We previously demonstrated that curcumin, a well-known antioxidant, inhibits collagen deposition in carbon tetrachloride-induced liver injury in rats. The major effector cells responsibleforcollagensynthesis in the liver are activated hepatic stellate cells. In this study,we investigated the inhibitory effects of curcumin on the collagen synthesis and activation of rat hepatic stellate cells in-vitro, and on hepatic stellate cell activation in-vivo. The effects of curcumin on the production of collagen and smooth muscle alpha-actin proteins and of alpha1(I) collagen mRNA were studied in-vivo and in-vitro. The effect of curcumin on DNA synthesis was also determined in-vitro. In-vivo, treatment with curcumin reduced collagen deposition and smooth muscle alpha-actin-positive areas and lowered mRNA levels of type I collagen in the liver. In-vitro, curcumin at a concentration of 5 microg mL(-1) reduced DNA synthesis, and downregulated smooth muscle alpha-actin and type I collagen expression, and alpha1(I) collagen mRNA expression. We concluded that curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro, and thus may prove a valuable anti-fibrogenic agent.

Abstract:We have studied the inhibitory effect of aloe emodin on hepatic stellate cells activation and proliferation, as these cells play a key role in the pathogenesis of hepatic fibrosis. Rat hepatic stellate cells were activated by contact with plastic dishes, resulting in their transformation into myofibroblast-like cells. Primary hepatic stellate cells were exposed to aloe emodin (1-10 mg/ml). Possible cytotoxic effects were measured on stellate cells and hepatocytes using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of aloe emodin on production of type I collagen and smooth muscle cell a-actin were examined at the same concentration, by quantitative immunoprecipitation. Antiproliferative effects were examined by bromodeoxyuridine incorporation. Aloe emodin at 10 mg/ml restored the morphological changes characteristic of activated primary stellate cells, reduced DNA synthesis to 95% of control hepatic stellate cells at 10 mg/ml without affecting cell viability, and inhibited type I collagen production and smooth muscle aactin expression by 86.77% and 99%, respectively, which suggest that aloe emodin is a potent inhibitor of stellate cell transformation.During chronic liver damage, hepatic stellate cells undergo a transform by ''activation,'' which is the transition of quiescent cells into proliferative, fibrogenic, and contractile myofibroblasts expressing collagen and smooth muscle cell aactin, leading ultimately to liver fibrosis (Friedman et al. 1985;Knittel et al. 1992;Friedman 2000). Therefore, agents that inhibit hepatic stellate cells activation might be candidates for the therapeutic prevention of chronic liver injury and/or liver fibrosis (Friedman 1993).Stellate cells cultured in a medium supplemented with serum undergo spontaneous activation. This in vitro model is useful for understanding the molecular mechanisms underlying the activation and/or inactivation of stellate cells in the injured liver. In this context, interferons (Rockey et al. 1990; Mallat et al. 1995), prostaglandin E2 (Beno et al. 1994, retinoids (Sato et al. 1995), adenosine 3ø,5ø-cyclic monophosphate (cAMP) and methylxanthines (Kawada et al. 1996), pentoxyphylline (Windmeier & Gressner 1996) Aloe emodin (1,8-dihydroxy-3-hydroxymethyl-9,10-anthracenedione) is a hydroxyanthraquinone present in Aloe vera leaves. It has been reported to have antioxidative activity (Yen et al. 2000), to reduce the acute liver injury induced by carbon tetrachloride (Arosio et al. 2000), and to possess hepatoprotective activity (Malterud et al. 1993).Author for correspondence: Dong Hwan Sohn, Department of Pharmacy, Wonkwang University, Iksan, Jeonbuk 570-749, South Korea (fax π82 63 854 6038, e-mail dhsohn/wonkwang.ac.kr).For several years we have been screening candidate hepatoprotectants and antifibrotics from natural products, which have been used in traditional medicine for treating liver disease. As stated above, aloe emodin has hepatoprotective activity, but direct evidence to support its effect on...

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Our current observations provide data on the prevalence of polymorphisms of ethanol-metabolizing enzymes, which should be useful in assessing the comparative susceptibility of different populations to diseases related to ethanol consumption.