title: Cucurbitacin E ameliorates hepatic fibrosis in vivo and in vitro through activation of AMPK and blocking mTOR-dependent signaling pathway.
abstract: The study evaluated the potential protective effect and underlying mechanism of Cucurbitacin E (CuE) in both thioacetamide-induced hepatic fibrosis and activated HSCs. CuE inhibited the proliferation of activated HSC/T-6 cells in a concentration- and time-dependent manner; triggered the activation of caspase-3, cleaved PARP, altered ratio of bcl-2-to-bax, and affected cytochrome C protein in a time- and concentration-dependent manner. CuE arrested activated HSCs at the G2/M phase. Furthermore, CuE reduced levels of p-Erk/MAPK and also inhibited the protein and mRNA expressions of α-SMA, TIMP-1 and collagen I in activated HSC-T6 cells. CuE inhibited PI3K and Akt phosphorylation, and reduced the levels of p-mTOR and p-P70S6K and increased the expression of p-AMPK, which is similar with AICAR and metformin. C57BL/6 mice were intraperitoneally injected with thioacetamide (TAA) for five continuous weeks (100 or 200mg/kg, three times per week) along with daily administration of CuE (5 or 10mg/kg/d) and curcumin (Cur, 20mg/kg). CuE treatments significantly reduced serum ALT/AST levels, α-SMA, TIMP-1, and collagen I protein expressions. HE, Masson trichrome, Sirius red and immunohistochemical staining also suggested that CuE could ameliorate hepatic fibrosis. Our findings suggest that CuE induces apoptosis of activated HSC and ameliorates TAA-induced hepatic fibrosis through activation of AMPK and blocking mTOR-dependent signaling pathway.
authors.affiliation: Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Wu
authors.affiliation: Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
authors.forename: You-Li
authors.initials: YL
authors.lastname: Yao
authors.affiliation: Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
authors.forename: Zhi-Man
authors.initials: ZM
authors.lastname: Li
authors.affiliation: Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.affiliation: Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Lian
authors.affiliation: Department of Traditional Chinese Material Medica, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Zhao
authors.affiliation: Key Laboratory for Natural Resource of ChangBai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Clinical Research Center, Yanbian University Hospital, China. Electronic address: jxnan@ybu.edu.cn.
authors.forename: Ji-Xing
authors.initials: JX
authors.lastname: Nan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004789:Enzyme Activation; D016195:G2 Phase; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013853:Thioacetamide; D014315:Triterpenes / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D014315:Triterpenes; D013853:Thioacetamide; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C102326:cucurbitacin E
keywords: AMP-activated protein kinase; Cucurbitacin e; Hepatic fibrosis; Hepatic stellate cell