| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 5846722 | Toxicology and Applied Pharmacology | 2012 | 8 Pages |
Withaferin A (WFA), an active compound from Withania somnifera, is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In this study, we first investigated the possible barrier protective effects of WFA against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice induced by high mobility group box 1 protein (HMGB1) and the associated signaling pathways. The barrier protective activities of WFA were determined by measuring permeability, leukocytes adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs. We found that WFA inhibited lipopolysaccharide (LPS)-induced HMGB1 release and HMGB1-mediated barrier disruption, expression of cell adhesion molecules (CAMs) and adhesion/transendothelial migration of leukocytes to human endothelial cells. WFA also suppressed acetic acid-induced hyperpermeability and carboxymethylcellulose-induced leukocytes migration in vivo. Further studies revealed that WFA suppressed the production of interleukin 6, tumor necrosis factor-α (TNF-α) and activation of nuclear factor-κB (NF-κB) by HMGB1. Collectively, these results suggest that WFA protects vascular barrier integrity by inhibiting hyperpermeability, expression of CAMs, adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases.
⺠Withaferin A inhibited LPS induced HMGB1 release. ⺠Withaferin A reduced HMGB1-mediated hyperpermeability. ⺠Withaferin A inhibited HMGB1-mediated adhesion and migration of leukocytes. ⺠Withaferin A inhibited HMGB1-mediated activation of NF-κB, IL-6 and TNF-α.
