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

Ruehl, Martin; Erben, Ulrike; Kim, Kiyoung; Freise, Christian; Dagdelen, Tarkan; Eisele, Silke; Trowitzsch-Kienast, Wolfram; Zeitz, Martin; Jia, Jidong; Stickel, Felix; Somasundaram, Rajan (2009). Extracts of Lindera obtusiloba induce antifibrotic effects in hepatic stellate cells via suppression of a TGF-beta-mediated profibrotic gene expression pattern. Journal of nutritional biochemistry, 20(8), pp. 597-606. Stoneham, Mass.: Butterworths 10.1016/j.jnutbio.2008.06.003

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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 mug/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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Clinical Pharmacology and Visceral Research [discontinued] 04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
UniBE Contributor:	Eisele, Silke, Stickel, Felix
ISSN:	0955-2863
ISBN:	18824344
Publisher:	Butterworths
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:05
Last Modified:	05 Dec 2022 14:20
Publisher DOI:	10.1016/j.jnutbio.2008.06.003
PubMed ID:	18824344
Web of Science ID:	000268518700005
URI:	https://boris.unibe.ch/id/eprint/28349 (FactScience: 120247)