Dihydro-stilbene gigantol relieves CCl4-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver

doi:10.1038/s41401-020-0406-6

	Dihydro-stilbene gigantol relieves CCl4-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver
	Xue, Ya-ru 2,3; Yao, Sheng 2,4,5; Liu, Qian 2,3; Peng, Zhao-liang 2; Deng, Qiang-qiang 2; Liu, Bo 2,3; Ma, Zheng-hua 1,4,5; Wang, Le 2,3; Zhou, Hu 2,3; Ye, Yang 1,2,4,5
刊名	ACTA PHARMACOLOGICA SINICA
	2020-05-13
页码	14
关键词	gigantol Chinese traditional medicine liver injury oxidative stress inflammation label-free proteomic complement and coagulation cascades terminal complement complex
ISSN号	1671-4083
DOI	10.1038/s41401-020-0406-6
通讯作者	Ye, Yang(yye@simm.ac.cn) ; Pan, Guo-yu(gypan@simm.ac.cn)
英文摘要	In general, anti-inflammatory treatment is considered for multiple liver diseases despite the etiology. But current drugs for alleviating liver inflammation have defects, making it necessary to develop more potent and safer drugs for liver injury. In this study, we screened a series of (dihydro-)stilbene or (dihydro-)phenanthrene derivatives extracted from Pholidota chinensis for their potential biological activities. Among 31 compounds, the dihydro-stilbene gigantol exerted most potent protective effects on human hepatocytes against lithocholic acid toxicity, and exhibited solid antioxidative and anti-inflammatory effect in vitro. In mice with CCl4-induced acute liver injury, pre-administration of gigantol (10, 20, 40 mg center dot kg(-1)center dot d(-1), po, for 7 days) dose-dependently decreased serum transaminase levels and improved pathological changes in liver tissues. The elevated lipid peroxidation and inflammatory responses in the livers were also significantly alleviated by gigantol. The pharmacokinetic studies showed that gigantol was highly concentrated in the mouse livers, which consisted with its efficacy in preventing liver injury. Using a label-free quantitative proteomic analysis we revealed that gigantol mainly regulated the immune system process in liver tissues of CCl4-treated mice, and the complement and coagulation cascades was the predominant pathway; gigantol markedly inhibited the expression of complement component C9, which was a key component for the formation of terminal complement complex (TCC) C5b-9. These results were validated by immunohistochemistry (IHC) or real time-PCR. Confocal microscopy analysis showed that gigantol significantly inhibited the vascular deposition of TCC in the liver. In conclusion, we demonstrate for the first time that oral administration of gigantol potently relieves liver oxidative stress and inflammation, possibly via a novel mechanism of inhibiting the C5b-9 formation in the liver.
资助项目	Chinese Academy of Sciences[XDA16020205] ; National Science Foundation of China[81872927] ; International Partnership Program of Chinese Academy of Sciences[153631KYSB20160004] ; Independent Deployment Program of the Institute of Pharmaceutical Innovation of the Chinese Academy of Sciences[CASIMM0120184005] ; China Postdoctoral Science Foundation[2019M651623]
WOS关键词	MEMBRANE ATTACK COMPLEX ; FATTY LIVER ; REACTIVE OXYGEN ; NITRIC-OXIDE ; INJURY ; EXPRESSION ; GENE ; BILE ; C3 ; ACETYLCYSTEINE
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000532622200002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280192]
专题	中国科学院上海药物研究所
通讯作者	Ye, Yang; Pan, Guo-yu
作者单位	1.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Chinese Acad Sci, State Key Lab Drug Res & Nat Prod, Chem Dept, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 5.SIMM CUHK Joint Res Lab Promoting Globalizat Trad, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Xue, Ya-ru,Yao, Sheng,Liu, Qian,et al. Dihydro-stilbene gigantol relieves CCl4-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver[J]. ACTA PHARMACOLOGICA SINICA,2020:14.
APA	Xue, Ya-ru.,Yao, Sheng.,Liu, Qian.,Peng, Zhao-liang.,Deng, Qiang-qiang.,...&Pan, Guo-yu.(2020).Dihydro-stilbene gigantol relieves CCl4-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver.ACTA PHARMACOLOGICA SINICA,14.
MLA	Xue, Ya-ru,et al."Dihydro-stilbene gigantol relieves CCl4-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver".ACTA PHARMACOLOGICA SINICA (2020):14.