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Tetramethylpyrazine prevents liver fibrotic injury in mice by targeting hepatocyte-derived and mitochondrial DNA-enriched extracellular vesicles.

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Pubmed体系：

收录情况： ◇ 统计源期刊 ◇ CSCD-C ◇ 卓越：重点期刊

作者：
Li Ya-Jing[1] * ; Liu Run-Ping[2] * ; Ding Ming-Ning[1] ; Zheng Qi[2] ; Wu Jian-Zhi[1] ; Xue Xiao-Yong[1] ; Gu Yi-Qing[2] ; Ma Bo-Ning[1] ; Cai Ya-Jie[2] ; Li Shuo[2] ; Lin Sheng[3] ; Zhang Lu-Yong[4] ; Li Xiaojiaoyang[1] ;
机构： [1]School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China. [2]School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China. [3]Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100029, China. [4]Center for Drug Screening and Pharmacodynamics Evaluation, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China
出处：
DOI： 10.1038/s41401-021-00843-w
ISSN：

关键词： liver fibrosis tetramethylpyrazine CCl4 acetaminophen extracellular vesicle intercellular communication mouse primary hepatocytes hepatic stellate cells

摘要：
Liver fibrosis is the common consequence of almost all liver diseases and has become an urgent clinical problem without efficient therapies. Recent evidence has shown that hepatocytes-derived extracellular vesicles (EVs) play important roles in liver pathophysiology, but little is known about the role of damaged hepatocytes-derived EVs in hepatic stellate cell (HSC) activation and following fibrosis. Tetramethylpyrazine (TMP) from Ligusticum wallichii Franchat exhibits a broad spectrum of biological activities including liver protection. In this study, we investigated whether TMP exerted liver-protective action through regulating EV-dependent intercellular communication between hepatocytes and HSCs. Chronic liver injury was induced in mice by CCl4 (1.6 mg/kg, i.g.) twice a week for 8 weeks. In the last 4 weeks of CCl4 administration, mice were given TMP (40, 80, 160 mg·kg-1·d-1, i.g.). Acute liver injury was induced in mice by injection of a single dose of CCl4 (0.8 mg/kg, i.p.). After injection, mice were treated with TMP (80 mg/kg) every 24 h. We showed that TMP treatment dramatically ameliorated CCl4-induced oxidative stress and hepatic inflammation as well as acute or chronic liver fibrosis. In cultured mouse primary hepatocytes (MPHs), treatment with CCl4 or acetaminophen resulted in mitochondrial dysfunction, release of mitochondrial DNA (mtDNA) from injured hepatocytes to adjacent hepatocytes and HSCs through EVs, mediating hepatocyte damage and fibrogenic responses in activated HSCs; pretreatment of MPHs with TMP (25 μM) prevented all these pathological effects. Transplanted serum EVs from TMP-treated mice prevented both initiation and progression of liver fibrosis caused by CCl4. Taken together, this study unravels the complex mechanisms underlying the protective effects of TMP against mtDNA-containing EV-mediated hepatocyte injury and HSC activation during liver injury, and provides critical evidence inspiring the development of TMP-based innovative therapeutic agents for the treatment of liver fibrosis.© 2021. The Author(s), under exclusive licence to CPS and SIMM.

基金：
Beijing Municipal Science & Technology Commission (Grant No. 7212174 to XL); National Natural Science Foundation of China (Grant No. 82004045 to XL); Beijing Nova Program of Science & Technology (Grant No. Z191100001119088 to XL; Grant No. Z201100006820025 to RL); and the Young Talents Promotion Project of China Association of Traditional Chinese Medicine (Grant No. 2020-QNRC2-01 to XL); Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (Grant No. ZYYCXTD-C-202006 to XL).
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外文
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中科院(CAS)分区：
出版当年[2021]版：
大类 | 1 区 医学
小类 | 1 区 药学 2 区 化学综合
最新[2025]版：
大类 | 2 区 医学
小类 | 1 区 药学 2 区 化学：综合
第一作者：
第一作者机构： [1]School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Li Ya-Jing,Liu Run-Ping,Ding Ming-Ning,et al.Tetramethylpyrazine prevents liver fibrotic injury in mice by targeting hepatocyte-derived and mitochondrial DNA-enriched extracellular vesicles.[J].Acta Pharmacologica Sinica.2022,doi:10.1038/s41401-021-00843-w.
APA：
Li Ya-Jing,Liu Run-Ping,Ding Ming-Ning,Zheng Qi,Wu Jian-Zhi...&Li Xiaojiaoyang.(2022).Tetramethylpyrazine prevents liver fibrotic injury in mice by targeting hepatocyte-derived and mitochondrial DNA-enriched extracellular vesicles..Acta Pharmacologica Sinica,,
MLA：
Li Ya-Jing,et al."Tetramethylpyrazine prevents liver fibrotic injury in mice by targeting hepatocyte-derived and mitochondrial DNA-enriched extracellular vesicles.".Acta Pharmacologica Sinica .(2022)

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