Anti-fibrotic effects of tetrandrine on bile-duct ligated rats

Abstract

Tetrandrine (Tet) (C38H42O8N2; molecular weight, 622), an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to elicit anti-inflammatory and anti-fibrotic effects in pulmonary diseases, but the mechanism of action has yet to be investigated. In this study, we tested whether Tet exerts anti-fibrotic effects on rat hepatic fibrosis through anti-NFkappaB pathways. After bile-duct ligation, rats were given Tet (1 or 5 mg/kg) or silymarin (50 mg/kg, as a positive control) by gavage twice daily for 3 weeks. Liver sections were taken for Sirius red quantitative scoring, immunofluorescence double staining of alpha-smooth muscle actin (alpha-SMA) and NFkappaB, and for quantitative determinations of the mRNA expression levels of TGF-beta1, alpha-SMA, collagen 1alpha2, inducible nitric oxide synthase (iNOS), intercellular adhesion molecule 1 (ICAM-1), metallothionein, vascular endothelial growth factor (VEGF), and VEGF type II receptor (VEGFR2) genes. The results showed that both Tet and silymarin treatment significantly reduced the fibrosis scores and hepatic collagen content of BDL rats, compared with no treatment. Both Tet and silymarin treatments decreased the number of alpha-SMA- and NFkappaB-positive cells in fibrotic livers. Moreover, Tet and silymarin treatments attenuated the mRNA expression levels of TGF-beta1,alpha-SMA, collagen 1alpha2, iNOS, ICAM-1, VEGF, and VEGFR2 genes, and induced the mRNA expression of the metallothionein gene. This study suggests that the anti-fibrotic effects of Tet were related to the reduction of fibrosis-related gene transcription, the attenuation of NFkappaB-activated pathways, and the induction of metallothionein gene transcription in the livers of BDL rats.

Protective effects of silymarin on fumonisin B1-induced hepatotoxicity in mice

“…This beneficial effect involves the up-regulated expression of antioxidant/anti-apoptotic cytoprotective genes similar to that of the silymarin used in this study [25]. Furthermore, silymarin treatment was found to diminish VEGF mRNA levels in the fibrotic livers of bile duct-ligated rats [12]. The anti-angiogenic effect of silymarin is associated with increased VEGF receptor gene expression (Flt-1) [29].…”

Review of experimental models for inducing hepatic cirrhosis by bile duct ligation and carbon tetrachloride injection

“…By 8 weeks, a micronodular cirrhosis takes place 31 . It has been used mainly by intraperitoneal injection 12 or oral administration 20 , the dosage 0,2 to 5ml/kg and LC is achieved between 36 hours to 18 weeks 15,20,11,24 .…”

The Effect of Antifibrotic Drugs in Rat Precision-Cut Fibrotic Liver Slices

“…Treatment of BDL rats with tetrandrine directly after surgery, reduced the number of αSma positive cells [37], [38], Sirius red staining [37] hydroxyproline content [38] and the gene expression of αSma and Col1A2 [37]. However, in the fPCLS model, tetrandrine was added when the slices were already fibrotic, which might explain the fact that Sirius red was not reduced after tetrandrine treatment, as it can be assumed that the formation of fibrillar collagen occurs after the synthesis of collagen.…”