JH-4 reduces HMGB1-mediated septic responses and improves survival rate in septic mice |
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Authors: | Wonhwa Lee O Yuseok Sumin Yang Bong-Seon Lee Jee-Hyun Lee Eui Kyun Park Moon-Chang Baek Gyu-Yong Song Jong-Sup Bae |
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Institution: | 1. Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea;2. College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea;3. College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu, Republic of Korea;4. AREZ Co. Ltd., Sejong, Republic of Korea;5. Department of Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea;6. Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University, Daegu, Republic of Korea |
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Abstract: | 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. |
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Keywords: | endothelium high mobility group box 1 (HMGB1) JH-4 sepsis |
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