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Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis.

Li JP, Gao Y, Chu SF, Zhang Z, Xia CY, Mou Z, Song XY, He WB, Guo XF, Chen NH - Acta Pharmacol. Sin. (2014)

Bottom Line: Rg1 significantly increased the activities of antioxidant enzymes (SOD, GSH-Px and CAT) and reduced MDA levels in liver tissues.Furthermore, Rg1 significantly increased the expression and nuclear translocation of Nrf2 that regulated the expression of many antioxidant enzymes.Knockdown of Nrf2 gene diminished these actions of Rg1 in CCl4-treated HSCs in vitro.

View Article: PubMed Central - PubMed

Affiliation: State Key of Laboratory Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

ABSTRACT

Aim: To investigate the anti-fibrosis effects of ginsenoside Rg1 on alcohol- and CCl4-induced hepatic fibrosis in rats and to explore the mechanisms of the effects.

Methods: Rats were given 6% alcohol in water and injected with CCl4 (2 mL/kg, sc) twice a week for 8 weeks. Rg1 (10, 20 and 40 mg/kg per day, po) was administered in the last 2 weeks. Hepatic fibrosis was determined by measuring serum biochemical parameters, HE staining, Masson's trichromic staining, and hydroxyproline and α-SMA immunohistochemical staining of liver tissues. The activities of antioxidant enzymes, lipid peroxidation, and Nrf2 signaling pathway-related proteins (Nrf2, Ho-1 and Nqo1) in liver tissues were analyzed. Cultured hepatic stellate cells (HSCs) of rats were prepared for in vitro studies.

Results: In the alcohol- and CCl4-treated rats, Rg1 administration dose-dependently suppressed the marked increases of serum ALT, AST, LDH and ALP levels, inhibited liver inflammation and HSC activation and reduced liver fibrosis scores. Rg1 significantly increased the activities of antioxidant enzymes (SOD, GSH-Px and CAT) and reduced MDA levels in liver tissues. Furthermore, Rg1 significantly increased the expression and nuclear translocation of Nrf2 that regulated the expression of many antioxidant enzymes. Treatment of the cultured HSCs with Rg1 (1 μmol/L) induced Nrf2 translocation, and suppressed CCl4-induced cell proliferation, reversed CCl4- induced changes in MDA, GPX, PCIII and HA contents in the supernatant fluid and α-SMA expression in the cells. Knockdown of Nrf2 gene diminished these actions of Rg1 in CCl4-treated HSCs in vitro.

Conclusion: Rg1 exerts protective effects in a rat model of alcohol- and CCl4-induced hepatic fibrosis via promoting the nuclear translocation of Nrf2 and expression of antioxidant enzymes.

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Effects of Rg1 on CCl4-induced hepatic fibrogenesis. Hepatic fibrosis was detected by Masson's trichromic staining. Representative photomicrographs of liver histology from each group are shown as follows: Control (A), CCl4 alone (B), CCl4+Bicyclol (C), CCl4+Rg1-10 mg/kg (D), CCl4+Rg1-20 mg/kg (E) and CCl4+Rg1-40 mg/kg (F). Original magnification: ×40. Scale bar, 100 μm. The fibrosis score (G) was evaluated in ten randomly selected fields from each slide at a magnification of ×200. (H) The content of hydroxyproline in liver tissues. All data were expressed as means±SD of six animals. cP<0.01 vs control. fP<0.01 vs CCl4 alone.
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fig2: Effects of Rg1 on CCl4-induced hepatic fibrogenesis. Hepatic fibrosis was detected by Masson's trichromic staining. Representative photomicrographs of liver histology from each group are shown as follows: Control (A), CCl4 alone (B), CCl4+Bicyclol (C), CCl4+Rg1-10 mg/kg (D), CCl4+Rg1-20 mg/kg (E) and CCl4+Rg1-40 mg/kg (F). Original magnification: ×40. Scale bar, 100 μm. The fibrosis score (G) was evaluated in ten randomly selected fields from each slide at a magnification of ×200. (H) The content of hydroxyproline in liver tissues. All data were expressed as means±SD of six animals. cP<0.01 vs control. fP<0.01 vs CCl4 alone.

Mentions: Hepatic fibrosis was evaluated by Masson's trichrome staining. According to microscopic examinations, obvious bridging fibrosis was observed in the livers of untreated rats, masses of collagen deposition surrounded the portal area, and the divided liver fibrosis formation staggered and formed a large number of false lobules (Figure 2B). Rg1 significantly alleviated the extent of hepatic fibrosis (Figure 2D–2F). In the Rg1 20 mg/kg group (Figure 2E), liver fibrosis was mildly diminished, and merely disappeared in the 40 mg/kg group (Figure 2F). Further analysis showed that (Figure 2G) the fibrosis score was 0.30±0.11 in the control group, and the score was markedly increased (2.88±0.43, P<0.01) in the CCl4 group. Rats that were treated with Rg1 (20 and 40 mg/kg) had significantly decreased fibrosis scores compared with the model group (2.17±0.31 and 2.00±0.30; P<0.05 and P<0.01. Figure 2G).


Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis.

Li JP, Gao Y, Chu SF, Zhang Z, Xia CY, Mou Z, Song XY, He WB, Guo XF, Chen NH - Acta Pharmacol. Sin. (2014)

Effects of Rg1 on CCl4-induced hepatic fibrogenesis. Hepatic fibrosis was detected by Masson's trichromic staining. Representative photomicrographs of liver histology from each group are shown as follows: Control (A), CCl4 alone (B), CCl4+Bicyclol (C), CCl4+Rg1-10 mg/kg (D), CCl4+Rg1-20 mg/kg (E) and CCl4+Rg1-40 mg/kg (F). Original magnification: ×40. Scale bar, 100 μm. The fibrosis score (G) was evaluated in ten randomly selected fields from each slide at a magnification of ×200. (H) The content of hydroxyproline in liver tissues. All data were expressed as means±SD of six animals. cP<0.01 vs control. fP<0.01 vs CCl4 alone.
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fig2: Effects of Rg1 on CCl4-induced hepatic fibrogenesis. Hepatic fibrosis was detected by Masson's trichromic staining. Representative photomicrographs of liver histology from each group are shown as follows: Control (A), CCl4 alone (B), CCl4+Bicyclol (C), CCl4+Rg1-10 mg/kg (D), CCl4+Rg1-20 mg/kg (E) and CCl4+Rg1-40 mg/kg (F). Original magnification: ×40. Scale bar, 100 μm. The fibrosis score (G) was evaluated in ten randomly selected fields from each slide at a magnification of ×200. (H) The content of hydroxyproline in liver tissues. All data were expressed as means±SD of six animals. cP<0.01 vs control. fP<0.01 vs CCl4 alone.
Mentions: Hepatic fibrosis was evaluated by Masson's trichrome staining. According to microscopic examinations, obvious bridging fibrosis was observed in the livers of untreated rats, masses of collagen deposition surrounded the portal area, and the divided liver fibrosis formation staggered and formed a large number of false lobules (Figure 2B). Rg1 significantly alleviated the extent of hepatic fibrosis (Figure 2D–2F). In the Rg1 20 mg/kg group (Figure 2E), liver fibrosis was mildly diminished, and merely disappeared in the 40 mg/kg group (Figure 2F). Further analysis showed that (Figure 2G) the fibrosis score was 0.30±0.11 in the control group, and the score was markedly increased (2.88±0.43, P<0.01) in the CCl4 group. Rats that were treated with Rg1 (20 and 40 mg/kg) had significantly decreased fibrosis scores compared with the model group (2.17±0.31 and 2.00±0.30; P<0.05 and P<0.01. Figure 2G).

Bottom Line: Rg1 significantly increased the activities of antioxidant enzymes (SOD, GSH-Px and CAT) and reduced MDA levels in liver tissues.Furthermore, Rg1 significantly increased the expression and nuclear translocation of Nrf2 that regulated the expression of many antioxidant enzymes.Knockdown of Nrf2 gene diminished these actions of Rg1 in CCl4-treated HSCs in vitro.

View Article: PubMed Central - PubMed

Affiliation: State Key of Laboratory Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

ABSTRACT

Aim: To investigate the anti-fibrosis effects of ginsenoside Rg1 on alcohol- and CCl4-induced hepatic fibrosis in rats and to explore the mechanisms of the effects.

Methods: Rats were given 6% alcohol in water and injected with CCl4 (2 mL/kg, sc) twice a week for 8 weeks. Rg1 (10, 20 and 40 mg/kg per day, po) was administered in the last 2 weeks. Hepatic fibrosis was determined by measuring serum biochemical parameters, HE staining, Masson's trichromic staining, and hydroxyproline and α-SMA immunohistochemical staining of liver tissues. The activities of antioxidant enzymes, lipid peroxidation, and Nrf2 signaling pathway-related proteins (Nrf2, Ho-1 and Nqo1) in liver tissues were analyzed. Cultured hepatic stellate cells (HSCs) of rats were prepared for in vitro studies.

Results: In the alcohol- and CCl4-treated rats, Rg1 administration dose-dependently suppressed the marked increases of serum ALT, AST, LDH and ALP levels, inhibited liver inflammation and HSC activation and reduced liver fibrosis scores. Rg1 significantly increased the activities of antioxidant enzymes (SOD, GSH-Px and CAT) and reduced MDA levels in liver tissues. Furthermore, Rg1 significantly increased the expression and nuclear translocation of Nrf2 that regulated the expression of many antioxidant enzymes. Treatment of the cultured HSCs with Rg1 (1 μmol/L) induced Nrf2 translocation, and suppressed CCl4-induced cell proliferation, reversed CCl4- induced changes in MDA, GPX, PCIII and HA contents in the supernatant fluid and α-SMA expression in the cells. Knockdown of Nrf2 gene diminished these actions of Rg1 in CCl4-treated HSCs in vitro.

Conclusion: Rg1 exerts protective effects in a rat model of alcohol- and CCl4-induced hepatic fibrosis via promoting the nuclear translocation of Nrf2 and expression of antioxidant enzymes.

Show MeSH
Related in: MedlinePlus