Antifibrotic effects of Salvia miltiorrhiza on dimethylnitrosamine-intoxicated rats.
Excessive oxidative stress is implicated in hepatic fibrogenesis. Extracts of Salvia miltiorrhiza (Sm) have been shown to protect cells against oxidative stress. In this study we investigated the in vitro and in vivo effects of Sm on hepatic fibrosis. A cell line of rat hepatic stellate cells (HSC-T6) was stimulated with transforming growth factor-beta1 (TGF-beta1). The inhibitory effects of Sm (50-400 microg/ml) on TGF-beta1-induced alpha-smooth muscle actin (alpha-SMA) secretion and the mRNA expressions of fibrosis-related genes, including alpha-SMA, connective tissue growth factor (CTGF), and tissue inhibitor of metalloproteinase-1 (TIMP-1), were assessed. Fibrosis was induced by dimethylnitrosamine (DMN) administration in rats. DMN-treated rats were randomly assigned to 1 of 4 groups: saline, Sm (20 mg/kg), Sm (100 mg/kg), or silymarin (100 mg/kg), each given by gavage twice daily for 5 weeks starting from the onset of DMN administration. Sm (200 and 400 microg/ml) significantly inhibited TGF-beta1-stimulated alpha-SMA secretion and the mRNA expressions of alpha-SMA, CTGF, and TIMP-1 in HSC-T6 cells. Fibrosis scores of livers from DMN-treated rats with either a low (1.8 +/- 0.2) or high (1.8 +/- 0.1) dose of Sm, or silymarin (1.4 +/- 0.2) were significantly reduced in comparison with DMN-treated rats receiving saline (3.1 +/- 0.1). Hepatic collagen contents were also significantly reduced by either Sm or silymarin treatment. The mRNA expression levels of alpha-SMA, TGF-beta1, and procollagen I were all attenuated in Sm- and silymarin-treated rats. Moreover, levels of plasma aspartate transaminase activities were reduced by Sm and silymarin treatment. In conclusion, our results show that Sm exerted antifibrotic effects in both HSC-T6 cells and in rats with DMN-induced fibrosis.
Hsu
Yi-Chao
YC
Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Lin
Yun-Lian
YL
Chiu
Yung-Tsung
YT
Shiao
Ming-Shi
MS
Lee
Chang-Yin
CY
Huang
Yi-Tsau
YT
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D055513:Connective Tissue Growth Factor; D004128:Dimethylnitrosamine / Q000633:toxicity*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D008297:Male; D010936:Plant Extracts / Q000737:chemistry / Q000627:therapeutic use*; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D000199:Actins; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010936:Plant Extracts; D011347:Procollagen; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D004128:Dimethylnitrosamine