Bioactive coumarin-derivative esculetin decreases hepatic stellate cell activation via induction of cellular senescence via the PI3K-Akt-GSK3βpathway  

作　　者：Mengfan Zhang Turtushikh Damba Zongmei Wu Sandra Serna-Salas Manon Buist-Homan Klaas Nico Faber Han Moshage 

机构地区：[1]Department of Gastroenterology and Hepatology,University Medical Center Groningen,University of Groningen,the Netherlands

出　　处：《Food Bioscience》2022年第6期1866-1875,共10页食品生物科学（英文）

基　　金：Supported by a grant from the Chinese Scholarship Council;Supported by a grant from the Mongolian State Training Foundation。

摘　　要：Background Activation of hepatic stellate cells(HSC)leads to initiation and progression of hepatic fibrosis.HSC senescence is inversely correlated with HSC proliferation and activation.Therefore,induction of HSC senescence may be a strategy to treat hepatic fibrosis.Coumarin-derivatives like esculetin have been suggested to inhibit proliferation of fibrogenic cells.Therefore,in this study we aimed to investigate the effect of esculetin on HSC activation and senescence.Methods Primary rat HSC were used in all experiments.Real-time cell analyzer and BrdU incorporation assay were used to determine HSC proliferation.Gene expression of the senescence-associated genes Cdkn1a(p21),P53,activation markers Acta2,Col1a1 and quiescence markers Pparg and Lrat were measured by RT-qPCR.Senescence associatedβ-Galactosidase(SA-β-Gal)staining was used to identify senescent HSC.Results Our results demonstrate that esculetin increased markers of senescence and decreased proliferation and activation markers in HSC.Protein expression of P21Cip1,accompanied by phosphorylation of Ser473 Akt and Ser9 GSK3βwas increased by esculetin.The effect of esculetin was dependent on PI3K-Akt signaling.Conclusion We conclude that esculetin induces HSC senescence and reverses the activated phenotype of HSC.The induction of senescence depends on PI3K-Akt-GSK3βsignaling.Esculetin could be a potential therapeutic drug for the treatment of hepatic fibrosis by inducing stellate cell senescence.

关 键 词：Fibrosis ESCULETIN Hepatic stellate cell Senescence P21 Akt 

分 类 号：TS201[轻工技术与工程—食品科学]