Showing papers on "Withania somnifera published in 2021"

Identification of bioactive molecule from Withania somnifera (Ashwagandha) as SARS-CoV-2 main protease inhibitor.

Abstract: SARS-CoV-2 is the causative agent of COVID-19 and has been declared as pandemic disease by World Health Organization. Lack of targeted therapeutics and vaccines for COVID-2019 have triggered the sc...

Withanone from Withania somnifera Attenuates SARS-CoV-2 RBD and Host ACE2 Interactions to Rescue Spike Protein Induced Pathologies in Humanized Zebrafish Model.

Abstract: Purpose: SARS-CoV-2 engages human ACE2 through its spike (S) protein receptor binding domain (RBD) to enter the host cell. Recent computational studies have reported that withanone and withaferin A, phytochemicals found in Withania somnifera, target viral main protease (MPro) and host transmembrane TMPRSS2, and glucose related protein 78 (GRP78), respectively, implicating their potential as viral entry inhibitors. Absence of specific treatment against SARS-CoV-2 infection has encouraged exploration of phytochemicals as potential antivirals. Aim: This study aimed at in silico exploration, along with in vitro and in vivo validation of antiviral efficacy of the phytochemical withanone. Methods: Through molecular docking, molecular dynamic (MD) simulation and electrostatic energy calculation the plausible biochemical interactions between withanone and the ACE2-RBD complex were investigated. These in silico observations were biochemically validated by ELISA-based assays. Withanone-enriched extract from W. somnifera was tested for its ability to ameliorate clinically relevant pathological features, modelled in humanized zebrafish through SARS-CoV-2 recombinant spike (S) protein induction. Results: Withanone bound efficiently at the interacting interface of the ACE2-RBD complex and destabilized it energetically. The electrostatic component of binding free energies of the complex was significantly decreased. The two intrachain salt bridge interactions (K31-E35) and the interchain long-range ion-pair (K31-E484), at the ACE2-RBD interface were completely abolished by withanone, in the 50 ns simulation. In vitro binding assay experimentally validated that withanone efficiently inhibited (IC50=0.33 ng/mL) the interaction between ACE2 and RBD, in a dose-dependent manner. A withanone-enriched extract, without any co-extracted withaferin A, was prepared from W. somnifera leaves. This enriched extract was found to be efficient in ameliorating human-like pathological responses induced in humanized zebrafish by SARS-CoV-2 recombinant spike (S) protein. Conclusion: In conclusion, this study provided experimental validation for computational insight into the potential of withanone as a potent inhibitor of SARS-CoV-2 coronavirus entry into the host cells.

Withanolides from Withania somnifera as an immunity booster and their therapeutic options against COVID-19.

Abstract: Traditionally, Withania somnifera is widely used as an immune booster, anti-viral, and for multiple medicinal purposes. The present study investigated the withanolides as an immune booster and anti...

Withania somnifera (L.) Dunal: Opportunity for Clinical Repurposing in COVID-19 Management

Abstract: As the COVID-19 pandemic is progressing, the therapeutic gaps in conventional management have highlighted the need for the integration of traditional knowledge systems with modern medicine. Ayurvedic medicines, especially Ashwagandha (Withania somnifera (L.) Dunal, WS), may be beneficial in the management of COVID-19. WS is a widely prescribed Ayurvedic botanical known as an immunomodulatory, antiviral, anti-inflammatory, and adaptogenic agent. The chemical profile and pharmacological activities of WS have been extensively reported. Several clinical studies have reported its safety for use in humans. This review presents a research synthesis of in silico, in vitro, in vivo, and clinical studies on Withania somnifera (L.) Dunal (WS) and discusses its potential for prophylaxis and management of COVID-19. We have collated the data from studies on WS that focused on viral infections (HIV, HSV, H1N1 influenza, etc.) and noncommunicable diseases (hypertension, diabetes, cancer, etc.). The experimental literature indicates that WS has the potential for 1) maintaining immune homeostasis, 2) regulating inflammation, 3) suppressing pro-inflammatory cytokines, 4) organ protection (nervous system, heart, lung, liver, and kidney), and 5) anti-stress, antihypertensive, and antidiabetic activities. Using these trends, the review presents a triangulation of Ayurveda wisdom, pharmacological properties, and COVID-19 pathophysiology ranging from viral entry to end-stage acute respiratory distress syndrome (ARDS). The review proposes WS as a potential therapeutic adjuvant for various stages of COVID-19 management. WS may also have beneficial effects on comorbidities associated with the COVID-19. However, systematic studies are needed to realize the potential of WS for improving clinical outcome of patients with COVID-19.

Pharmacological evaluation of Ashwagandha highlighting its healthcare claims, safety, and toxicity aspects.

Abstract: Withania somnifera, commonly known as “Ashwagandha” or “Indian ginseng” is an essential therapeutic plant of Indian subcontinent regions. It is regularly used, alone or in combination with other pl...

Computational investigation of phytochemicals from Withania somnifera (Indian ginseng/ashwagandha) as plausible inhibitors of GluN2B-containing NMDA receptors.

Abstract: N-Methyl-d-aspartate receptor (NMDAR)-mediated excitotoxicity has been implicated in multi-neurodegenerative diseases. Owing to dearth of efficacy and adverse effects of NMDA receptor antagonists, ...

Medicinal and therapeutic potential of withanolides from Withania somnifera against COVID-19

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the potentially fatal coronavirus disease 2019 (COVID-19), has currently affected over 87 million people with worldwide deaths nearing 1 9 million Amidst the developing vaccines and effective therapies, there is a need to develop alternative and supportive strategies for ameliorating the effects of SARS-CoV-2 infections in humans and treat COVID-19 patients Several medicinal plants and herbs contain useful phytochemicals, which are being explored to develop medicines and drugs to counter the COVID-19 pandemic Withania somnifera is a medicinal herb of growing importance that is extensively utilized in Ayurveda The medicinal attributes of W somnifera are owing to a broad range of bioactive secondary metabolites including steroidal lactones [withanone, withanolide D, withanolide A, and withaferin A (WFA)] Among these, WFA is one of the most interesting naturally occurring bioactive compounds that possess potent anti-tumorigenic, antiinflammatory, pro-apoptotic, anti-angiogenic, and anti-invasive activities It might bind to SARS-CoV-2 S protein and alter the S protein, thereby hindering its access into the host cells Withanone and Withanoside V can impede the functional activities of SARS-CoV-2 main protease (Mpro) Withanolides have been found to control cytokine secretions during infection and could alleviate the cytokine storm in the lungs The combined use of withanolides are several other drugs or therapeutic modalities, such as hydroxychloroquine and dexamethasone, has been demonstrated as an efficient strategy to improve the effectiveness of standard chemotherapy or design a robust therapeutic regime for COVID-19 treatment Nevertheless, exhaustive research efforts are required to explore the anti-inflammatory and immunomodulatory potentialities of withanolides for alleviating the severity of the disease during SARS-CoV-2 infections This review highlights the medicinal and therapeutic potential of withanolides against COVID-19 © 2021 Manish Dhawan et al This is an open access article distributed under the terms of the Creative Commons Attribution 4 0 International License (https://creativecommons org/licenses/by/4 0/)

Critical review of the Withania somnifera (L.) Dunal: ethnobotany, pharmacological efficacy, and commercialization significance in Africa.

Abstract: Background Withania somnifera (L.) Dunal (W. somnifera) is a herb commonly known by its English name as Winter Cherry. Africa is indigenous to many medicinal plants and natural products. However, there is inadequate documentation of medicinal plants, including W. somnifera, in Africa. There is, therefore, a need for a comprehensive compilation of research outcomes of this reviewed plant as used in traditional medicine in different regions of Africa. Methodology Scientific articles and publications were scooped and sourced from high-impact factor journals and filtered with relevant keywords on W. somnifera. Scientific databases, including GBIF, PubMed, NCBI, Google Scholar, Research Gate, Science Direct, SciFinder, and Web of Science, were accessed to identify the most influential articles and recent breakthroughs published on the contexts of ethnography, ethnomedicinal uses, phytochemistry, pharmacology, and commercialization of W. somnifera. Results This critical review covers the W. somnifera ethnography, phytochemistry, and ethnomedicinal usage to demonstrate the use of the plant in Africa and elsewhere to prevent or alleviate several pathophysiological conditions, including cardiovascular, neurodegenerative, reproductive impotence, as well as other chronic diseases. Conclusion W. somnifera is reportedly safe for administration in ethnomedicine as several research outcomes confirmed its safety status. The significance of commercializing this plant in Africa for drug development is herein thoroughly covered to provide the much-needed highlights towards its cultivations economic benefit to Africa.

Structure-activity relationship (SAR) and molecular dynamics study of withaferin-A fragment derivatives as potential therapeutic lead against main protease (M pro ) of SARS-CoV-2.

Abstract: The spread of novel coronavirus SARS-CoV-2 has directed to a state of an unprecedented global pandemic. Many synthetic compounds and FDA-approved drugs have been significantly inhibitory against the virus, but no SARS-CoV-2 solution has been identified. However, small molecule fragment–based derivatives of potent phytocompounds may serve as promising inhibitors against SARS-CoV-2. In the pursuit of exploring novel SARS-CoV-2 inhibitors, we generated small molecule fragment derivatives from potent phytocompounds using neural networking and machine learning–based tools, which can cover unexplored regions of the chemical space that still retain lead-like properties. Out of 300 derivative molecules from withaferin-A, hesperidin, and baicalin, 30 were screened out with synthetic accessibility scores > 4 having the best ADME properties. The withaferin-A derivative molecules 61 and 64 exhibited a significant binding affinity of − 7.84 kcal/mol and − 7.94 kcal/mol. The docking study reveals that withaferin-A mol 61 forms 5 polar H-bonds with the Mpro where amino acids involved are GLU166, THR190, CYS145, MET165, and GLN152 and upon QSAR analysis showed a minimal predicted IC50 value of 7762.47 nM. Furthermore, the in silico cytotoxicity predictions, pharmacophore modeling, and molecular dynamics simulation studies have resulted in predicting the highly potent small molecule derivative from withaferin-A (phytocompound from Withania somnifera) to be the potential inhibitor of SARS-CoV 2 protease (Mpro) and a promising future lead candidate against COVID-19. The rationale of choosing withaferin-A from Withania somnifera (Ashwagandha) was propelled by the innumerous applications of Ashwagandha for the treatment of various antiviral diseases, common cold, and fever since time immemorial.

DNA damage by Withanone as a potential cause of liver toxicity observed for herbal products of Withania somnifera (Ashwagandha).

Abstract: Withania somnifera, commonly known as Ashwagandha, is a medicinal plant used for thousands of years for various remedies. Extracts of Ashwagandha contain more than 200 metabolites, with withanone (win) being one of the major ones responsible for many of its medicinal properties. Recently, several cases of liver toxicity resulting from commercially available Ashwagandha products have been reported. The first report of Ashwagandha-related liver damage was from Japan, which was quickly resolved after drug-withdrawal. Later, similar cases of liver toxicity due to Ashwagandha consumption were reported from the USA and Iceland. Towards understanding the liver toxicity of Ashwagandha extracts, we studied win, a representative withanolide having toxicophores or structural alerts that are commonly associated with adverse drug reactions. We found that win can form non-labile adducts with the nucleosides dG, dA, and dC. Using various biochemical assays, we showed that win forms adducts in DNA and interfere with its biological property. Win also forms adducts with amines and this process is reversible. Based on the data presented here we concluded that win is detoxified by GSH but under limiting GSH levels it can cause DNA damage. The work presented here provides a potential mechanism for the reported Ashwagandha-mediated liver damage.

Immunomodulatory Effect of Withania somnifera (Ashwagandha) Extract—A Randomized, Double-Blind, Placebo Controlled Trial with an Open Label Extension on Healthy Participants

Abstract: The immunomodulatory effect of Withania somnifera (WS) extract was tested in healthy adults. In this randomized placebo-controlled double-blinded study, subjects were allocated either 60 mg WS extract or placebo. It consists of a blinded 30-day period and an open-label extension study of another 30 days with crossover of only placebo to test. After the 30-day blinded study period, the WS test group reported significant increase (p 0.05). In the extension period on day 60, the subjects on placebo who were crossed over to the WS test group showed significant increase (p < 0.05) in Ig's, cytokines and TBNK cells and the subjects who continued on the WS group showed a further significant improvement (p < 0.05) in Ig's, cytokines and TBNK cells. There were no adverse events reported in the study. WS extract significantly improved the immune profile of healthy subjects by modulating the innate and adaptive immune systems. Boosting the immune system of people at risk of infection and during widespread infections can be targeted with WS extract.

Mechanisms of Anti-Tumor Activity of Withania somnifera (Ashwagandha).

Abstract: Increasing herbal formulations have been used to treat several diseases including cancer W somnifera (Ashwagandha) is one such plant the extracts of which have been tested against a number of ailments including cancer, which remains as one of the most dreadful diseases on the globe The ever-increasing number of cancer related mortality demands the development of novel chemopreventive agents with minimum side effects Different compounds isolated from various parts of the plant like root, stem, and leaves have been reported to display significant anti-cancerous and immunomodulating properties and thus can be used alone or in combination with other chemotherapeutic drugs for cancer treatment Through this review, we highlight the importance of W somnifera in countering the potential oncogenic signaling mediators that are modulated by active constituents of W somnifera in a variety of cancer types Further, we hope that active constituents of W somnifera will be tested in clinical trials so that they can be used as an important adjuvant in the near future for the effective treatment of cancer

Overexpression of WssgtL3.1 gene from Withania somnifera confers salt stress tolerance in Arabidopsis

Abstract: Overexpression of Withania somnifera SGT gene (WssgtL3.1) in transgenic Arabidopsis improves various agronomic and physiological traits and alters conjugated sterol levels to mitigate the effect of salt stress. Sterols are essential constituents of cell membranes that are involved in several biological functions, including response to various biotic and abiotic stresses by altering membrane permeability and signaling pathways. Sterol glycosyltransferases (SGTs) are enzymes that are involved in sterol modification by converting sterols into sterol-conjugates to play essential roles in adaptive responses. However, their roles under abiotic stresses are lesser-known. Among abiotic stresses, salinity imposes serious threat to crop yield worldwide, hence the present study intends to investigate the role of WssgtL3.1-overexpressed Arabidopsis plants under salt stress indicating the crosstalk between SGT gene and salinity to develop improved crop varieties with better stress tolerance ability. The findings revealed that overexpression of WssgtL3.1 gene in A. thaliana improved the resistance against salt stress in the overexpressing lines. Transgenic lines showed significantly higher germination rate, increased plant growth with less chlorophyll damage compared to wild-type (WT) control plants. Moreover, better tolerance also correlated with enhanced osmolytes (proline and soluble sugar), better membrane integrity, decreased H2O2 production and lesser MDA accumulation and Na+/K+ ratio with more negative osmotic potential in overexpressed lines. Additionally, in sterol profiling, significant enhancement in stigmasterol was also observed in transgenic lines than WT plants. Furthermore, in expression profiling, salt responsive genes LEA 4–5, sucrose synthase, and transporter of monosaccharide (ERD) significantly upregulated in overexpressing lines as compared to WT. Thus our data strongly support the defensive role of Withania somnifera SGT gene (WssgtL3.1) against salt stress and contribute to improved salinity tolerance in plants through sterol modulation.

Biocontrol potential of Pseudomonas stutzeri endophyte from Withania somnifera (Ashwagandha) seed extract against pathogenic Fusarium oxysporum and Rhizoctonia solani

Abstract: Agricultural crops are susceptible to abiotic and biotic factors. Among biotic factors, plant pathogens attacks are prominent and significantly reduce the crop productivity and production. Long ter...

Defining the role of a caffeic acid 3-O-methyltransferase from Azadirachta indica fruits in the biosynthesis of ferulic acid through heterologous over-expression in Ocimum species and Withania somnifera.

Abstract: The recombinant caffeic acid 3-O-methyltransferase gene has been cloned and characterized from Neem. The gene is involved in ferulic acid biosynthesis, a key intermediate component of lignin biosynthesis. Azadirachta indica (Neem) is a highly reputed traditional medicinal plant and is phytochemically well-known for its limonoids. Besides limonoids, phenolics are also distinctively present, which add more medicinal attributes to Neem. Caffeic acid is one of such phenolic compound and it can be converted enzymatically into another bioactive phytomolecule, ferulic acid. This conversion requires transfer of a methyl group from a donor to caffeic acid under the catalytic action of an appropriate methyltransferase. In this study, caffeic acid 3-O-methyltransferase gene from Neem (NCOMT) fruits has been isolated and heterologously expressed in E. coli. The recombinant NCOMT enzyme was purified, which exhibited efficient catalytic conversion of caffeic acid into ferulic acid, a highly potential pharmaceutical compound. The purified recombinant enzyme was physico-kinetically characterized for its catalysis. The analysis of tissue-wide expression of NCOMT gene revealed interesting pattern of transcript abundance reflecting its role in the development of fruit tissues. Further, NCOMT was heterologously overexpressed in Withania somnifera and Ocimum species, to analyze its role in ferulic acid biosynthesis in planta. Thus, the study provides insight for the endogenous role of NCOMT in ferulic acid biosynthesis en route to lignin, an important structural component. To the best of our knowledge, NCOMT pertains to be the first enzyme of the secondary metabolism that has been purified and kinetically characterized from Neem. This study may also have important prospects of applications as the observation on heterologous expression of NCOMT showed its involvement in the maintenance of the in vivo pool of ferulic acid in the plants. Thus, the study involving NCOMT opens up new dimensions of metabolic engineering approaches for the biosynthesis of potential therapeutically important phytomolecules in heterologous systems.

Network pharmacological evaluation of Withania somnifera bioactive phytochemicals for identifying novel potential inhibitors against neurodegenerative disorder.

Abstract: Neurodegenerative disorders are illnesses that are responsible for neuronal cell death and resulting in lifelong cognitive problems. Due to their unclear mechanism, there are no effective drugs available for the treatment. For a long time, herbal drugs have been used as a role model in the field of the drug discovery process. Withania somnifera (Ashwagandha) in the Indian medicinal system (Ayurveda) is used for several neuronal disorders like insomnia and memory loss for decades. This study aims to identify active components of W. somnifera (WS) as potential inhibitors for the treatment of neurodegenerative diseases (ND). To fulfill this objective, Network pharmacology approach, gene ontology, pharmacokinetics analysis, molecular docking, and molecular dynamics simulation (MDS) studies were performed. A total of 77 active components in WS, 175 predicted neurodegenerative targets of WS, and 8085 ND-related targets were identified from different databases. The network analysis showed that the top ten targets APP, EGFR, MAPK1, ESR1, HSPA4, PRKCD, MAPK3, ABL1, JUN, and GSK3B were found as significant target related to ND. On the basis of gene ontology and topology analysis results, APP was found as a significant target related to Alzheimer's disease pathways. Molecular docking results found that Anahygrine, Cuscohygrine, Isopelletierine, and Nicotine showed the best binding affinities -5.55, -4.73, -4.04, and -4.11 Kcal/mol. Further, MDS results suggested that Isopelletierine and Nicotine could be used as potential inhibitors against APP protein and could be useful for the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.

Assessment of Chemopreventive Potential of the Plant Extracts against Liver Cancer Using HepG2 Cell Line.

Abstract: The edible parts of the plants Camellia sinensis, Vitis vinifera and Withania somnifera were extensively used in ancient practices such as Ayurveda, owing to their potent biomedical significance. They are very rich in secondary metabolites such as polyphenols, which are very good antioxidants and exhibit anti-carcinogenic properties. This study aims to evaluate the anti-cancerous properties of these plant crude extracts on human liver cancer HepG2 cells. The leaves of Camellia sinensis, Withania somnifera and the seeds of Vitis vinifera were collected and methanolic extracts were prepared. Then, these extracts were subjected to DPPH, α- amylase assays to determine the antioxidant properties. A MTT assay was performed to investigate the viability of the extracts of HepG2 cells, and the mode of cell death was detected by Ao/EtBr staining and flow cytometry with PI Annexin- V FITC dual staining. Then, the protein expression of BAX and BCl2 was studied using fluorescent dye to determine the regulation of the BAX and BCl2 genes. We observed that all the three extracts showed the presence of bioactive compounds such as polyphenols or phytochemicals. The W. somnifera bioactive compounds were found to have the highest anti-proliferative activity on human liver cancer cells.

Cytological, genetical and phytochemically stable meta-Topolin (mT) - induced mass propagation of underutilized Physalis minima L. for production of withaferin A

Abstract: Physalis minima L. is commonly known as wild Gooseberry. Traditionally this plant has been used in different ethnopharmacological and modern medicinal practices. No systematic evaluation is done from an underutilized alternative resource of withaferin A content from P. minima. Withaferin A is a steroidal lactone withanolide mainly found in the plant Withania somnifera and other few members of family Solanaceae. The present investigation evaluated withaferin A content from 30 chemotypes collected from different geographical regions in India. Among 30 different chemotypes, an elite clone (17.13 ± 0.31 mg/g dry weight (DW) withaferin A) was selected for in vitro shoot multiplication. Well-organized micropropagation has been studied using five different cytokinins in Murashige and Skoog (MS) medium. Among them, aromatic cytokinin “meta-Topolin” (mT) at 1.0 mg/l triggered the highest number (83.26 ± 1.02) of multiple shoots and shoot length (4.87 ± 0.69) after 28 days of explant implantation. Maximum root induction was showed in ½ MS medium with 0.5 mg/l indole-3-butyric acid (IBA) to trigger 75.65 ± 1.03 roots and root length 4.56 ± 0.25 cm after 14 days of culture. In vitro well-rooted plantlets were excised for hardening and show; 99.02% survival rate. Genetic stability of micropropagated plants were performed with cytological and molecular marker-based selection. Simultaneously, phytochemical stability was performed with HPLC (High performance liquid chromatography) analysis. In our experiment no significant difference showed between the mother plant and micropropagated plants. Thus, our protocol can be used for large-scale commercial cultivation of elite chemotype of this medicinal plant.

Antifungal Activity of Isolated Compounds from the Leaves of Combretum erythrophyllum (Burch.) Sond. and Withania somnifera (L.) Dunal against Fusarium Pathogens.

Abstract: Crop diseases caused by Fusarium pathogens, among other microorganisms, threaten crop production in both commercial and smallholder farming. There are increasing concerns about the use of conventional synthetic fungicides due to fungal resistance and the associated negative effects of these chemicals on human health, livestock and the environment. This leads to the search for alternative fungicides from nature, especially from plants. The objectives of this study were to characterize isolated compounds from Combretum erythrophyllum (Burch.) Sond. and Withania somnifera (L.) Dunal leaf extracts, evaluate their antifungal activity against Fusarium pathogens, their phytotoxicity on maize seed germination and their cytotoxicity effect on Raw 264.7 macrophage cells. The investigation led to the isolation of antifungal compounds characterized as 5-hydroxy-7,4′-dimethoxyflavone, maslinic acid (21-hydroxy-3-oxo-olean-12-en-28-oic acid) and withaferin A (4β,27-dihydroxy-1-oxo-5β,6β-epoxywitha-2-24-dienolide). The structural elucidation of the isolated compounds was established using nuclear magnetic resonance (NMR) spectroscopy, mass spectroscopy (MS) and, in comparison, with the available published data. These compounds showed good antifungal activity with minimum inhibitory concentrations (MIC) less than 1.0 mg/mL against one or more of the tested Fusarium pathogens (F. oxysporum, F. verticilloides, F. subglutinans, F. proliferatum, F. solani, F. graminearum, F. chlamydosporum and F. semitectum). The findings from this study indicate that medicinal plants are a good source of natural antifungals. Furthermore, the isolated antifungal compounds did not show any phytotoxic effects on maize seed germination. The toxicity of the compounds A (5-hydroxy-7,4′-dimethoxyflavone) and AI (4β,27-dihydroxy-1-oxo-5β,6β-epoxywitha-2-24-dienolide) was dose-dependent, while compound B (21-hydroxy-3-oxo-olean-12-en-28-oic acid) showed no toxicity effect against Raw 264.7 macrophage cells.