Anti-fibrotic effects of a hot-water extract from Salvia miltiorrhiza roots on liver fibrosis induced by biliary obstruction in rats.

The anti-fibrotic effects of a hot-water extract form the traditional Chinese medicinal herb Salvia miltiorrhiza (Labiatae) on liver fibrosis induced by biliary obstruction was studied in rats. Liver fibrosis was induced in male Sprague-Dawley rats by bile duct ligation and scission (BDL). After surgery, the hot-water extract of S. miltiorrhiza roots (100 mg kg(-1), p.o.) was administered daily for 28 days. The concentrations of aspartate transaminase, alanine transaminase, alkaline phosphatase, total bilirubin and total cholesterol in serum and hydroxyproline and malondialdehyde contents in liver were significantly increased in BDL rats. Treatment with the extract of S. miltiorrhiza significantly reduced (P < 0.01) the serum aspartate transaminase, alanine transaminase, alkaline phosphatase, and total cholesterol concentrations in BDL rats. The liver hydroxyproline content in BDL rats treated with extract was also reduced to 68% of that in BDL control rats (P < 0.01). The liver malondialdehyde content in BDL rats treated with the extract was also reduced to 47% of that in BDL control rats (P < 0.01). The morphological characteristics of fibrotic livers were improved in BDL rats treated with extract. Immunohistochemical examination of fibrotic liver showed that the extract of S. miltiorrhiza markedly reduced protein expression of alpha-smooth muscle cell-like actin, which indicates that hepatic stellate cell activation was inhibited during liver fibrosis development. The results indicate that the hot-water extract of S. miltiorrhiza roots inhibits fibrosis and lipid peroxidation in rats with liver fibrosis induced by biliary obstruction.

The ethanol-soluble part of a hot-water extract from Artemisia iwayomogi inhibits liver fibrosis induced by carbon tetrachloride in rats.

This study was carried out to investigate the protective effects of the hot-water extract from Artemisia iwayomogi (Compositae) on carbon tetrachloride-induced liver fibrosis in rats. Liver injury was induced by oral administration of carbon tetrachloride (1 mL kg(-1)) twice a week during 4 weeks of A. iwayomogi treatment. Extracts from A. iwayomogi were prepared and administered to rats orally (2 g kg(-1) as A. iwayomogi for 4 weeks) as follows: group 1, hot-water extract; group 2, ethanol-soluble part of hot-water extract; group 3, ethanol-insoluble part of hot-water extract; and group 4, methanol extract. In rats treated with the ethanol-soluble part of the hot-water extract, liver hydroxyproline content was reduced to 74% that of carbon tetrachloride control rats (P < 0.05). Protein expression of alpha smooth muscle cell like actin was also decreased in rats treated with the ethanol-soluble part of the hot-water extract, which indicates inhibition of hepatic stellate cell activation. Liver malondialdehyde levels were significantly lowered in rats treated with the ethanol-soluble part of hot-water extract (P < 0.05). Serum cholesterol levels in rats treated with hot-water extract, ethanol-soluble or -insoluble parts of hot-water extract or methanol extract were significantly reduced when compared with those of carbon tetrachloride control rats (P < 0.05). The ethanol-soluble part of the hot-water extract from A. iwayomogi inhibited fibrosis and lipid peroxidation in rats with liver fibrosis induced by carbon tetrachloride. Both hot-water extract (either ethanol-soluble or -insoluble) and methanol extract of A. iwayomogi also lowered serum cholesterol levels in fibrotic rats.

The increment of purine specific sodium nucleoside cotransporter mRNA in experimental fibrotic liver induced by bile duct ligation and scission.

We investigated the expression profiles of rat fibrotic liver induced by bile duct ligation and scission (BDL/S) using the 3'-directed cDNA libraries. The possibility that the 3'directed cDNA library represents the mRNA population faithfully was examined by northern blots. During the northern analysis based on fibrotic liver expression profile, we found for the first time that purine specific sodium nucleoside cotransporter (SPNT) was upregulated in BDL/S-induced fibrotic liver. To determine whether the accumulation of bile juice could affect the expression of SPNT mRNA or not, we examined the change of SPNT mRNA expression at 3, 14, 28 days after BDL/S operation. No change in SPNT expression was observed in rat liver at 3 days after surgery. In contrast, there were significant increases in SPNT expression at 14 and 28 days after surgery. We also examined whether chronic liver damage affected SPNT mRNA expression. SPNT mRNA level was significantly increased in BDL/S-induced fibrotic rat liver, whereas no significant change was obserbed in fibrotic livers chronically exposed to carbon tetrachloride or dimethylnitrosamine. From the above results, although further study might be needed, it was considered that the increment of SPNT mRNA in BDL/S liver morphological compatibility to human was remarkable.

Antifibrotic effect of Stephania tetrandra on experimental liver fibrosis induced by bile duct ligation and scission in rats.

We examined the antifibrotic effect of a methanol extract from Stephania tetrandra (ST) on experimental liver fibrosis. Liver fibrosis was induced by bile duct ligation and scission (BDL/S) in rats. In BDL/S rats, activity levels of aspartate transaminase (AST), alanine transaminse (ALT), alkaline phosphatase (ALP), concentration of total bilirubin in serum, and hydroxyproline content of the liver were significantly increased. The ST treatment (either 100 mg/kg/day or 200 mg/kg/day, p.o. for 4 weeks) in BDL/S rats reduced the serum AST, ALT and ALP activity levels significantly (p< 0.01). Similarly, when compared to the control group, the concentration of hydroxyproline in the livers of the BDL/S rats treated with 100mg or 200mg ST treated rats decreased by 40% and 33% respectively, when compared to the BDL/S control group (p<0.01). The morphological characteristics of fibrotic liver that were observed in the BDL/S control group, improved in the ST treated BDL/S group. In the fibrotic liver of BDL/S rats treated with ST, a marked reduction in the numbers of alpha smooth muscle cell actin positive stellate cells was observed. These results indicate that doses of either 100 or 200 mg/kg/day of methanol extract from S. tetrandra, had an antifibrotic effect in rats with liver fibrosis induced by bile duct ligation and scission.

Antifibrotic effect of extracellular biopolymer from submerged mycelial cultures of Cordyceps militaris on liver fibrosis induced by bile duct ligation and scission in rats.

The antifibrotic effects of hot water extract (WEC), intracellular biopolymer (IPC) and extracellular biopolymers (EPC) from mycelial liquid culture of Cordyceps militaris on liver fibrosis were studied. Liver fibrosis was induced by a bile duct ligation and scission (BDL/S) operation, duration of 4 weeks in rats. In BDL/S rats, the levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin in serum and hydroxyproline content in liver were dramatically increased. The WEC or IPC treatment (30 mg/kg/day for 4 weeks, p.o.) in BDL/S rats reduced the serum AST, ALT and ALP levels significantly (p<0.01). The EPC treatment (30 mg/kg/day for 4 weeks, p.o.) reduced the serum ALT, AST and ALP levels significantly (p<0.01). Malondialdehyde contents in liver treated with WEC, IPC or EPC were significantly reduced (p<0.05). But Liver hydroxyproline content was decreased only in EPC treated BDL/S rats to 55% that of BDL/S control rats (p<0.01). The morphological characteristics and expression of alpha smooth muscle like actin in fibrotic liver, which appeared in BDL/S control group were improved in EPC treated fibrotic liver. These results indicate that EPC (30 mg/kg/day for 4 weeks, p.o.) has an antifibrotic effect on fibrotic rats induced by BDL/S.

Antifibrotic effects of the methanol extract of Polygonum aviculare in fibrotic rats induced by bile duct ligation and scission.

The antifibrotic effect of the methanol extract from Polygonum aviculare (PA), Artemisia capillaris (AC) and an aqueous solution of biphenyl dimethyl dicarboxylate (DDB) on liver fibrosis were studied. Liver fibrosis was induced by a bile duct ligation and scission (BDL/S) operation, duration of 4 weeks in rats. In BDL/S rats, the levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin in serum and hydroxyproline content in liver were dramatically increased. The PA treatment in BDL/S rats reduced the serum AST, ALT and ALP levels significantly (p<0.01). Liver hydroxyproline content in PA treated BDL/S group was also reduced to 40% that of BDL/S control group (p<0.01). The morphological characteristics of fibrotic liver, which appeared in BDL/S control group were improved in the PA treated BDL/S group. But neither AC nor DDB treatment improved any parameters in fibrotic rats induced by BDL/S. These results indicate that PA has an antifibrotic effect on fibrotic rats induced by BDL/S.

Effect of tetrandrine on experimental hepatic fibrosis induced by bile duct ligation and scission in rats.

Tetrandrine, an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to elicit antifibrotic effects in various cell types. In the present study, the effect of tetrandrine on liver fibrosis was investigated by using bile duct ligation and scission in rats as a model of hepatic fibrosis. Treatment with tetrandrine in fibrotic rats reduced serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels to 72%, 52% and 51% that of controls at 10 mg/kg/day, respectively. Liver hydroxyproline contents in tetrandrine-treated rats with bile duct ligation and scission were also reduced to 65% of that of control rats with bile duct ligation and scission at 10 mg/kg/day. The morphological characteristics of fibrotic liver, which appeared in control bile duct ligation and scission group, were improved in tetrandrine-treated bile duct ligation and scission group. We also examined the effect of tetrandrine on cultured rat hepatic stellate cells, which plays an important role in the pathogenesis of hepatic fibrosis, activation to investigate whether it could act mainly by direct action on rat hepatic fibroblastic cells. In cultured rat hepatic stellate cells, tetrandrine reduced DNA synthesis to 57% of control hepatic stellate cells at 10 microg/ml without affecting cell viability. Smooth muscle-alpha-actin expression, the phenotypic marker of activated hepatic stellate cells, was also decreased. We conclude that tetrandrine has an antifibrotic effect on liver fibrosis in rats induced by bile duct ligation and scission, indicating that it might exert a direct effect on rat hepatic stellate cells.