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Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1

Department of Gastroenterology and Hepatology, Friedrich-Alexander University, Erlangen-Nuernberg, Erlangen, Germany.
Journal of Hepatology (Impact Factor: 10.4). 09/2001; 35(3):392-8.
Source: PubMed

ABSTRACT Silymarin reduces hepatic collagen accumulation by 35% in rats with secondary biliary cirrhosis. The aim of the present study was to explore its antifibrotic mechanism.
Thirty female adult Wistar rats were allocated to (1) bile duct occlusion, (2) bile duct occlusion and oral silymarin at 50 mg/kg per day, and (3) sham operation and oral silymarin at 50 mg/kg per day. Steady-state mRNA levels for procollagen alpha1(I), tissue inhibitor of metalloproteinases-1 (TIMP-1), and transforming growth factor (TGF) beta1 were determined by multi-probe ribonuclease protection assay.
After 6 weeks of bile duct occlusion, liver collagen content was increased 12-fold, when compared with the sham-operated controls. These animals displayed 17-, 6.5- and 16-fold higher transcript levels for procollagen alpha1(I), TIMP-1 and TGFbeta1 (P < 0.01). Silymarin downregulated elevated procollagen alpha1(I), TIMP-1 and TGFbeta1 mRNA levels by 40-60% (P < 0.01). These lowered hepatic profibrogenic transcript levels correlated with decreased serum levels of the aminoterminal propeptide of procollagen type III.
Silymarin suppresses expression of profibrogenic procollagen alpha1(I) and TIMP-1 most likely via downregulation of TGFbeta1 mRNA in rats with biliary fibrosis. The serum procollagen type III propeptide level mirrors profibrogenic mRNA expression in the liver.

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    • "Liver transplantation is currently the only therapeutic option for liver cirrhosis or tumor, but such method is risky and painful for the patient. Antifibrotic agents, such as silymarin, are widely accepted for the treatment of liver diseases and can downregulate TIMP-1 and TGF-␤1 expression, as well as suppress collagen synthesis (Jia et al., 2001); however, the treatment effect of silymarin is not outstanding. Therefore, the search for more effective antifibrotic agents with fewer side effects remains an active area of research. "
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    • "The primary active constituent of milk thistle is silymarin that is composed of four isomers: silybin, isosilybin, silychristin, and silydianin (El-Kamary et al. 2009). Silymarin medical properties are associated with antioxidant, anti-inflammatory, anti-carcinogenic (Kaur and Agarwal 2007; Ramasamy and Agarwal 2008), and anti-fibrotic properties (Jia et al. 2001) as well as with increased cellular-reduced glutathione (GSH) content, cellular protein biosynthesis potency, stimulation of regeneration ability, and increased stability of the cellular membrane in liver (Flora et al. 1998; Basiglio et al. 2009). However, there is a lack of reports on the side effect of silymarin in laboratory models (S ˇ eršeň et al. 2006) such as mice, rat, rabbit, and dog, and there is no information about oral administration of silymarin in fishes. "
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    • "Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s in vitro and is known to be involved in hepatic tissue repair [15] [16]. The fibrotic effect of TGF-β1 in lung fibroblasts results in an increase in the secretion and deposition of total ECM and collagens because of a decrease in MMP-1 secretion and an increase in TIMP-1 expression [14]. "
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