Leukamenin F suppresses liver fibrogenesis by inhibiting both hepatic stellate cell proliferation and extracellular matrix production.

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 (CCl(4))-treated mouse model in vivo and in hepatic stellate cells (HSC) in vitro were used. The effect on CCl(4)-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 TGFbeta/Smad pathways was studied using Western blot and cell image analysis. RESULTS:Leukamenin F (0.1-1 mg/kg, ip, q.d.x28) significantly reduced alpha-SMA and collagen specific Sirius red staining areas in CCl(4) -treated mouse livers. This compound at 1-2 micromol/L dose-dependently inhibited alpha-SMA expression, cell proliferation and type I procollagen mRNA expression in activated HSC. Furthermore it inhibited the Akt/mTOR/p70S6K pathway and suppressed TGFbeta -induced Smad2/Smad3 phosphorylation and nuclear translocation in HSC. CONCLUSION:Our results demonstrated that Leukamenin F could attenuate CCl(4)-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.

journal_name

Acta Pharmacol Sin

authors

Liu Q,Wang X,Zhang Y,Li CJ,Hu LH,Shen X

doi

10.1038/aps.2010.64

subject

Has Abstract

pub_date

2010-07-01 00:00:00

pages

839-48

issue

7

eissn

1671-4083

issn

1745-7254

pii

aps201064

journal_volume

31

pub_type

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