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Toxicol Appl Pharmacol. 2017 Aug 15;329:202-211. doi: 10.1016/j.taap.2017.06.006. Epub 2017 Jun 10.

Zingerone reduces HMGB1-mediated septic responses and improves survival in septic mice.

Author information

1
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.
2
Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, 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 41566, Republic of Korea. Electronic address: baejs@knu.ac.kr.

Abstract

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-α and IL-6 and the activation of NF-κB 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.

KEYWORDS:

Endothelium; HMGB1; Sepsis; Zingerone

PMID:
28610995
DOI:
10.1016/j.taap.2017.06.006
[Indexed for MEDLINE]

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