Objective To optimize the therapeutic dosage of tetrandrine (Tet) in rat hepatic fibrosis model. Methods 50 Wistar ratswere divided into 5 groups at random including normal control, model control, Tet-treated model gr...Objective To optimize the therapeutic dosage of tetrandrine (Tet) in rat hepatic fibrosis model. Methods 50 Wistar ratswere divided into 5 groups at random including normal control, model control, Tet-treated model groups of 10 mg.kg-1.d-1, 5 mg.kg-1.d-1and 2.5 mg.kg-1.d-1(n=10 in each group). All rats, except for the normal controls, were injected with axenic porcine serum(0.5ml each time, twice a week) intraperitoneally for8 weeks to establish hepatic fibrosis. After the 8th week, rats of Tet-treated modelgroups were given by gavage once a day with different doses of Tet for another8 weeks. Then the liver function, serum levels of hyaluron-ic acid (HA), laminin (LM), and procollagen type III (PCIII) were tested. Collagen type I and III, pathological changes in liver tissuewere also assessed. Results Most indices of liver function including alanine minotransferase ( ALT), aspartate aminotransferase(AST), albumin (ALB), albumin /globulin ratio (A/G) and alkaline phosphatase (ALP) improved significantly in Tet-treated groupswith the exception ofγ-glutamyl transpeptidase (γ-GT) and total bilirubin (TBIL). Secondly, markedly lowered levels of HA, LMandcollagen type I, III were also detected by radioimmunology and immunohistochemistry in the 5 mg.kg-1.d-1Tet-treated model group.Moreover, pathological findings confirmed the statistically significant improvement in hepatofibrotic degree resulted from the treatment of5 mg.kg-1.d-1rather than other doses of Tet. Conclusion For experimental Wistar rats, Tet exhibited an anti-hepatofibrotic action indoses within the range of 2.5 mg.kg-1.d-1to 10 mg.kg-1.d-1, and 5 mg.kg-1.d-1may be the optimum one among all doses.展开更多
Background Pioglitazone is effective in nonalcoholic steatohepatitis （NASH）, but the mechanisms of action are not completely understood. This study was designed to investigate the effects of pioglitazone on hepatic ...Background Pioglitazone is effective in nonalcoholic steatohepatitis （NASH）, but the mechanisms of action are not completely understood. This study was designed to investigate the effects of pioglitazone on hepatic nuclear factor-kappa B （NF-KB） and cyclooxygenases-2 （COX-2） expression in NASH rats. Methods Thirty Sprague-Dawley male rats were randomly assigned to a control group （n=10）, NASH group （n=10）, and pioglitazone treatment group （n=10）. Liver tissues were processed for histology by hematoxylin ＆ eosin and Masson stained. Serum alanine aminotransferase （ALT）, cholesterol, triglyceride, fasting blood glucose （FBG）, fasting insulin （FINS） levels and biochemical parameters of antioxidant enzyme activities, tumor necrosis factor alpha （TNF-a）, prostaglandin E2 （PGE2） levels in serum and liver were measured. The mRNA and protein expression of peroxisome proliferator-activated receptor gamma （PPARy）, NF-KB and COX-2 were determined by real-time polymerase chain reaction, Western blotting and immunohistochemistry. One-way analysis of variance （ANOVA） and Wilcoxon＇s signed-rank test was used for the statistical analysis. Results There were severe steatosis, moderate inflammatory cellular infiltration and fibrosis in NASH rats. After pioglitazone treatment, steatosis, inflammation and fibrosis were significantly improved compared with the NASH group （X2=20.40, P 〈0.001; X2=20.17, P 〈0.001; X2=13.98, P=0.002）. Serum ALT, cholesterol, triglyceride, FBG, FINS levels were significantly elevated in the NASH group （P 〈0.05）. In the NASH group, total anti-oxidation competence （T-AOC）, superoxide dismutase （SOD）, catalase （CAT）, glutathione peroxidase （GSH-PX） and malondialdehyde （MDA） levels in serum and liver were conspicuous disordered than those parameters in the control group. Meanwhile, TNF-a and PGE2 levels in serum and liver were significantly increased compared with the control group. Immunohistochemistry showed NF-KB and COX-2 expression in liver was significantly elevated. However, PPARy level was decreased in the NASH group. Real-time PCR and Western blotting revealed mRNA and protein expression of COX-2 were increased in the NASH group compared with the control group （0.57±0.08 vs. 2.83±0.24; 0.38±0.03 vs. 1.00±0.03, P 〈0.001 and P=-0.004, respectively）. After pioglitazone intervention, all of those parameters markedly improved （P 〈0.05 or P 〈0.01）. Conclusion Down-regulating hepatic NF-KB and COX-2 expression, at least in part, is one of the possible therapeutic mechanisms of pioglitazone in NASH rats.展开更多
文摘Objective To optimize the therapeutic dosage of tetrandrine (Tet) in rat hepatic fibrosis model. Methods 50 Wistar ratswere divided into 5 groups at random including normal control, model control, Tet-treated model groups of 10 mg.kg-1.d-1, 5 mg.kg-1.d-1and 2.5 mg.kg-1.d-1(n=10 in each group). All rats, except for the normal controls, were injected with axenic porcine serum(0.5ml each time, twice a week) intraperitoneally for8 weeks to establish hepatic fibrosis. After the 8th week, rats of Tet-treated modelgroups were given by gavage once a day with different doses of Tet for another8 weeks. Then the liver function, serum levels of hyaluron-ic acid (HA), laminin (LM), and procollagen type III (PCIII) were tested. Collagen type I and III, pathological changes in liver tissuewere also assessed. Results Most indices of liver function including alanine minotransferase ( ALT), aspartate aminotransferase(AST), albumin (ALB), albumin /globulin ratio (A/G) and alkaline phosphatase (ALP) improved significantly in Tet-treated groupswith the exception ofγ-glutamyl transpeptidase (γ-GT) and total bilirubin (TBIL). Secondly, markedly lowered levels of HA, LMandcollagen type I, III were also detected by radioimmunology and immunohistochemistry in the 5 mg.kg-1.d-1Tet-treated model group.Moreover, pathological findings confirmed the statistically significant improvement in hepatofibrotic degree resulted from the treatment of5 mg.kg-1.d-1rather than other doses of Tet. Conclusion For experimental Wistar rats, Tet exhibited an anti-hepatofibrotic action indoses within the range of 2.5 mg.kg-1.d-1to 10 mg.kg-1.d-1, and 5 mg.kg-1.d-1may be the optimum one among all doses.
基金This study was supported by-a gran-t of the Natural Science Foundation of Shanghai （No. 05ZR14156）. The authors have no conflict of interest.
文摘Background Pioglitazone is effective in nonalcoholic steatohepatitis （NASH）, but the mechanisms of action are not completely understood. This study was designed to investigate the effects of pioglitazone on hepatic nuclear factor-kappa B （NF-KB） and cyclooxygenases-2 （COX-2） expression in NASH rats. Methods Thirty Sprague-Dawley male rats were randomly assigned to a control group （n=10）, NASH group （n=10）, and pioglitazone treatment group （n=10）. Liver tissues were processed for histology by hematoxylin ＆ eosin and Masson stained. Serum alanine aminotransferase （ALT）, cholesterol, triglyceride, fasting blood glucose （FBG）, fasting insulin （FINS） levels and biochemical parameters of antioxidant enzyme activities, tumor necrosis factor alpha （TNF-a）, prostaglandin E2 （PGE2） levels in serum and liver were measured. The mRNA and protein expression of peroxisome proliferator-activated receptor gamma （PPARy）, NF-KB and COX-2 were determined by real-time polymerase chain reaction, Western blotting and immunohistochemistry. One-way analysis of variance （ANOVA） and Wilcoxon＇s signed-rank test was used for the statistical analysis. Results There were severe steatosis, moderate inflammatory cellular infiltration and fibrosis in NASH rats. After pioglitazone treatment, steatosis, inflammation and fibrosis were significantly improved compared with the NASH group （X2=20.40, P 〈0.001; X2=20.17, P 〈0.001; X2=13.98, P=0.002）. Serum ALT, cholesterol, triglyceride, FBG, FINS levels were significantly elevated in the NASH group （P 〈0.05）. In the NASH group, total anti-oxidation competence （T-AOC）, superoxide dismutase （SOD）, catalase （CAT）, glutathione peroxidase （GSH-PX） and malondialdehyde （MDA） levels in serum and liver were conspicuous disordered than those parameters in the control group. Meanwhile, TNF-a and PGE2 levels in serum and liver were significantly increased compared with the control group. Immunohistochemistry showed NF-KB and COX-2 expression in liver was significantly elevated. However, PPARy level was decreased in the NASH group. Real-time PCR and Western blotting revealed mRNA and protein expression of COX-2 were increased in the NASH group compared with the control group （0.57±0.08 vs. 2.83±0.24; 0.38±0.03 vs. 1.00±0.03, P 〈0.001 and P=-0.004, respectively）. After pioglitazone intervention, all of those parameters markedly improved （P 〈0.05 or P 〈0.01）. Conclusion Down-regulating hepatic NF-KB and COX-2 expression, at least in part, is one of the possible therapeutic mechanisms of pioglitazone in NASH rats.
