SHSST-cyclodextrin complex inhibits TGF-beta/Smad3/CTGF to a greater extent than silymarin in a rat model of carbon tetrachloride-induced liver injury

摘要

At present, cirrhosis is an incurable liver disease. Transforming growth factor beta (TGF-beta) is important in myofibroblast induction during the cirrhosis initiation process. The current approach in the development of hepatoprotective drugs depends on TGF-beta inhibition. San Huang Shel Shin Tang (SHSST) is a traditional herbal decoction able to exert a protective effect on the liver, however, similar to silymarin, it is limited by its hydrophobicity. In the present study, SHSST was modified with beta-cyclodextrin to form a hydrophilic complex, which improved its bioavailability. In the carbon tetrachloride-induced acute injury animal model, the effects of pretreatment with silymarin, baicalein, SHSST and the SHSST-beta-CD-complex (SHSSTc) at a low and high dose were assessed. The biopsy results revealed marked liver protection following treatment with silymarin, baicalein and SHSST and these effects were improved further following pretreatment with SHSSTc. Protein analysis demonstrated that the hepatoprotective effects of silymarin occurred through inhibition of the TGF-beta/Smad-3/connective tissue growth factor (CTGF) signaling pathway. SHSSTc exerted the same protective mechanism, however, SHSSTc suppressed CTGF level to a greater extent compared with the groups treated with SHSST or silymarin. Only pretreatment with SHSST and SHSSTc exhibited partial enhancement in the expression of proteins involved in the regulation of liver regeneration, including extracellular-signal-regulated kinase 5, phospho-nuclear factor of activated T cells 3 and phospho-GATA4.