Cucurbitacin E (cas 18444-66-1) ameliorates hepatic fibrosis in vivo and in vitro through activation of AMPK and blocking mTOR-dependent signaling pathway

Add time:09/04/2019    Source:sciencedirect.com

The study evaluated the potential protective effect and underlying mechanism of Cucurbitacin E (cas 18444-66-1) (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.

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