In:
British Journal of Pharmacology, Wiley, Vol. 171, No. 21 ( 2014-11), p. 4820-4830
Abstract:
Activation of hepatic stellate cells ( HSCs ) is a crucial step in the pathogenesis of hepatic fibrosis. Histone deacetylase ( HDAC ) is an attractive target in liver fibrosis because it plays a key role in gene expression and cell differentiation. We have developed a HDAC inhibitor, N ‐hydroxy‐7‐(2‐naphthylthio)heptanomide ( HNHA ), and investigated the anti‐fibrotic activity of HNHA in vitro and in vivo . Experimental Approach We investigated the anti‐fibrotic effect of HNHA on mouse and human HSC activation in vitro and in the liver of bile duct‐ligated ( BDL ) rats in vivo using cell proliferation assays, cell cycle analysis, biochemical assay, immunohistochemistry and W estern blots. Liver pathology was assessed with histochemical techniques. Key Results HNHA inhibited proliferation and arrested the cell cycle via p21 induction in HSCs . In addition, HNHA induced apoptosis of HSCs , which was correlated with reduced COX ‐2 expression, NF ‐κ B activation and cell death signals. HNHA restored liver function and decreased the accumulation of extracellular matrix in the liver via suppression of HSC activation in BDL rats in vivo . HNHA administration also increased survival in BDL rats. Conclusions and Implications HNHA improved liver function, suppressed liver fibrosis and increased survival of BDL rats, accompanied by reduction of cell growth, activation and survival of HSCs . These findings show that HNHA may be a potent anti‐fibrosis agent against hepatic fibrosis because of its multi‐targeted inhibition of HSC activity in vivo and in vitro .
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
DOI:
10.1111/bph.2014.171.issue-21
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
2029728-2
SSG:
15,3
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