Abstract
Aim:
To investigate the inhibitory effect of the natural product Leukamenin F on liver fibrosis and explore its potential underlying mechanisms.
Methods:
Carbon tetrachloride (CCl4)-treated mouse model in vivo and in hepatic stellate cells (HSC) in vitro were used. The effect on CCl4-induced liver fibrosis was studied using histochemical and biochemical analysis, while the inhibition on HSC was assessed using cell proliferation/apoptosis assay and collagen I production using real-time PCR. The inhibitory effects of Leukamenin F on Akt/mTOR/p70S6K and TGFβ/Smad pathways was studied using Western blot and cell image analysis.
Results:
Leukamenin F (0.1–1 mg/kg, ip, q.d.×28) significantly reduced α-SMA and collagen specific Sirius red staining areas in CCl4 -treated mouse livers. This compound at 1–2 μmol/L dose-dependently inhibited α-SMA expression, cell proliferation and type I procollagen mRNA expression in activated HSC. Furthermore it inhibited the Akt/mTOR/p70S6K pathway and suppressed TGFβ -induced Smad2/Smad3 phosphorylation and nuclear translocation in HSC.
Conclusion:
Our results demonstrated that Leukamenin F could attenuate CCl4-induced liver fibrogenesis in mice as an efficient inhibitor against both HSC proliferation and ECM production. This natural product provides a valuable structural hint for the development of anti-liver fibrosis reagents.
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Acknowledgements
We thank Dr SL FRIEDMAN (Mount Sinai School of Medicine, New York) for kindly providing the human stellate cell line LX-2. This work was supported by the State Key Program of Basic Research of China (grants 2010CB912501, 2007CB914304), the National Natural Science Foundation of China (grants 30890044, 20721003), and Key New Drug Creation and Manufacturing Program (2009ZX09301-001).
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Liu, Q., Wang, X., Zhang, Y. et al. Leukamenin F suppresses liver fibrogenesis by inhibiting both hepatic stellate cell proliferation and extracellular matrix production. Acta Pharmacol Sin 31, 839–848 (2010). https://doi.org/10.1038/aps.2010.64
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DOI: https://doi.org/10.1038/aps.2010.64
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