily attributed to the genetic compositions rather than the reprogramming mechanisms (SCNT vs. iPSCs). Therefore, human iPSCs can replace nt-ESCs as alternatives for generating patient-specific differentiated cells for disease modeling and preclinical drug testing.
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Project description:AimTo elicit the experiences and perspectives of health professionals working on the frontline in the COVID-19 pandemic.BackgroundAlthough some qualitative studies have been carried out in health professionals during COVID-19 pandemic, to our knowledge, no study has used the Photovoice method.DesignA qualitative descriptive study using Photovoice was carried out between March and June 2020.MethodsA total of 20 health professionals were recruited from public and private healthcare services. The participants were invited to share photographs about their experiences while working during COVID-19 pandemic. Following the Photovoice method, audio-recorded interviews were conducted. The data were analysed using the 'SHOWED' mnemonic, with five questions answered about each photograph. The EQUATOR checklist has been used.Results/findingsThree themes emerged: (1) Personal attitudes of health professionals; (2) Support from the community; and (3) Management of institutional resources. Despite the fact that health professionals in this study were exposed to major risks while caring for patients with COVID-19' they felt a strong sense of responsibility towards the community. In order to handle these stressful situations, they used coping mechanisms, good humour and leisure, but also received support from the population, who saw them as highly skilled health professionals.ConclusionThese findings highlight the essential role of health professionals in the COVID-19 pandemic and the tireless work they are carrying out to provided highly skilled care.Relevance to clinical practiceThese findings could contribute to raise awareness on the needs of health professionals during the pandemic, allowing managers to plan strategies to ensure the safety, and well-being of these professionals, as well as adopting similar strategies in their practice to create a space for critical reflection through participatory approaches.
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Project description:Advances in protein structure determination, led by the structural genomics initiatives have increased the proportion of novel folds deposited in the Protein Data Bank. However, these structures are often not accompanied by functional annotations with experimental confirmation. In this review, we reassess the meaning of structural novelty and examine its relevance to the complexity of the structure-function paradigm. Recent advances in the prediction of protein function from structure are discussed, as well as new sequence-based methods for partitioning large, diverse superfamilies into biologically meaningful clusters. Obtaining structural data for these functionally coherent groups of proteins will allow us to better understand the relationship between structure and function.
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Project description:ObjectiveTo investigate the molecular mechanism of quercetin in the treatment of heart failure (HF) based on network pharmacology and molecular docking.MethodsQuercetin and HF-related targets were obtained using TCMSP, PharmMapper, CTD and GeneCards databases, and quercetin-HF intersection targets were obtained through the online website Venn; the protein interaction network was constructed and imported into Cytoscape 3.7.2 to identify the core targets of quercetin in the treatment of HF.GO and KEGG pathway enrichment analyses were performed using R package, and molecular docking was performed using Auto Dock Vina.The protein levels of AKT1, phospho-AKT(Ser473), eNOS, MMP9, and caspase-3 in quercetin-treated HF cell models were detected using protein immunoblotting.ResultsWe identified 80 quercetin-HF intersectional targets (AKT1, CASP3, MAPK1, MMP9, and MAPK8) and 5 core targets of quercetin for treatment of HF.GO analysis suggested that the therapeutic effect of quercetin for HF was mediated mainly by such biological processes as responses to peptide hormones, phosphatidylinositol-mediated signalling, responses to lipopolysaccharides, responses to molecules of bacterial origin and regulation of inflammatory responses.KEGG pathway enrichment analysis identified lipid and atherosclerosis pathway, proteoglycans in cancer, PI3K-AKT signaling pathway, diabetic cardiomyopathy and MAPK signaling pathway as the most significantly enriched signaling pathways.Molecular docking showed a good binding activity of quercetin to the 5 core targets.The results of protein immunoblotting showed that 100 μmol/L quercetin significantly reduced AKT1, phospho-AKT (Ser473), eNOS, MMP9 and caspase-3 levels in the cell models of HF (P < 0.01).ConclusionQuercetin improves the pathological changes in HF possibly by regulating the AKT1-eNOS-MMP9 pathway to inhibit cell apoptosis.
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Project description:Dexamethasone, a widely used corticosteroid, has recently been reported as the first drug to increase the survival chances of patients with severe COVID-19. Therapeutic agents, including dexamethasone, are mostly transported through the body by binding to serum albumin. Herein, we report the first structure of serum albumin in complex with dexamethasone. We show that it binds to Drug Site 7, which is also the binding site for commonly used nonsteroidal anti-inflammatory drugs and testosterone, suggesting potentially problematic binding competition. This study bridges structural findings with our analysis of publicly available clinical data from Wuhan and suggests that an adjustment of dexamethasone regimen should be considered for patients affected by two major COVID-19 risk-factors: low albumin levels and diabetes.
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Project description:Dexamethasone, a widely used corticosteroid, has recently been reported as the first drug to increase the survival chances of patients with severe COVID-19. Therapeutic agents, including dexamethasone, are mostly transported through the body by binding to serum albumin. Here, the first structure of serum albumin in complex with dexamethasone is reported. Dexamethasone binds to drug site 7, which is also the binding site for commonly used nonsteroidal anti-inflammatory drugs and testosterone, suggesting potentially problematic binding competition. This study bridges structural findings with an analysis of publicly available clinical data from Wuhan and suggests that an adjustment of the dexamethasone regimen should be further investigated as a strategy for patients affected by two major COVID-19 risk factors: low albumin levels and diabetes.
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Project description:Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward in several centers in Greece and the Netherlands and whole blood transcriptomic analysis was performed before and after starting dexamethasone treatment. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 ex vivo in the presence or absence of dexamethasone and their transcriptome was assessed.
2023-07-26 | GSE227585 | GEO
Project description:Here we performed genome-wide RNA-seq and Reduced Representation Bisulfite Sequencing (RRBS-seq) in isogenic human induced pluripotent stem cells (iPSCs) and somatic cell nuclear transfer-derived embryonic stem cells (nt-ESCs), genetically matched in vitro fertilization-derived ESCs (IVF-ESCs), and their respective differentiated cells (cardiomyocytes and endothelial cells). We generated the transcriptome and DNA methylome map in human pluripotent stem cells and their differentiated cells with single-nucleotide resolution. We compared the genetic (genetic makeup) and epigenetic (reprogramming approach) influence on the gene expression and DNA methylation profiles and found that genetic composition is the major contributor of the transcriptional and epigenetic variances observed in the undifferentiated and differentiated cells originated from different reprogramming mechanisms.
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