Abstract
BackgroundDiwu Yanggan (DWYG) is a Chinese compound herbal preparation which consists of five Chinese herbs. This study investigates the preventative effects of DWYG on liver fibrosis induced by carbon tetrachloride (CCl4) and explores its possible mechanisms of action.MethodsLiver fibrosis was induced in male Wistar rats by injecting a 50% CCl4/soybean oil solution subcutaneously twice a week for six weeks. After six weeks of treatment, serum aspartate transaminase (AST) and alanine transaminase (ALT) assay, liver tissue histological assessment and hepatic hydroxyproline assay were respectively carried out to examine the effects of DWYG on liver function and fibrosis degree. The impacts of DWYG on the expression levels of epithelial marker E-cadherin, mesenchymal marker Vimentin, transforming growth factor β1 (TGF-β1) and bone morphogenetic protein-7 (BMP-7) were further examined by quantitative real-time RT-PCR and Western blot analysis. In addition, the differences of Hedgehog (Hh) signaling pathway activity between DWYG-treated and DWYG-untreated fibrotic liver tissues were also evaluated by quantitative real-time RT-PCR and Western blot analysis.ResultsUpon DWYG treatment, the serum levels of ALT and AST, hepatic hydroxyproline content and the degree of fibrosis in CCl4-induced fibrotic model rats were dramatically declined. In accompany with the alleviation of the degree of fibrosis, DWYG treatment provoked the reversal of epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) in the fibrotic liver tissues, which was characterized with the up-regulation expression of E-cadherin and down-regulation expression of Vimentin. Furthermore, we observed that the expression level of TGF-β1 was reduced whereas the expression level of BMP-7 was enhanced in liver tissues of DWYG-treated rats, therefore the expression ratio of TGF-β1/BMP-7 was dramatically decreased compared to CCl4-induced fibrosis model rats. In addition, quantitative real-time RT-PCR and Western blot analysis demonstrated that after DWYG treatment the expressions of Hh ligand Shh, receptor Smo and Ptc, and transcription factor Gli1 in CCl4-induced fibrotic liver tissues were dramatically repressed.ConclusionsDWYG demonstrates therapeutic potential to prevent liver fibrosis by modulating the balance between EMT and MET through reducing the expression ratio of TGF-β1/BMP-7 and inhibiting the excessive activation of Hh signaling pathway.
Highlights
Diwu Yanggan (DWYG) is a Chinese compound herbal preparation which consists of five Chinese herbs
As important markers to evaluate liver function, the serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) in CCl4-induced model group substantially elevated compared with blank control group (Figure 2B, #p < 0.05), while DWYG treatment significantly inhibited the increase in serum levels of ALT and AST induced by CCl4 (Figure 2B, *p < 0.05)
DWYG treatment inhibited the excessive activation of Hh signaling in the fibrotic livers of rats induced by CCl4 To assess the mechanism by which DWYG treatment regulate epithelial-to-mesenchymal transition (EMT)/mesenchymal-to-epithelial transition (MET) in CCl4-induced rat, we focused our investigation on Hh signaling because it has been implicated in the regulation of EMT [21]
Summary
Diwu Yanggan (DWYG) is a Chinese compound herbal preparation which consists of five Chinese herbs. Many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in human are not always satisfactory [2] This highlights the urgent need to both increase our understanding of the mechanisms of liver fibrogenesis and develop novel therapies to arrest or reverse the fibrotic process as even advance fibrosis is reversible [3,4]. The important roles of EMT and MET in liver tissue injury and repair, in addition to their potential reversibility, made this trans-differentiation process a relevant and suitable target for anti-fibrogenic strategies in liver fibrosis. This transdifferentiation process is known to be tightly controlled by modulating factors, such as TGF-β1, BMP-7 and Hh signaling. Therapeutic manipulations of these known modulating factors have generally been demonstrated to influence liver regeneration and fibrosis in rodents [12]
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