Published online Feb 21, 2014. doi: 10.3748/wjg.v20.i7.1822
Revised: November 13, 2013
Accepted: November 28, 2013
Published online: February 21, 2014
Processing time: 185 Days and 21.8 Hours
AIM: To explore the effect of sophocarpine on experimental liver fibrosis and the potential mechanism involved.
METHODS: Sophocarpine was injected intraperitoneally in two distinct rat hepatic fibrosis models induced either by dimethylnitrosamine or bile duct ligation. Masson’s trichrome staining, Sirius red staining and hepatic hydroxyproline level were used for collagen determination. Primary hepatic stellate cells (HSCs) were isolated and treated with different concentrations of sophocarpine. Real-time reverse transcription-polymerase chain reaction was used to detect the mRNA levels of fibrotic markers and cytokines. The expression of pathway proteins was measured by Western blot. The Cell Counting Kit-8 test was used to detect the proliferation rate of activated HSCs treated with a gradient concentration of sophocarpine.
RESULTS: Sophocarpine decreased serum levels of aminotransferases and total bilirubin in rats under chronic insult. Moreover, administration of sophocarpine suppressed extracellular matrix deposition and prevented the development of hepatic fibrosis. Furthermore, sophocarpine inhibited the expression of α-smooth muscle actin (SMA), interleukin (IL)-6, transforming growth factor-β1 (TGF-β1), Toll-like receptor 4 (TLR4), and extracellular-related kinase (ERK) in rats. Sophocarpine also down-regulated the mRNA expression of α-SMA, collagen I, collagen III, TGF-β1, IL-6, tumor necrosis factor-α and monocyte chemoattractant protein-1, and decreased protein levels of TLR4, p-ERK, p-JNK, p-P38 and p-IKK in vitro after Lipopolysaccharide induction. In addition, sophocarpine inhibited the proliferation of HSCs accompanied by a decrease in the expression of Cyclin D1. The protein level of proliferating cell nuclear antigen was decreased in activated HSCs following a gradient concentration of sophocarpine.
CONCLUSION: Sophocarpine can alleviate liver fibrosis mainly by inhibiting the TLR4 pathway. Sophocarpine may be a potential chemotherapeutic agent for chronic liver diseases.
Core tip: Sophocarpine significantly ameliorated liver function and hepatic fibrosis in both the dimethylnitrosamine and bile duct ligation models. In addition, sophocarpine inhibited the activation and proliferation of hepatic stellate cells in vitro, which contributed to the anti-fibrotic effect of sophocarpine in vivo. Toll-like receptor 4 signaling was blocked by sophocarpine in vivo and in vitro, accompanied by a reduction in pro-inflammatory and fibrotic cytokines, as well a decrease in the expression of Cyclin D1 and proliferating cell nuclear antigen.