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

Abstract

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.