Cucurbitacin E ameliorates hepatic fibrosis in vivo and in vitro through activation of AMPK and blocking mTOR-dependent signaling pathway. (6th September 2016)

• Record Type: Journal Article
• Authors: Wu, Yan-Ling; Zhang, Yu-Jing; Yao, You-Li; Li, Zhi-Man; Han, Xin; Lian, Li-Hua; Zhao, Yu-Qing; Nan, Ji-Xing
• Is Part Of: Toxicology letters. Volume 258(2016)
• Page Start: 147
• Page End: 158
• Publication Date: 2016-09-06
• Subjects: CuE Cucurbitacin E -- ECM extracellular matrix -- HSCs Hepatic stellate cells -- TNF-α tumor necrosis factor-α -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- PARP poly ADP-ribose polymerase -- MAPK mitogen activated protein kinase -- ERK extracellular signal regulated kinase -- JNK c-Jun N-terminal kinase -- TAA thioacetamide -- Cur curcumin group -- ALT alanine aminotransferase -- AST aspartate aminotransferase -- α-SMA alpha-smooth - muscle actin -- TIMP-1 tissue inhibitor of metalloproteinases-1 -- PI3K phosphatidyl inositol 3-kinase -- Akt pH domain of protein kinase B -- AMPK AMP-activated protein kinase -- mTOR mammalian target of rapamycin; Cucurbitacin e -- Hepatic fibrosis -- AMP-activated protein kinase -- Hepatic stellate cell; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2016.06.2102
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: Cucurbitacin E induces apoptosis and attenuates activation of hepatic stellate cells. Cucurbitacin E alleviated thioacetamide-induced hepatic fibrosis. Cucurbitacin E regulates Akt-AMPK-mTOR 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 PI3 K and Akt phosphorylation, and reduced the levels of p-mTOR and p-P70S6 K 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 200 mg/kg, three times per week) along with daily administration of CuE (5 or 10 mg/kg/d) and curcumin (Cur, 20 mg/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.