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  2. 上海药物研究所
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  4. 新药研究国家重点实验室
Cyclin-dependent kinase inhibitor roscovitine attenuates liver inflammation and fibrosis by influencing initiating steps of liver injury

文献类型：期刊论文

作者Liu, Yanjun1; Li, Jiacheng2,3; Liao, Liping2,3; Huang, Heming1; Fan, Shijie2,3; Fu, Rong1,2; Huang, Jing2,3; Shi, Cuicui1; Yu, Liang2; Chen, Kai-xian2,3
刊名CLINICAL SCIENCE
出版日期2021-04-01
卷号135期号:7页码:925-941
ISSN号0143-5221
DOI10.1042/CS20201111
通讯作者Zhang, Yuan-yuan(zhangyy@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn) ; Li, Guang-ming(liguangming@xinhuamed.com.cn)
英文摘要Liver diseases present a significant public health burden worldwide. Although the mechanisms of liver diseases are complex, it is generally accepted that inflammation is commonly involved in the pathogenesis. Ongoing inflammatory responses exacerbate liver injury, or even result in fibrosis and cirrhosis. Here we report that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, exerts beneficial effects on acute and chronic liver inflammation as well as fibrosis. Animal models of lipopolysaccharide (LPS)/D-galactosamine- and acute or chronic CCl4-induced liver injury showed that roscovitine administration markedly attenuated liver injury, inflammation and histological damage in LPS/D-galactosamine- and CCl4-induced acute liver injury models, which is consistent with the results in vitro. RNA sequencing (RNA-seq) analysis showed that roscovitine treatment repressed the transcription of a broad set of pro-inflammatory genes involved in many aspects of inflammation, including cytokine production and immune cell proliferation and migration, and inhibited the TGF-beta signaling pathway and the biological process of tissue remodeling. For further validation, the beneficial effect of roscovitine against inflammation was evaluated in chronic CCl4-challenged mice. The anti-inflammation effect of roscovitine was observed in this model, accompanied with reduced liver fibrosis. The anti-fibrotic mechanism involved inhibition of profibrotic genes and blocking of hepatic stellate cell (HSC) activation. Our data show that roscovitine administration protects against liver diseases through inhibition of macrophage inflammatory actions and HSC activation at the onset of liver injury.
WOS关键词KAPPA-B ACTIVATION ; HEPATIC STELLATE CELLS ; PROTEIN-KINASES ; MECHANISMS ; MACROPHAGES ; RESOLUTION ; IMMUNOLOGY ; EXPRESSION ; RESPONSES ; IMMUNITY
资助项目National Natural Science Foundation of China[81070344] ; National Natural Science Foundation of China[81803554] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81821005] ; Ministry of Science and Technology of China[2015CB910304] ; National Science & Technology Major Project of China[2018ZX09711002]
WOS研究方向Research & Experimental Medicine
语种英语
出版者PORTLAND PRESS LTD
WOS记录号WOS:000648650800006
源URL[http://119.78.100.183/handle/2S10ELR8/297338]  
专题新药研究国家重点实验室
通讯作者Zhang, Yuan-yuan; Luo, Cheng; Li, Guang-ming
作者单位1.Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Gastroenterol, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China
2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Yanjun,Li, Jiacheng,Liao, Liping,et al. Cyclin-dependent kinase inhibitor roscovitine attenuates liver inflammation and fibrosis by influencing initiating steps of liver injury[J]. CLINICAL SCIENCE,2021,135(7):925-941.
APA Liu, Yanjun.,Li, Jiacheng.,Liao, Liping.,Huang, Heming.,Fan, Shijie.,...&Li, Guang-ming.(2021).Cyclin-dependent kinase inhibitor roscovitine attenuates liver inflammation and fibrosis by influencing initiating steps of liver injury.CLINICAL SCIENCE,135(7),925-941.
MLA Liu, Yanjun,et al."Cyclin-dependent kinase inhibitor roscovitine attenuates liver inflammation and fibrosis by influencing initiating steps of liver injury".CLINICAL SCIENCE 135.7(2021):925-941.

入库方式： OAI收割

来源：上海药物研究所

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