Sirtuin 1 (SIRT1) is a NAD-dependent deacetylase that is critically involved in diverse cellular processes including metabolic disease, cancer, and possibly aging. Despite extensive studies on SIRT1 function, how SIRT1 levels are regulated remains relatively unknown. Here, we report that the nuclear bile acid receptor farnesoid X receptor (FXR) inhibits microRNA-34a (miR34a) in the liver, which results in a positive regulation of SIRT1 levels. Activation of FXR by the synthetic agonist GW4064 decreases hepatic miR-34a levels in normal mice, and consistently, hepatic miR-34a levels are elevated in FXR-null mice. FXR induces expression of small heterodimer partner (SHP), an orphan nuclear receptor and transcriptional corepressor, which in turn results in repression of p53, a key activator of the miR34a gene, by inhibiting p53 occupancy at the promoter. MiR-34a decreased SIRT1 levels by binding to the 3-untranslated region of SIRT1 mRNA, and adenovirus-mediated overexpression of miR-34a substantially decreased SIRT1 protein levels in mouse liver. Remarkably, miR-34a levels were elevated, and SIRT1 protein levels were reduced in diet-induced obese mice, and FXR activation in these mice reversed the miR-34a and SIRT1 levels, indicating an intriguing link among FXR activation, decreased miR-34a, and subsequently, increased SIRT1 levels. Our study demonstrates an unexpected role of the FXR/SHP pathway in controlling SIRT1 levels via miR-34a inhibition and that elevated miR-34a levels in obese mice contribute to decreased SIRT1 levels. Manipulation of this regulatory network may be useful for treating diseases of aging, such as metabolic disease and cancer.The NAD ϩ -dependent Sirtuin 1 (SIRT1) 3 deacetylase plays a critical role in cellular metabolism, the stress response, and possibly aging, by modulating the activity of its target proteins via protein deacetylation (1-4). Recent studies demonstrate that SIRT1 plays an important role in maintaining metabolic homeostasis in response to hormonal and nutritional fluctuations by modulating the activity of PGC-1␣, a master metabolic regulator (5, 6). During nutritional deprivation, SIRT1 promotes fat mobilization and suppresses adipogenesis and regulates hepatic glucose and lipid metabolism by activating key metabolic regulators, including PGC-1␣ (5, 6). Activation of SIRT1 by natural or synthetic SIRT1 activators reduced acetylation levels of PGC-1␣ and protected against diet-induced obesity and insulin resistance by promoting mitochondrial function (7-9). SIRT1 levels are dynamically regulated in response to fasting and feeding under physiological conditions but markedly reduced in diet-induced obese mice (10). However, the molecular basis by which SIRT1 levels are regulated under normal conditions and why they are substantially reduced in metabolic disease states remains largely unknown.The nuclear receptor, farnesoid X receptor (FXR), is the primary biosensor for endogenous bile acids and regulates expression of numerous genes involved in lipid and glucose metabolism (...

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Since commencement of COVID-19 pandemic, several SARS-CoV-2 variants have emerged amid containment efforts via vaccination. The Delta variant (B.1.617.2), discovered in October 2020, was designated as a VOC by the WHO on May 11, 2021. The enhanced transmissibility of Delta variant has been associated with critical mutations such as D614G, L452R, P681R, and T478K in the S-protein. The increased affinity of the S-protein and ACE2 has been postulated as a key reason for decreased vaccine efficacy. As per evidence, the Delta variant possesses increased transmissibility and decreased vaccine efficacy compared to other VOCs like Alpha and Beta. This has led to concerns regarding the acquisition of novel mutations in the Delta variant and outbreaks in vulnerable communities, including vaccinated people. In this mini-review of Delta variant, we have explained its evolution and characteristics, the impact of spike mutations on infectivity and immune evasion, and measures to combat future outbreaks.

The recently emerged COVID-19 has been declared a pandemic by the World Health Organization as to date; no therapeutic drug/vaccine is available for the treatment. Due to the lack of time and the urgency to contain the pandemic, computational screening appears to be the best tool to find a therapeutic solution. Accumulated evidence suggests that many phyto-compounds possess anti-viral activity. Therefore, we identified possible phyto-compounds that could be developed and used for COVID-19 treatment. In particular, molecular docking was used to prioritize the possible active phytocompounds against two key targets namely RNA dependent RNA polymerase (RdRp) and main protease (M pro) of SARS-CoV-2. In this study, an antiviral drug-Remdesivir (RdRp inhibitor) and Darunavir (M pro inhibitor) are used as reference drugs. This study revealed that phyto-molecules-Mulberroside-A/C/E/F, Emblicanin A, Nimbolide, and Punigluconin showed high binding affinity against RdRp while Andrographolides, Mulberrosides, Anolignans, Chebulic acid, Mimusopic acid, and Punigluconin showed better binding affinity against M pro as compared with the reference drug. Furthermore, ADME profiles validated the drug-likeness properties of prioritized phyto-compounds. Besides, to assess the stability, MD simulations studies were performed along with reference inhibitors for M pro (Darunavir) and RdRp (Remdesivir). Binding free energy calculations (MM-PBSA) revealed the estimated value (DG) of M pro _Darunavir; M pro _Mulberroside E; RdRp_Remdesivir and RdRp_Emblicanin A were À111.62 ± 6.788, À141.443 ± 9.313, 30.782 ± 5.85 and À89.424 ± 3.130 kJmol À1 , respectively. Taken together, the study revealed the potential of these phyto-compounds as inhibitors of RdRp and M pro inhibitor that could be further validated against SARS-CoV-2 for clinical benefits.