Shimizu I, Ma Y R, Mizobuchi Y, Liu F, Miura T, Nakai Y, Yasuda M, Shiba M, Horie T, Amagaya S, Kawada N, Hori H, Ito S
Second Department of Internal Medicine, School of Medicine, University of Tokushima, Tokushima,
Hepatology. 1999 Jan;29(1):149-60. doi: 10.1002/hep.510290108.
It has been shown that lipid peroxidation is associated with hepatic fibrosis and stellate cell activation. Sho-saiko-to (TJ-9) is an herbal medicine, which is commonly used to treat chronic hepatitis in Japan, although the mechanism by which TJ-9 protects against hepatic fibrosis is not known. As a result, we assayed the preventive and therapeutic effects of TJ-9 on experimental hepatic fibrosis, induced in rats by dimethylnitrosamine (DMN) or pig serum (PS), and on rat stellate cells and hepatocytes in primary culture, and assessed the antioxidative activities and the active components of TJ-9. Male Wistar rats were given a single intraperitoneal injection of 40 mg/kg DMN or 0.5 mL PS twice weekly for 10 weeks. In each model, rats were fed a basal diet throughout, or the same diet, which also contained 1.5% TJ-9, for 2 weeks before treatment or for the last 2 weeks of treatment. TJ-9 suppressed the induction of hepatic fibrosis, increased hepatic retinoids, and reduced the hepatic levels of collagen and malondialdehyde (MDA), a production of lipid peroxidation. Immunohistochemical examination showed that TJ-9 reduced the deposition of type I collagen and the number of alpha-smooth muscle actin (alpha-SMA) positive-stellate cells in the liver and inhibited, not only lipid peroxidation in cultured rat hepatocytes that were undergoing oxidative stress, but also the production of type I collagen, alpha-SMA expression, cell proliferation, and oxidative burst in cultured rat stellate cells. In addition, TJ-9 inhibited Fe2+/adenosine 5'-diphosphate-induced lipid peroxidation in rat liver mitochondria in a dose-dependent manner and showed radical scavenging activity. Among the active components of TJ-9, baicalin and baicalein were found to be mainly responsible for the antioxidative activity. These findings suggest that Sho-saiko-to (TJ-9) functions as a potent antifibrosuppressant by inhibition of lipid peroxidation in hepatocytes and stellate cells in vivo.
已有研究表明，脂质过氧化与肝纤维化及星状细胞活化有关。小柴胡汤（TJ - 9）是一种草药，在日本常用于治疗慢性肝炎，但其预防肝纤维化的机制尚不清楚。因此，我们检测了TJ - 9对二甲基亚硝胺（DMN）或猪血清（PS）诱导的大鼠实验性肝纤维化的预防和治疗作用，以及对原代培养的大鼠星状细胞和肝细胞的作用，并评估了TJ - 9的抗氧化活性和活性成分。雄性Wistar大鼠每周两次腹腔注射40 mg/kg DMN或0.5 mL PS，持续10周。在每个模型中，大鼠在整个实验过程中喂食基础饲料，或在治疗前2周或治疗的最后2周喂食含1.5% TJ - 9的相同饲料。TJ - 9抑制了肝纤维化的诱导，增加了肝脏类视黄醇含量，并降低了肝脏中胶原蛋白和丙二醛（MDA，脂质过氧化产物）的水平。免疫组织化学检查显示，TJ - 9减少了肝脏中I型胶原蛋白的沉积和α - 平滑肌肌动蛋白（α - SMA）阳性星状细胞的数量，不仅抑制了遭受氧化应激的培养大鼠肝细胞中的脂质过氧化，还抑制了培养大鼠星状细胞中I型胶原蛋白的产生、α - SMA表达、细胞增殖和氧化爆发。此外，TJ - 9以剂量依赖的方式抑制大鼠肝线粒体中Fe2+/腺苷5'-二磷酸诱导的脂质过氧化，并表现出自由基清除活性。在TJ - 9的活性成分中，黄芩苷和黄芩素被发现是抗氧化活性的主要贡献者。这些发现表明，小柴胡汤（TJ - 9）通过抑制体内肝细胞和星状细胞中的脂质过氧化发挥强效抗纤维化作用。
