Safety, toxicity and pharmacokinetic assessment of oral Withaferin-A in mice

Gupta, Saurabh Kumar; Jadhav, Shraddha; Gohil, Dievya; Panigrahi, Girish Ch.; Kaushal, Rajiv Kumar; Gandhi, Khushboo; Patil, Anand; Chavan, Preeti; Gota, Vikram

doi:10.1016/j.toxrep.2022.05.012

Cited by 15 publications

(10 citation statements)

References 33 publications

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“…With a few exceptions, bioavailability (0.55) complied with drug-likeness requirements and fell within medium range (T½ ≤ 3). Overall drug-likeness properties adhered to established rules, except for certain deviations [ 51 , 55 , 56 ] enumerated in Supplementary Table S6 .…”

Section: Resultsmentioning

confidence: 64%

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Integrating network pharmacology and in silico analysis deciphers Withaferin-A’s anti-breast cancer potential via hedgehog pathway and target network interplay

Srinivasan,

Gangurde,

Chandane

et al. 2024

Briefings in Bioinformatics

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This study examines the remarkable effectiveness of Withaferin-A (WA), a withanolide obtained from Withania somnifera (Ashwagandha), in encountering the mortiferous breast malignancy, a global peril. The predominant objective is to investigate WA’s intrinsic target proteins and hedgehog (Hh) pathway proteins in breast cancer targeting through the application of in silico computational techniques and network pharmacology predictions. The databases and webtools like Swiss target prediction, GeneCards, DisGeNet and Online Mendelian Inheritance in Man were exploited to identify the common target proteins. The culmination of the WA network and protein–protein interaction network were devised using Stitch and String web tools, through which the drug–target network of 30 common proteins was constructed employing Cytoscape-version 3.9. Enrichment analysis was performed by incorporating Gprofiler, Metascape and Cytoscape plugins. David compounded the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, and enrichment was computed through bioinformatics tools. The 20 pivotal proteins were docked harnessing Glide, Schrodinger Suite 2023-2. The investigation was governed by docking scores and affinity. The shared target proteins underscored the precise Hh and WA network roles with the affirmation enrichment P-value of <0.025. The implications for hedgehog and cancer pathways were profound with enrichment (P < 0.01). Further, the ADMET and drug-likeness assessments assisted the claim. Robust interactions were noticed with docking studies, authenticated through molecular dynamics, molecular mechanics generalized born surface area scores and bonds. The computational investigation emphasized WA’s credible anti-breast activity, specifically with Hh proteins, implying stem-cell-level checkpoint restraints. Rigorous testament is imperative through in vitro and in vivo studies.

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Section: Resultsmentioning

confidence: 64%

“…Furthermore, toxicity studies were conducted on WA, which revealed a no observable effect level (NOEL) dose of 500 mg. Significantly, this compound exhibited safety even at doses exceeding 2000 mg [ 56 ]. The toxicity profile is categorized and listed in Supplementary Table S7 .…”

Section: Resultsmentioning

confidence: 99%

Integrating network pharmacology and in silico analysis deciphers Withaferin-A’s anti-breast cancer potential via hedgehog pathway and target network interplay

Srinivasan,

Gangurde,

Chandane

et al. 2024

Briefings in Bioinformatics

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“…Next, we established that ex vivo graft manipulation with WA could prevent aGvHD 23 . Furthermore, to bring WA one-step closure to clinic, we established safety, pharmacokinetics and anti-GvHD efficacy of oral WA 13 , 24 . Pharmacodynamically, WA was shown to regulate JAK/PI3K/NF-kB/Akt/mTOR signaling and exert potent immune-modulatory response 13 .…”

Section: Discussionmentioning

confidence: 99%

Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

Gupta,

Gohil,

Momin

et al. 2024

Cell Transplant

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Acute graft versus host disease (aGvHD) is the major contributor of nonrelapse mortality in alloHSCT. It is associated with an inflammatory immune response manifesting as cytokine storm with ensuing damage to target organs such as liver, gut, and skin. Prevention of aGvHD while retaining the beneficial graft versus leukemia (GvL) effect remains a major challenge. Withania somnifera extract (WSE) is known for its anti-inflammatory, immune-modulatory, and anticancer properties, which are appealing in the context of aGvHD. Herein, we demonstrated that prophylactic and therapeutic use of WSE in experimental model of alloHSCT mitigates aGvHD-associated morbidity and mortality. In the prophylaxis study, a dose of 75 mg/kg of WSE offered greatest protection against death due to aGvHD (hazard ratio [HR] = 0.15 [0.03-0.68], P ≤ .01), whereas 250 mg/kg was most effective for the treatment of aGvHD (HR = 0.16 [0.05-0.5], P ≤ .01). WSE treatment protected liver, gut, and skin from damage by inhibiting cytokine storm and lymphocytic infiltration to aGvHD target organs. In addition, WSE did not compromise the GvL effect, as alloHSCT with or without WSE did not allow the leukemic A20 cells to grow. In fact, WSE showed marginal antileukemic effect in vivo. WSE is currently under clinical investigation for the prevention and treatment of aGvHD.

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“…Singh et al [29] have reported the oral acute LD50 of Withania somnifera to be 1750 mg/kg body weight in albino mice. Sharada et al [30] of Withaferin A to be a minimum of 500 mg/kg body weight [31].…”

Section: Safety Of Withaferin a And W-ferinamax Ashwagandhamentioning

confidence: 99%

Chemical, microbial and safety profiling of a standardized Withania somnifera (Ashwagandha) extract and Withaferin A, a potent novel phytotherapeutic of the millennium

Kumar¹,

Banik²,

GOEL³

et al. 2023

FFHD

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Background:Withania somnifera (L.) Dunal, popularly known as Ashwagandha, is an ethnomedicinal plant with multiple pharmacotherapeutic applications. The diverse medicinal properties of the plant are largely due to the presence of withanolides, a group of C28 ergostane based steroidal lactones, with several sites of unsaturation and oxygenation. Withaferin A, a major with anolide present in Ashwagandha plant accounts for its emerging new roles to treat cancer, arthritis, inflammatory responses, immunomodulatory properties, and neuronal disorders. The root and leaf extracts are specifically important constituent materials for the development of phytotherapeutics, mostly intended for oral consumption. Several studies have been carried out to delineate the toxic manifestations of the extract for human consumption.Objective:Establish the broad-spectrum safety of W-ferinAmax ashwagandha (WFA).Study: This investigation demonstrated a novel, standardized W-ferinAmax ashwagandha (WFA) extraction technology from the whole herb of Withania sominfera, conducted HPLC analysis to identify the constituents, detected the heavy metals, microbiological contaminants, pesticides contaminants, and safety profile.Results:A novel extraction technology was employed to obtain WFA from the whole plant of Withania sominfera. HPLC analysis revealed that WFA contains a total of 15.4% Withanolides. In particular, Withaferin A, Withanoside IV, and Withanolide A contents were 6.469%, 1.022%, and 0.073%, respectively. The extract contained only 0.403 ppm of heavy metals out of which traces of arsenic, mercury and lead were detected, and cadmium was absent. USP recommended 80 residue basic pesticide screen indicated that the extraction was safe for human consumption. It was also found to be free from pathogenic microbes as assessed by the absence of E. coli and other coliforms, Salmonella and Staphylococcus species.Conclusion: The data generated cumulatively indicated that WFA is safe for further downstream processing to and for human consumption.Keywords: Ashwagandha, Withaferin A, phytotherapeutics, material safety; heavy metals; pesticides

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Safety, toxicity and pharmacokinetic assessment of oral Withaferin-A in mice

Cited by 15 publications

References 33 publications

Integrating network pharmacology and in silico analysis deciphers Withaferin-A’s anti-breast cancer potential via hedgehog pathway and target network interplay

Integrating network pharmacology and in silico analysis deciphers Withaferin-A’s anti-breast cancer potential via hedgehog pathway and target network interplay

Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

Chemical, microbial and safety profiling of a standardized Withania somnifera (Ashwagandha) extract and Withaferin A, a potent novel phytotherapeutic of the millennium

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