Anti-septic effects of phenolic glycosides from Rhododendron brachycarpum in vitro and in vivo

Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity is emerging as an attractive therapeutic strategy in the management of sepsis. Here, we examined the effects of three phenolic glycosides (. 1-. 3) found in Rhododendron brachycarpum, which has been used as food and medicinal resources for anti-rheumatic agent, diuretic, and anti-inflammatory in Asia, on inflammatory responses by monitoring the effects on lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-mediated release of HMGB1, and on the modulation of HMGB1-mediated inflammatory responses. The anti-inflammatory activities of phenolic glycosides 1-. 3 were determined by measuring permeability, monocyte adhesion and migration, and the activation of pro-inflammatory proteins in HMGB1-activated HUVECs and mice. All three phenolic glycosides inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. Phenolic glycosides 1-. 3 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with compounds 1-. 3 reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury. Our results indicate that phenolic glycosides 1-. 3 could be candidate therapeutic agents for various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.