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Phytother Res. 2017 Jan;31(1):152-163. doi: 10.1002/ptr.5746. Epub 2016 Nov 17.

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

Author information

1
Department of Biochemistry, Biotechnology and Bioinformatics, Avinashilingam Institute for Home Science and Higher Education for Women University, Coimbatore, 641043, Tamil Nadu, India.
2
Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Korea.
3
Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, Korea.

Abstract

Innate inflammations are dominant causes of poor health and high mortality. The pathogen-associated molecular pattern and lipopolysaccharide (LPS) are sensed by immune cells through activation of toll-like receptor 4 leading to mitogen-activated protein kinases (MAPKs) and NF-κB activations. Controlled MAPK and Nf-κB inhibitors have been proposed as potential antiinflammatory drugs. Withania somnifera is an important medicinal herb with known antiinflammatory activity. In this study, the selected Withania somnifera extracts and withanolides were analysed on LPS-induced macrophages comparatively. Molecular docking analysis revealed withaferin A, withanone and withanolide A as effective withanolides against inflammatory target molecules. In experiments, withaferin A and withanone treatment had prominent suppressions on LPS-induced expression of pro-inflammatory cytokines in bone marrow-derived macrophages. Withaferin A regulated all the major four pathways (MAPKs and NF-κB) involved in innate inflammations. Similarly among the Withania extracts analysed, the in vitro propagated leaf and field grown root extracts containing high withaferin A content suppressed the inflammatory molecules through NF-κB and MAPK pathways. Withaferin A was found to be best in suppressing the activated inflammatory pathways among all the analysed withanolides. Therefore, withaferin A and extracts with high withaferin A content can be used as promising drug candidates against innate inflammations.

KEYWORDS:

MAPK; NF-κB; Withania somnifera; Withanolides; cytokines; docking

PMID:
27859734
DOI:
10.1002/ptr.5746
[Indexed for MEDLINE]

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