Suppressive activities of KC1-3 on HMGB1-mediated septic responses

Biochem Pharmacol. 2019 May:163:260-268. doi: 10.1016/j.bcp.2019.02.027. Epub 2019 Feb 26.

Abstract

In the present study, several decursin analogues (KC1-3) were synthesized and evaluated in terms of their anti-septic activities on high mobility group box 1 (HMGB1)-mediated septic responses and survival rate in a mouse model of sepsis. KC1 and KC3, but not KC2, significantly reduced HMGB1 release in lipopolysaccharide (LPS)-activated human umbilical vein endothelial cells (HUVECs) and attenuated the cecal ligation and puncture (CLP)-induced release of HMGB1. Additionally, in vitro analyses revealed that KC1 and KC3 both alleviated HMGB1-mediated vascular disruptions and inhibited hyperpermeability in mice, and in vivo analyses revealed that KC1 and KC3 reduced sepsis-related mortality and tissue injury. Taken together, the present results suggest that KC1 and KC3 both reduced HMGB1 release and septic mortality and, thus, may be useful for the treatment of sepsis.

Keywords: Endothelium; HMGB1; KC1-3; Sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology*
  • Butyrates / chemistry
  • Cell Adhesion / drug effects
  • Cell Movement / drug effects
  • Cell Survival
  • Enzyme Activators / chemical synthesis*
  • Enzyme Activators / chemistry
  • Enzyme Activators / pharmacology*
  • Gene Expression Regulation / drug effects
  • HMGB1 Protein / genetics
  • HMGB1 Protein / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Leukocytes / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Neutrophils / drug effects
  • Peritonitis / drug therapy
  • Peritonitis / etiology
  • Sepsis / drug therapy*

Substances

  • Benzopyrans
  • Butyrates
  • Enzyme Activators
  • HMGB1 Protein
  • decursin