Inhibitory Functions of Novel Compounds from Dioscorea batatas Decne Peel on HMGB1-mediated Septic Responses

Inhibition of high mobility group box 1 (HMGB1) signaling and restoration of endothelial integrity are emerging as promising therapeutic strategies for managing severe vascular inflammatory diseases. Dioscorea batatas Decne (DBD, Chinese yam), a perennial plant which belongs to Dioscoreaceae, is widely cultivated across Korea, Japan, China, and other tropical and subtropical regions, and both the aerial parts and roots of this plant are used for food and medicinal purposes. Here, we determined the effects of the two phenanthrene compounds from DBD peel, 2,7-dihydroxy-4,6-dimethoxyphenanthrene (1) and 6,7-dihydroxy-2,4-dimethoxyphenanthrene (2), on HMGB1-mediated septic responses and survival rate in cecal ligation and puncture (CLP)-induced septic model. The anti-inflammatory activities of compounds 1 and 2 were monitored by lipopolysaccharide (LPS)- or CLP-induced release of HMGB1. The anti-septic activities of compounds 1 and 2 were determined by measuring permeability, leukocyte adhesion and migration, and pro-inflammatory protein activation in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and mice. Compounds 1 and 2 inhibited HMGB1 release and downregulated HMGB1-mediated inflammatory responses in HUVECs. Compounds 1 and 2 also inhibited HMGB1-induced hyperpermeability and leukocyte migration in mice. Additionally, treatment with compounds 1 and 2 reduced CLP-induced HMGB1 release and sepsis-related mortality and pulmonary damage in vivo. Our results indicate that the compounds 1 and 2 are potential therapeutic agents for treating severe vascular inflammatory diseases via HMGB1 signaling pathway inhibition.