Lee Wonhwa, Ku Sae-Kwang, Bae Jong-Sup
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.
Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea.
Toxicol Appl Pharmacol. 2017 Aug 15;329:202-211. doi: 10.1016/j.taap.2017.06.006. Epub 2017 Jun 10.
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.
高迁移率族蛋白B1（HMGB1）被认为是脓毒症的晚期介质，抑制HMGB1介导的严重炎症反应和恢复内皮完整性已成为脓毒症治疗中颇具吸引力的治疗策略。姜辣素（ZGR）是一种从生姜中分离出的酚类烷酮，据报道具有多种药理活性。我们在脓毒症小鼠模型中研究了ZGR对HMGB1介导的脓毒症反应和存活率的影响。在HMGB1攻击后给予ZGR。通过测量HMGB1激活的人脐静脉内皮细胞（HUVECs）和小鼠的通透性、白细胞黏附和迁移、促炎蛋白的激活以及组织损伤标志物的产生，来确定ZGR的抗菌活性。ZGR通过SIRT1介导的HMGB1去乙酰化作用，显著降低了脂多糖（LPS）激活的HUVECs中HMGB1的释放。此外，ZGR抑制了HMGB所诱导的肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的产生以及核因子-κB（NF-κB）和细胞外信号调节激酶1/2（ERK 1/2）的激活。ZGR还抑制了HMGB1介导的小鼠高通透性和白细胞迁移。另外，ZGR治疗降低了盲肠结扎穿孔（CLP）诱导的HMGB1释放、脓毒症相关死亡率以及体内组织损伤。我们的结果表明，ZGR可能通过靶向HMGB1来治疗脓毒症。
