Extracts of Lindera obtusiloba induce antifibrotic effects in hepatic stellate cells via suppression of a TGF-β-mediated profibrotic gene expression pattern

被引:29
作者
Ruehl, Martin [1 ]
Erben, Ulrike [1 ]
Kim, Kiyoung [2 ]
Freise, Christian [1 ]
Dagdelen, Tarkan [1 ]
Eisele, Silke [1 ,5 ]
Trowitzsch-Kienast, Wolfram [3 ]
Zeitz, Martin [1 ]
Jia, Jidong [4 ]
Stickel, Felix [5 ]
Somasundaram, Rajan [1 ]
机构
[1] Charite Campus Benjamin Franklin, Dept Gastroenterol, D-12200 Berlin, Germany
[2] Wonkwang Univ, Human Environm Sci Coll, Fac Beauty Design, Iksan 570749, South Korea
[3] Univ Appl Sci, Dept Math Phys & Chem, D-13353 Berlin, Germany
[4] Capital Med Univ, Beijing Friendship Hosp, Liver Res Ctr, Beijing 100050, Peoples R China
[5] Univ Bern, Dept Clin Pharmacol, CH-3010 Bern, Switzerland
关键词
Plant extracts; L; obtusiloba; Hepatic stellate cells; Liver fibrosis; Oxidative stress; SHO-SAIKO-TO; PREVENTS LIVER FIBROSIS; ENZYME-ALTERED LESIONS; ACID-DEFINED DIET; HERBAL MEDICINE; MATRIX METALLOPROTEINASES; RAT; TJ-9; CIRRHOSIS; APOPTOSIS;
D O I
10.1016/j.jnutbio.2008.06.003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Liver fibrosis is characterized by high expression of the key profibrogenic cytokine transforming growth factor (TGF)-beta and the natural tissue inhibitor of metalloproteinases (TIMP)-1, leading to substantial accumulation of extracellular matrix. Liver fibrosis originates from various chronic liver diseases, such as chronic viral hepatitis that, to date, cannot be treated sufficiently. Thus, novel therapeutics, for example, those derived from Oriental medicine, have gained growing attention. In Korea, extracts prepared from Lindera obtusiloba are used for centuries for treatment of inflammation, improvement of blood circulation and prevention of liver damage, but experimental evidence of their efficacy is lacking. We studied direct antifibrotic effects in activated hepatic stellate cells (HSCs), the main target cell in the fibrotic liver. L. obtusiloba extract (135 mu g/ml) reduced the de novo DNA synthesis of activated rat and human HSCs by about 90%, which was not accompanied by cytotoxicity of HSC, primary hepatocytes and HepG2 cells, pointing to induction of cellular quiescence. As determined by quantitative polymerase chain reaction, simultaneous treatment of HSCs with TGF-beta and L. obtusiloba extract resulted in reduction of TIMP-1 expression to baseline level, disruption of the autocrine loop of TGF-beta autoinduction and increased expression of fibrolytic matrix metalloproteinase (MMP)-3. In addition, L. obtusiloba reduced gelatinolytic activity of HSC by interfering with profibrogenic MMP-2 activity. Since L. obtusiloba extract prevented intracellular oxidative stress experimentally induced by tert-butylhydroperoxide, we concluded that the direct antifibrotic effect of L. obtusiloba extract might be mediated by antioxidant activity. Thus, L. obtusiloba, traditionally used in Oriental medicine, may complement treatment of chronic liver disease. (C) 2009 Elsevier Inc. All fights reserved.
引用
收藏
页码:597 / 606
页数:10
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