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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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Related in: MedlinePlus

Effects of Rg1 on the hepatic CYP2E1 mRNA levels and ADH activity in rats with ethanol exposure. Rats were treated with 6% (v/v) alcohol water for 8 weeks, and Rg1 and Bicyclol were administrated at the last two weeks (once a day). (A) The ethanol intake was record during the modeling period. (B) CYP2E1 mRNA levels were quantified with GAPDH as an internal control. Quantitative analysis was taken three independent qPCR analyses. (C) ADH activity in rat liver with ethanol exposure. n=6. Data are presented as mean±SD.
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fig4: Effects of Rg1 on the hepatic CYP2E1 mRNA levels and ADH activity in rats with ethanol exposure. Rats were treated with 6% (v/v) alcohol water for 8 weeks, and Rg1 and Bicyclol were administrated at the last two weeks (once a day). (A) The ethanol intake was record during the modeling period. (B) CYP2E1 mRNA levels were quantified with GAPDH as an internal control. Quantitative analysis was taken three independent qPCR analyses. (C) ADH activity in rat liver with ethanol exposure. n=6. Data are presented as mean±SD.

Mentions: CYP2E1 is the most important enzyme of the liver cytochrome P450 system related to alcohol metabolism. Activity of ADH directly reflects the ability to eliminate alcohol. In the present study, we measured the CYP2E1 mRNA level and ADH activity in liver tissues. The average daily ethanol intake of the rats was 3.8–5.6 g/kg during the modeling period. There was no significant difference among the ethanol water groups (Figure 4A). Compared with the control group, the level of CYP2E1 mRNA in the alcohol-only group and Rg1 groups showed no significant difference (Figure 4B). There was also no distinct difference observed on the ADH activity among these groups (Figure 4C).


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 the hepatic CYP2E1 mRNA levels and ADH activity in rats with ethanol exposure. Rats were treated with 6% (v/v) alcohol water for 8 weeks, and Rg1 and Bicyclol were administrated at the last two weeks (once a day). (A) The ethanol intake was record during the modeling period. (B) CYP2E1 mRNA levels were quantified with GAPDH as an internal control. Quantitative analysis was taken three independent qPCR analyses. (C) ADH activity in rat liver with ethanol exposure. n=6. Data are presented as mean±SD.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4125711&req=5

fig4: Effects of Rg1 on the hepatic CYP2E1 mRNA levels and ADH activity in rats with ethanol exposure. Rats were treated with 6% (v/v) alcohol water for 8 weeks, and Rg1 and Bicyclol were administrated at the last two weeks (once a day). (A) The ethanol intake was record during the modeling period. (B) CYP2E1 mRNA levels were quantified with GAPDH as an internal control. Quantitative analysis was taken three independent qPCR analyses. (C) ADH activity in rat liver with ethanol exposure. n=6. Data are presented as mean±SD.
Mentions: CYP2E1 is the most important enzyme of the liver cytochrome P450 system related to alcohol metabolism. Activity of ADH directly reflects the ability to eliminate alcohol. In the present study, we measured the CYP2E1 mRNA level and ADH activity in liver tissues. The average daily ethanol intake of the rats was 3.8–5.6 g/kg during the modeling period. There was no significant difference among the ethanol water groups (Figure 4A). Compared with the control group, the level of CYP2E1 mRNA in the alcohol-only group and Rg1 groups showed no significant difference (Figure 4B). There was also no distinct difference observed on the ADH activity among these groups (Figure 4C).

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