Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 329, Issue -, Pages 202-211Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2017.06.006
Keywords
Zingerone; Endothelium; HMGB1; Sepsis
Categories
Funding
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health and Welfare, Republic of Korea [HI15C0001]
- Korea of Health & Welfare, Republic of Korea [20-11-0-090-091-3000-3033-320]
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High mobility group box 1 (HMGB1) is considered a late mediator of sepsis and the inhibition of HMGB1-mediated severe inflammatory responses and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Zingerone (ZGR), a phenolic alkanone isolated from ginger, has been reported to possess various pharmacological activities. We examined the effects of ZGR on HMGB1-mediated septic responses and survival rate in a mouse model of sepsis. ZGR was administered after HMGB1 challenge. The antiseptic activity of ZGR was determined from the measurements of permeability, leukocyte adhesion and migration, activation of pro-inflammatory proteins, and the production of tissue injury markers in HMGB1-activated HUVECs and mice. ZGR significantly reduced HMGB1 release in LPS-activated HUVECs via the SIRT1-mediated deacetylation of HMGB1. And, ZGR suppressed the production of TNF-alpha and IL-6 and the activation of NF-kappa B and ERK 1/2 by HMGB1. ZGR also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ZGR reduced the CLP-induced release of HMGB1, sepsis-related mortality, and tissue injury in vivo. Our results indicated that ZGR might be useful in the treatment of sepsis by targeting HMGB1. (C) 2017 Elsevier Inc. All rights reserved.
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