Abstract
High mobility group box 1 (HMGB1) acts as a late mediator of vascular inflammatory conditions. Pellitorine (PT), an active amide compound from Asarum sieboldii, is known to possess antibacterial and anticancer properties. In this study, we investigated the anti-septic effects of PT against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) induced by HMGB1 and the associated signaling pathways. According to our findings, treatment with PT resulted in inhibited release of HMGB1, down-regulation of HMGB1-dependent inflammatory responses in HUVECs, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with PT resulted in reduced cecal ligation and puncture (CLP)-induced release of HMGB1 and sepsis-related mortality. PT suppressed the production of tumor necrosis factor-α and interleukin 6 and the activation of nuclear factor-κB and extracellular regulated kinases 1/2 by HMGB1. Collectively, these results indicate the potential of PT as a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Infective Agents, Local / pharmacology*
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Anti-Inflammatory Agents / pharmacology*
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Capillary Permeability / drug effects
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Cell Adhesion / drug effects
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Cell Movement / drug effects
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Cells, Cultured
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Fatty Acids, Unsaturated / pharmacology*
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HMGB1 Protein / administration & dosage
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HMGB1 Protein / antagonists & inhibitors*
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HMGB1 Protein / metabolism
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Human Umbilical Vein Endothelial Cells / drug effects*
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Human Umbilical Vein Endothelial Cells / immunology
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Inflammation Mediators / metabolism*
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Interleukin-6 / metabolism
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Lipopolysaccharides / pharmacology
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Male
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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NF-kappa B / metabolism
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Polyunsaturated Alkamides / pharmacology*
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Sepsis / immunology
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Sepsis / metabolism
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Sepsis / microbiology
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Sepsis / prevention & control*
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Signal Transduction / drug effects
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Time Factors
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Anti-Infective Agents, Local
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Anti-Inflammatory Agents
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Fatty Acids, Unsaturated
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HMGB1 Protein
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HMGB1 protein, human
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IL6 protein, human
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Inflammation Mediators
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Interleukin-6
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Lipopolysaccharides
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NF-kappa B
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Polyunsaturated Alkamides
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Tumor Necrosis Factor-alpha
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lipopolysaccharide, Escherichia coli O111 B4
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pellitorine
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3