Withania somnifera commonly known as Ashwagandha in India is used in many herbal formulations to treat various cardiovascular diseases. The key metabolite of this plant, Withaferin A was analyzed for its molecular mechanism through docking studies on different targets of cardiovascular disease. Six receptor proteins associated with cardiovascular disease were selected and interaction studies were performed with Withaferin A using AutoDock Vina. CORINA was used to model the small molecules and HBAT to compute the hydrogen bonding. Among the six targets, β1- adrenergic receptors, HMG-CoA and Angiotensinogen-converting enzyme showed significant interaction with Withaferin A. Pharmacophore modeling was done using PharmaGist to understand the pharmacophoric potential of Withaferin A. Clustering of Withaferin A with different existing drug molecules for cardiovascular disease was performed with ChemMine based on structural similarity and physicochemical properties. The ability of natural active component, Withaferin A to interact with different receptors associated with cardiovascular disease was elucidated with various modeling techniques. These studies conclusively revealed Withaferin A as a potent lead compound against multiple targets associated with cardiovascular disease.
Background:Ambrex is a polyherbal formulation which consists of Withania somnifera, Orchis mascula, Cycas circirnalis, Shorea robusta with amber.Objective:The present study was designed to explore the potential effects of ambrex on the antioxidant status in high fat diet fed rats and to investigate the possible mechanisms focusing on the gene expression involved in adipogenesis and inflammation in 3T3-L1 cell line.Materials and Methods:Male Wistar rats were divided into four groups (n = 6); Group A received normal diet, Group B received high fat diet for 30 days, Group C and D received high fat diet for 30 days and treated with ambrex (40 mg/kg b.w) and atorvastatin (10 mg/kg b.w) for successive 15 days respectively. This study also assesses the effect of ambrex on adipogenesis in 3T3-L1 adipocytes.Results:The serum total cholesterol and triglycerides were significantly decreased in ambrex treated hyperlipidemic animals when compared to untreated animals. The activities of catalase, superoxide dismutase and reduced glutathione were significantly augmented in the serum, liver, and heart of hyperlipidemic rats treated with ambrex when compared to control. Ambrex treated rats had significant reductions in malondiadehyde levels in the serum, liver and heart compared to untreated rats. In addition, we observed that treatment with ambrex resulted in a major inhibition of pre-adipocyte differentiation of 3T3-L1 cells in vitro by suppression of peroxisome proliferator activated receptor gamma, sterol regulatory binding proteins, tumor necrosis factor-α, inducible nitricoxide synthase, leptin, and upregulation of thioredoxin 1 (TRX1) and TRX2 mRNA expression.Conclusion:Therefore, ambrex may be a potential drug for treatment of hyperlipidemia and related disorders.
Aims and objectives:The current study characterized the morphology of Ambrex formulation by Scanning Electron Microscopy and assessed its cardioprotective activity against Isoproterenol (ISPH)-induced myocardial necrosis in rats by biochemical and histopathological evaluations, and also attempted to predict the prospective protein-targets of Ambrex and the signaling pathway that mediates this activity through molecular docking approach.Materials and methods: Sprague-Dawley male rats (4 groups, 6 rats per group) chosen for the current study were acclimatized to the laboratory conditions for 7 days prior to actual treatment; they were pretreated with Ambrex (40 mg/kg b.wt/day, p.o) everday for 21 days and then intoxicated with ISPH (85 mg/kg b.wt, s.c) on day-20 and 21 to experimentally induce myocardial necrosis. The extent of ISPH-induced myocardial necrosis was quantified in terms of the serum levels of two cardiac biomarkers: creatine kinase-MB and lactate dehydrogenase. The extent of ISPH-induced oxidative stress was quantified in terms of the tissue levels of five oxidative stress biomarkers: superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase and lipid peroxidation. Results and discussion:The Scanning Electron Microscopy image of Ambrex formulation showed the formation of nanoparticles with thickness of 65 nm, making Ambrex a unique metal-deficient Siddha-medicine based polyherbal nano-formulation characterized and evaluated in India. Pretreatment with Ambrex attenuated the extent of ISPH-induced oxidative stress, lipid peroxidation and generation of reactive oxygen species as reflected by biochemical evaluations, and also ameliorated the degree of ISPH-induced myocardial necrosis and membrane damage as reflected by histopathological evaluations. The results of molecular docking revealed that Withaferin-A and Methyl Commate-A (the key metabolites of Withania somnifera and Ambrex respectively) inhibit Protein Kinase-C Beta, and renders Ambrex its cardioprotective activity by maintaining the intracellular antioxidant homeostasis and myocardial membrane architecture.
Background: Cardiovascular Diseases (CVDs) remain the leading cause of death worldwide, which urges for effective strategies of prevention and treatment. Withaferin-A (WFA), the key metabolite identified in Withania somnifera, has been known for its cardioprotective properties. Although it has been traditionally employed to treat cardiovascular ailments for several decades, its exact mechanism of action still remains unexplained Objective: The current study modelled and scored the interactions of WFA with nine prospective protein-targets associated with cardiovascular diseases through molecular docking and DSX-scoring. Methods: Molecular docking was carried out using Autodock and DSX-scoring was carried out using DSX standalone software. WFA was observed to favorably interact with six targets before DSX-based rescoring, but only with Poly (ADP-Ribose) Polymerase-1 and P2Y Purinoceptor-1 after DSX-based rescoring. The spatial orientation, physicochemical properties and structural features of Withaferin-A were compared with that of these approved drugs by pharmacophore modeling and hierarchical clustering Results: The results of molecular docking, DSX-based rescoring and complete pharmacophore modeling together revealed that PARP1 and P2Y1 receptor could be prospective targets of WFA for the treatment of CVD. Conclusion: Simulation using GROMACS has revealed that WFA forms a more stable complex with PARP1 and will be useful in developing the broad-spectrum drugs against cardiovascular diseases. Further computational studies through machine learning and network pharmacology methods can be carried out to improve Withaferin-A compound features by incorporating additional functional groups necessary for molecular recognition of the target genes in network responsible for cardiovascular diseases.
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