Inhibitory effects of epi-sesamin on HMGB1-induced vascular barrier disruptive responses in vitro and in vivo

• Published in: Toxicology and applied pharmacology 2013-03, Vol.267 (3), p.201-208
• Main Authors: Lee, Wonhwa, Ku, Sae-Kwang, Kim, Jeong Ah, Lee, Taeho, Bae, Jong-Sup
• Format: Article
• Language: English
• Subjects: Animals; Antiinflammatory agents; Asarum; Biological and medical sciences; Capillary Permeability - drug effects; Capillary Permeability - physiology; Cecum; Cell Adhesion - drug effects; Cell Adhesion - physiology; Cell Survival - drug effects; Cell Survival - physiology; Dioxoles - pharmacology; Dioxoles - therapeutic use; DNA-binding protein; Endothelial cells; Endothelium; Epi-sesamin; High mobility group proteins; HMGB1; HMGB1 protein; HMGB1 Protein - antagonists & inhibitors; HMGB1 Protein - secretion; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Inflammation; Inflammatory diseases; Leukocyte migration; Lignans - pharmacology; Lignans - therapeutic use; Lipopolysaccharides; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mortality; Roots; Sepsis; Septic shock; Sesame Oil - pharmacology; Sesame Oil - therapeutic use; Sesamin; Signal transduction; Toxicology; Vasculitis - drug therapy; Vasculitis - metabolism
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.01.008

Nuclear DNA-binding protein high mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions, such as sepsis and septic shock. Epi-sesamin (ESM), an important component of Asarum sieboldii roots, is known to exhibit anti-allergic, anti-nociceptive, and anti-fungal effects. However, little is known of its effects on HMGB1-mediated inflammatory responses. Here, we investigated this issue by monitoring the effects of ESM on lipopolysaccharide (LPS) or cecal ligation and the puncture (CLP)-mediated release of HMGB1, and on modulation of HMGB1-mediated inflammatory responses. ESM potently inhibited HMGB1 release, down-regulated HMGB1-dependent inflammatory responses in human endothelial cells, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ESM resulted in reduced CLP-induced release of HMGB1 and sepsis-related mortality. Of particular interest, ESM inhibition of HMGB1-mediated anti-inflammatory activity was more potent than that by sesamin (SM), likely due to differences between their three-dimensional structures. These results indicate that ESM could be a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway. [Display omitted] ► ESM inhibited LPS and CLP induced HMGB1 release. ► ESM reduced HMGB1 and CLP-mediated hyperpermeability. ► ESM inhibited HMGB1-mediated activation of IL-6, and TNF-α. ► ESM reduced sepsis-related mortality.