👤 Rashmi Priya

Alzheimer's disease (AD) is a neurodegenerative disease that leads to development of cognition and memory dysfunctions. Currently, there is no known cure for AD, although limited medications are approved for the management of disease condition. Various plant-based leads give new hope for considering phytoconstituents as anti-AD drugs. The Piper nigrum L. fruit extract was reported to have anti-Alzheimer's activity. It creates an interest in the finding of active moieties that may be accountable for anti-AD activity. Identification of multitarget directed ligands isolated from Piper nigrum fruits through AI based studies. The phytochemical analysis of alkaloid fraction was carried out by LCMS, followed by the evaluation of constituents through in silico studies. The fruits methanolic extract was prepared by cold maceration technique. The chemical profiling of the alkaloidal fraction was carried out using LCMS/MS analysis. The obtained compound's target hit genes were identified through network pharmacology studies using String, Metascape, and Cytoscape tools. Further, docking studies and MD simulations were carried out using AutoDock4 and Desmond-Maestro software. Then, electrochemical properties of hit compound P4 were determined using Gaussview6 software. From LCMS/MS analysis data, 29 compounds were considered based on compound intensity and accuracy (>95 %). Then, 41 common gene targets were identified from AD genes and compound-targeted genes. The 41 common genes in the PPI network suggested that AChE and BACE1 were the most abundant proteins. Further, docking studies revealed the hit compound P4 binding interaction and energies when compared to other 28 ligands. The molecular dynamics studies showed that P4-AChE and P4-BACE1 complexes were stable, and there were no RMSD and RMSF fluctuations were observed up to 100 ns. Further, PCA and MM-GBSA analysis data supported that complexes (P4-AChE and P4-BACE1) were stable. The DFT and surface properties indicated that compound P4 was ideal candidate for AD treatment and must be considered for further biological activity studies. The study identified compound P4 (dehydropipernonaline) from alkaloidal fraction of Piper nigrum fruits, suggesting it may be hit candidate for AD treatment. Show less

Despite the loss of melanocytes, individuals with vitiligo have a significantly lower risk of developing skin malignancies compared to ethnicity-matched controls. The study investigated the molecular mechanisms that protect skin cells (keratinocytes) from UV-B-induced DNA damage in individuals with vitiligo. The study found that upregulation of stem cell factor (SCF) signaling significantly reduced γ-H2AX positivity and cyclobutane pyrimidine dimer formation and improved mitochondrial health (elongated mitochondria, reduced reactive oxygen species [ROS] and lipid peroxidation) in keratinocytes upon UV-B exposure. Interestingly, SCF treatment also reduced lipid droplet accumulation and triacylglyceride levels by upregulating lipoprotein lipase (LPL). Further, siLPL increased DNA damage and lipid droplet (LD) accumulation, while NO-1886, an LPL agonist, reversed both, suggesting a direct link between lipid metabolism and DNA damage. Downregulation of NAD-dependent deacetylase sirtuin1 (SIRT1) with siRNA or with Ex-527, a pharmacological inhibitor of SIRT1, diminished the protective effects mediated by SCF and NO-1886, suggesting SIRT1 to be the final effector protein in the SCF-LPL-SIRT1 signaling axis. Analysis of clinical samples of vitiligo corroborated the upregulation of SCF and LPL in lesional epidermis. In conclusion, our study demonstrates a novel SCF-LPL-SIRT1 signaling axis that confers protection to vitiligo keratinocytes from the harmful effects of UV-B radiation. Show less

The transcription factor Snai1, a well-known regulator of epithelial-to-mesenchymal transition, has been implicated in early cardiac morphogenesis as well as in cardiac valve formation. However, a role for Snai1 in regulating other aspects of cardiac morphogenesis has not been reported. Using genetic, transcriptomic, and chimeric analyses in zebrafish, we find that Snai1b is required in cardiomyocytes for myocardial wall integrity. Loss of Show less