Cyclin-dependent kinase inhibitor roscovitine attenuates liver inflammation and fibrosis by influencing initiating steps of liver injury

doi:10.1042/CS20201111

	Cyclin-dependent kinase inhibitor roscovitine attenuates liver inflammation and fibrosis by influencing initiating steps of liver injury
	Liu, Yanjun 1; Li, Jiacheng 2,3; Liao, Liping 2,3; Huang, Heming 1; Fan, Shijie 2,3; Fu, Rong 1,2; Huang, Jing 2,3; Shi, Cuicui 1; Yu, Liang 2; Chen, Kai-xian 2,3
刊名	CLINICAL SCIENCE
	2021-04-01
卷号	135 期号:7 页码:925-941
ISSN号	0143-5221
DOI	10.1042/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.
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关键词	KAPPA-B ACTIVATION ; HEPATIC STELLATE CELLS ; PROTEIN-KINASES ; MECHANISMS ; MACROPHAGES ; RESOLUTION ; IMMUNOLOGY ; EXPRESSION ; RESPONSES ; IMMUNITY
WOS研究方向	Research & Experimental Medicine
语种	英语
出版者	PORTLAND PRESS LTD
WOS记录号	WOS:000648650800006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297338]
专题	中国科学院上海药物研究所
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.