In the new millennium, the outbreak of new coronavirus has happened three times: SARS-CoV, MERS-CoV, and 2019-nCoV. Unfortunately, we still have no pharmaceutical weapons against the diseases caused by these viruses. The pandemic of 2019-nCoV reminds us of the urgency to search new drugs with totally different mechanism that may target the weaknesses specific to coronaviruses. Herein, we disclose a new targeted oxidation strategy (TOS II) leveraging non-covalent interactions potentially to oxidize and inhibit the activities of cytosolic thiol proteins via thiol/thiolate oxidation to disulfide (TOD). Quantum mechanical calculations show encouraging results supporting the feasibility to selectively oxidize thiol of targeted proteins via TOS II even in relatively reducing cytosolic microenvironments. Molecular docking against the two thiol proteases Mpro and PLpro of 2019-nCoV provide evidence to support a TOS II mechanism for two experimentally identified anti-2019-nCoV disulfide oxidants: disulfiram and PX-12. Remarkably, disulfiram is an anti-alcoholism drug approved by FDA 70 years ago, thus it can be immediately used in phase III clinical trial for anti-2019-nCoV treatment. Finally, a preliminary list of promising TOS II drug candidates targeting the two thiol proteases of 2019-nCoV are proposed upon virtual screening of 32143 disulfides
Abstract: Genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN, were employed as baits to build genomic-guided molecular maps of upstream regulatory elements, their expression and functions in the human body, and pathophysiologically relevant cell types. Repressors and activators of the ACE2 and FURIN genes were identified based on the analyses of gene silencing and overexpression experiments as well as relevant transgenic mouse models. Panels of repressors (VDR; GATA5; SFTPC; HIF1a) and activators (HMGA2; INSIG1; RUNX1; HNF4a; JNK1/c-FOS) were then employed to identify existing drugs manifesting in their effects on gene expression signatures of potential coronavirus infection mitigation agents. Using this strategy, vitamin D and quercetin have been identified as putative 2019 coronavirus disease (COVID-19) mitigation agents. Quercetin has been identified as one of top-scoring candidate therapeutics in the supercomputer SUMMIT drug-docking screen and Gene Set Enrichment Analyses (GSEA) of expression profiling experiments (EPEs), indicating that highly structurally similar quercetin, luteolin, and eriodictyol could serve as scaffolds for the development of efficient inhibitors of SARS-CoV-2 infection. In agreement with this notion, quercetin alters the expression of 98 of 332 (30%) of human genes encoding protein targets of SARS-CoV-2, thus potentially interfering with functions of 23 of 27 (85%) of the SARS-CoV-2 viral proteins in human cells. Similarly, Vitamin D may interfere with functions of 19 of 27 (70%) of the SARS-CoV-2 proteins by altering expression of 84 of 332 (25%) of human genes encoding protein targets of SARS-CoV-2. Considering the potential effects of both quercetin and vitamin D, the inference could be made that functions of 25 of 27 (93%) of SARS-CoV-2 proteins in human cells may be altered. GSEA and EPEs identify multiple drugs, smoking, and many disease conditions that appear to act as putative coronavirus infection-promoting agents. Discordant patterns of testosterone versus estradiol impacts on SARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during the coronavirus pandemic. Estradiol, in contrast with testosterone, affects the expression of the majority of human genes (203 of 332; 61%) encoding SARS-CoV-2 targets, thus potentially interfering with functions of 26 of 27 SARS-CoV-2 viral proteins. A hypothetical tripartite combination consisting of quercetin/vitamin D/estradiol may affect expression of 244 of 332 (73%) human genes encoding SARS-CoV-2 targets. Of major concern is the ACE2 and FURIN expression in many human cells and tissues, including immune cells, suggesting that SARS-CoV-2 may infect a broad range of cellular targets in the human body. Infection of immune cells may cause immunosuppression, long-term persistence of the virus, and spread of the virus to secondary targets. Present analyses and numerous observational studies indicate that age-associated vitamin D deficiency may contribute to the high mortality of older adults and the elderly. Immediate availability for targeted experimental and clinical interrogations of potential COVID-19 pandemic mitigation agents, Biomedicines 2020, 8, 129; doi:10.3390/biomedicines8050129 www.mdpi.com/journal/biomedicines Biomedicines 2020, 8, 129 2 of 26 namely vitamin D and quercetin, as well as of the highly selective (Ki, 600 pm) intrinsically specific FURIN inhibitor (a1-antitrypsin Portland (a1-PDX), is considered an encouraging factor. Observations reported in this contribution are intended to facilitate follow-up targeted experimental studies and, if warranted, randomized clinical trials to identify and validate therapeutically viable interventions to combat the COVID-19 pandemic. Specifically, gene expression profiles of vitamin D and quercetin activities and their established safety records as over-the-counter medicinal substances strongly argue that they may represent viable candidates for further considerations of their potential utility as COVID-19 pandemic mitigation agents. In line with the results of present analyses, a randomized interventional clinical trial evaluating effects of estradiol on severity of the coronavirus infection in COVID19+ and presumptive COVID19+ patients and two interventional randomized clinical trials evaluating effects of vitamin D on prevention and treatment of COVID-19 were listed on the ClinicalTrials.gov website
Overexposure to ultraviolet radiation can cause skin damage. This can be immediate and long-term, with effects ranging from sunburn and premature wrinkling to carcinogenesis.
Sunscreens have been used for many years on exposed areas to protect the skin from the damaging effects of ultraviolet light. Although sunscreens are essential, some have adverse effects such as estrogenic activity
full text: http://medpublics.com/docs/choquenet2008.pdf
Myocardial ischemia (MI) remains one of the leading causes of death worldwide. Angiogenic therapy with the vascular endothelial growth factor (VEGF) is a promising strategy to overcome hypoxia and its consequences. However, from the clinical data it is clear that fulfillment of the potential of VEGF warrants a better delivery strategy. On the other hand, the compelling evidences of the role of oxidative stress in diseases like MI encourage the use of antioxidant agents. Coenzyme Q10 (CoQ10) due to its role in the electron transport chain in the mitochondria seems to be a good candidate to manage MI but is associated with poor biopharmaceutical properties seeking better delivery approaches. The female Sprague Dawley rats were induced MI and were followed up with VEGF microparticles intramyocardially and CoQ10 nanoparticles orally or their combination with appropriate controls. Cardiac function was assessed by measuring ejection fraction before and after three months of therapy. Results demonstrate significant improvement in the ejection fraction after three months with both treatment forms individually; however the combination therapy failed to offer any synergism. In conclusion, VEGF microparticles and CoQ10 nanoparticles can be considered as promising strategies for managing MI.
Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg(-1) day(-1)), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.