decursin and Sepsis

The herbal plant

Topics: Angelica; Animals; Benzopyrans; Butyrates; Disease Models, Animal; Interleukin-6; Kaplan-Meier Estimate; Lipopolysaccharides; Macrophages; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; NF-kappa B; Proto-Oncogene Proteins c-akt; RAW 264.7 Cells; Reactive Oxygen Species; Sepsis; Signal Transduction; Tumor Necrosis Factor-alpha

Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as attractive therapeutic strategies for the management of severe vascular inflammatory diseases. Recently, we found that JH-4, a synthesized decursin derivative, exhibited a strong anti-Hutchinson-Gilford progeria syndrome by efficiently blocking progerin-lamin A/C binding. In this study, we examined the effects of JH-4 on HMGB1-mediated septic responses and the survival rate in a mouse sepsis model. The anti-inflammatory activities of JH-4 were monitored based on its effects on lipopolysaccharide- or cecal ligation and puncture (CLP)-mediated release of HMGB1. The antiseptic activities of JH-4 were determined by measuring permeability, leukocyte adhesion, migration, and the activation of proinflammatory proteins in HMGB1-activated human umbilical vein endothelial cells and mice. JH-4 inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. JH-4 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with JH-4 reduced CLP-induced release of HMGB1, sepsis-related mortality, and pulmonary injury in vivo. Our results indicate that JH-4 is a possible therapeutic agent to treat various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.

Topics: Angelica; Animals; Anti-Infective Agents, Local; Anti-Inflammatory Agents; Benzopyrans; Butyrates; Capillary Permeability; Cell Adhesion; Cell Movement; Cell Survival; Cells, Cultured; Disease Models, Animal; HMGB1 Protein; Human Umbilical Vein Endothelial Cells; Humans; Leukocytes; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Plant Extracts; Sepsis; Survival Rate

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.

Topics: Animals; Benzopyrans; Butyrates; Cell Adhesion; Cell Movement; Cell Survival; Enzyme Activators; Gene Expression Regulation; HMGB1 Protein; Human Umbilical Vein Endothelial Cells; Humans; Leukocytes; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Neutrophils; Peritonitis; Sepsis