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Withanolides against TLR4-Activated Innate Inflammatory Signalling Pathways: A Comparative Computational and

Preethi M Purushotham1, Jin-Man Kim2, Eun-Kyeong Jo3

  • 1Department of Biochemistry, Biotechnology and Bioinformatics, Avinashilingam Institute for Home Science and Higher Education for Women University, Coimbatore, 641043, Tamil Nadu, India.

Phytotherapy Research : PTR
|November 19, 2016
PubMed

Insights

Withaferin A from Withania somnifera effectively suppresses innate inflammation by inhibiting key pathways like MAPKs and NF-κB. This natural compound and its extracts show promise as anti-inflammatory drug candidates.

Area of Science:

  • Immunology
  • Pharmacology
  • Phytochemistry

Background:

  • Innate inflammation, driven by pathogen-associated molecular patterns and lipopolysaccharide (LPS), significantly contributes to disease and mortality.
  • Toll-like receptor 4 (TLR4) activation by LPS triggers mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathways, crucial in inflammatory responses.
  • Withania somnifera, a medicinal herb, possesses known anti-inflammatory properties, making its active compounds potential therapeutic agents.

Purpose of the Study:

  • To evaluate the anti-inflammatory potential of Withania somnifera extracts and isolated withanolides against LPS-induced inflammation in macrophages.
  • To identify specific withanolides and extracts that effectively modulate key inflammatory signaling pathways.

Main Methods:

  • In silico molecular docking analysis to predict the binding efficacy of withanolides against inflammatory targets.
  • In vitro experiments using LPS-induced bone marrow-derived macrophages to assess the effects of withanolides and extracts on inflammatory markers.
  • Analysis of signaling pathways, including MAPKs and NF-κB, affected by the treatments.

Main Results:

  • Molecular docking identified withaferin A, withanone, and withanolide A as potent inhibitors of inflammatory targets.
  • Withaferin A and withanone significantly suppressed the expression of pro-inflammatory cytokines in LPS-stimulated macrophages.
  • Withaferin A demonstrated comprehensive regulation of both MAPK and NF-κB pathways, while Withania extracts rich in withaferin A also exhibited significant anti-inflammatory effects.

Conclusions:

  • Withaferin A is the most effective withanolide in suppressing activated inflammatory pathways.
  • Withania somnifera extracts with high withaferin A content, particularly from in vitro propagated leaves and field-grown roots, are promising candidates for treating innate inflammation.
  • Withaferin A and these specific extracts represent potential therapeutic agents for managing inflammatory conditions.
Keywords:
MAPKNF-κBWithania somniferaWithanolidescytokinesdocking

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