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

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. Copyright © 2016 John Wiley & Sons, Ltd.

Ajudecumin A fromAjuga ovalifoliavar.calanthaexhibits anti-inflammatory activity in lipopolysaccharide-activated RAW264.7 murine macrophages and animal models of acute inflammation

“…Additionally, the unstimulated macrophages generally display spear and smooth shaped forms. Upon exposing to various inflammatory stimuli, such as LPS, the macrophages display an activated phenotype, which mainly manifested as irregular and rough form with accelerated spreading and pseudopodia-like formations (Purushotham et al 2017). As expected, LPS caused irregular and rough form with accelerated spreading in RAW264.7 cells, which can be obviously improved by ajudecumin A treatment (Figure 1(C)).…”

Withaferin A inhibits lymphocyte proliferation, dendritic cell maturation in vitro and prolongs islet allograft survival

“…WA suppressed Helicobacter Pylori induced NFkB activation and downstream signaling pathways in bone marrow derived dendritic cells and macrophages 48 . WA inhibited NFkB nuclear translocation in LPS induced bone marrow-derived macrophages 49 . In T and B lymphocytes, WA inhibited NFkB nuclear translocation, proliferation and secretion of Th1 and Th2 cytokines 26 .…”

Anti-Stress and Glial Differentiation Effects of a Novel Combination of Cucurbitacin B and Withanone (CucWi-N): Experimental Evidence

“…It was shown to cause selective cytotoxicity on cancer cells by irreversibly damaging DNA repair mechanisms, disturbing the cellular assembly and organization, and mortalin-p53 function [18,19,24]. Several studies have suggested anti-inflammatory and anti-stress potential of Wi-N [38,39]; they have attributed this property to the oxidized 5-7 carbons in its chemistry [40] that translates into weak binding affinity to target proteins [19]. In the normal cells, it delayed the onset of stress-induced senescence [27], and protected brain-derived cells from oxidative and glutamate stresses [22].…”