title: Barrier protective effects of withaferin A in HMGB1-induced inflammatory responses in both cellular and animal models.
abstract: 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.
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Lee
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Min
authors.forename: Hyun-Shik
authors.initials: HS
authors.lastname: Lee
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008813:Mice, Inbred ICR; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D015815:Cell Adhesion Molecules; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D054358:Withanolides; C009684:withaferin A