Alcoholic liver disease(ALD) and hepatitis C virus(HCV) infection represent, either alone or in combination, more than two thirds of all patients with liver disease in the Western world.This review discusses the epide...Alcoholic liver disease(ALD) and hepatitis C virus(HCV) infection represent, either alone or in combination, more than two thirds of all patients with liver disease in the Western world.This review discusses the epidemiology and combined impact of ALD and HCV on the progres sion of liver disease.ALD and HCV affect the progres sion of liver disease to liver cirrhosis and hepatocellular carcinoma(HCC) in a synergistic manner.Thus, the risk for HCC increases f ive times with a daily alcohol con sumption of 80 g;in the presence of HCV it is increased 20fold, and a combination of both risk factors leads to a more than 100fold risk for HCC development.Alcohol consumption also decreases the response to interferon treatment which is probably due to a lack of compliance than a direct effect on HCV replication.Several molecu lar mechanisms are discussed that could explain the synergistic interaction of alcohol and HCV on disease progression.They include modulation of the immune response and apoptosis, increased oxidative stress via induction of CYP2E1 and the hepatic accumulation of iron.Thus, both HCV and alcohol independently cause hepatic iron accumulation in > 50% of patients probably due to suppression of the liversecreted systemic iron hormone hepcidin.A better understanding of hepcidin regulation could help in developing novel therapeutic approaches to treat the chronic disease in the future.For now, it can be generally concluded that HCVinfect ed patients should abstain from alcohol and alcoholicsshould be encouraged to participate in detoxification programs.展开更多
Alcohol-induced fatty liver (steatosis) was believed to result from excessive generation of reducing equivalents from ethanol metabolism, thereby enhancing fat accumulation. Recent findings have revealed a more comple...Alcohol-induced fatty liver (steatosis) was believed to result from excessive generation of reducing equivalents from ethanol metabolism, thereby enhancing fat accumulation. Recent findings have revealed a more complex picture in which ethanol oxidation is still required, but specific transcription as well as humoral factors also have important roles. Transcription factors involved include the sterol regulatory element binding protein 1 (SREBP-1) which is activated to induce genes that regulate lipid biosynthesis. Conversely, ethanol consumption causes a general down-regulation of lipid (fatty acid) oxidation, a reflection of inactivation of the peroxisome proliferator- activated receptor-alpha (PPAR-α) that regulates genes involved in fatty acid oxidation. A third transcription factor is the early growth response-1 (Egr-1), which is strongly induced prior to the onset of steatosis. The activities of all these factors are governed by that of the principal regulatory enzyme, AMP kinase. Important humoral factors, including adiponectin, and tumor necrosis factor-α (TNF-α), also regulate alcohol-induced steatosis. Their levels are affected by alcohol consumption and by each other. This review will summarize the actions of these proteins in ethanol-elicited fatty liver. Because steatosis is now regarded as a significant risk factor for advanced liver pathology, an understanding of the molecular mechanisms in its etiology is essential for development of effective therapies.展开更多
AIM: To investigate the protective effects of Astragalus membranaceus(Am) against hapten-induced colitis in male Sprague-Dawley rats as well as its underlying mechanism.METHODS: Experimental colitis was induced in rat...AIM: To investigate the protective effects of Astragalus membranaceus(Am) against hapten-induced colitis in male Sprague-Dawley rats as well as its underlying mechanism.METHODS: Experimental colitis was induced in rats by enema administration of 2,4-dinitrobenzene sulfonic acid (DNBS). Rats were either pretreated with Am extract (2 or 4 g/kg, p.o. once daily) starting from 10 d before DNBS enema, or received Am post-treatment (2 or 4 g/kg, p.o.twice daily) on the three consecutive days following DNBS administration. Colonic lesion area and histological damage were determined, while the activities of myeloperoxidase (MPO) and xanthine oxidase, as well as reduced glutathione (GSH) content were measured in the excised colonic tissues. Besides, protein expression of inducible nitrite oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1) and P-selectin was also detected by Western blot analysis.RESULTS: Our findings had shown that both macroscopic lesion area and histological colonic damage induced by DNBS were significantly reduced by both Am pre- and post-treatments. These were accompanied by attenuation of the elevated colonic MPO activity and downregulation of the iNOS, P-selectin, and ICAM-1 protein expression.Besides, deprivation of colonic GSH level under colitis condition was also preserved.CONCLUSION: These results demonstrate that Am possesses both preventive and therapeutic potential in experimental colitis. The anti-inflammatory actions involve anti-oxidation along with inhibition of adhesion molecule synthesis in the colonic tissues.展开更多
Hepatitis C virus(HCV) replication is associated with the endoplasmic reticulum, where the virus can induce cellular stress. Oxidative cell damage plays an important role in HCV physiopathology. Oxidative stress is tr...Hepatitis C virus(HCV) replication is associated with the endoplasmic reticulum, where the virus can induce cellular stress. Oxidative cell damage plays an important role in HCV physiopathology. Oxidative stress is triggered when the concentration of oxygen species in the extracellular or intracellular environment exceeds antioxidant defenses. Cells are protected and modulate oxidative stress through the interplay of intracellular antioxidant agents, mainly glutathione system(GSH) and thioredoxin; and antioxidant enzyme systems such as superoxide dismutase, catalase, GSH peroxidase, and heme oxygenase-1. Also, the use of natural and synthetic antioxidants(vitamin C and E, N-acetylcysteine, glycyrrhizin, polyenylphosphatidyl choline, mitoquinone, quercetin, S-adenosylmethionine and silymarin) has already shown promising results as co-adjuvants in HCV therapy. Despite all the available information, it is not known how different agents with antiviral activity can interfere with the modulation of the cell redox state induced by HCV and decrease viral replication. This review describes an evidence-based consensus on molecular mechanisms involved in HCV replication and their relationship with cell damage induced by oxidative stress generated by the virus itself and cell antiviral machinery. It also describes some molecules that modify the levels of oxidative stress in HCV-infected cells.展开更多
Oxidative stress is becoming recognized as a key factor in the progression of chronic liver disease(CLD) and hepatocarcinogenesis. The metabolically important liver is a major reservoir of mitochondria that serve as s...Oxidative stress is becoming recognized as a key factor in the progression of chronic liver disease(CLD) and hepatocarcinogenesis. The metabolically important liver is a major reservoir of mitochondria that serve as sources of reactive oxygen species, which are apparently responsible for the initiation of necroinflammation. As a result, CLD could be a major inducer of oxidative stress. Chronic hepatitis C is a powerful generator of oxidative stress, causing a high rate of hepatocarcinogenesis among patients with cirrhosis. Non-alcoholic steatohepatitis is also associated with oxidative stress although its hepatocarcinogenic potential is lower than that of chronic hepatitis C. Analyses of serum markers and histological findings have shown that hepatocellular carcinoma correlates with oxidative stress and experimental data indicate that oxidative stress increases the likelihood of developing hepatocarcinogenesis. However, the results of antioxidant therapy have not been favorable. Physiological oxidative stress is a necessary biological response, and thus adequate control of oxidative stress and a balance between oxidative and anti-oxidative responses is important. Several agents including metformin and L-carnitine can reportedly control mechanistic oxidative stress. This study reviews the importance of oxidative stress in hepatocarcinogenesis and of control strategies for the optimal survival of patients with CLD and hepatocellular carcinoma.展开更多
AIM： To investigate the effect of quercetin （3,3,4,5, 7-pentahydroxy flavone）, a major flavonoid in human diet, on hyper-proliferation of gastric mucosal cells in rats treated with chronic oral ethanol. METHODS： F...AIM： To investigate the effect of quercetin （3,3,4,5, 7-pentahydroxy flavone）, a major flavonoid in human diet, on hyper-proliferation of gastric mucosal cells in rats treated with chronic oral ethanol. METHODS： Forty male Sprague-Dawley rats, weighing 200-250 g, were randomly divided into control group （tap wateradlibitum）, ethanol treatment group （6 mL/L ethanol）, quercetin treatment group （intragastric gavage with 100 mg/kg of quercetin per day）, and ethanol plus quercetin treatment group （quercetin and 6 mL/L ethanol）. Expression levels of proliferating cell nuclear antigen （PCNA）and Cyclin D1 were detected by Western blot to assay gastric mucosal cell proliferation in rats. To demonstrate the influence of quercetin on the production of extra-cellular reactive oxygen species/ nitrogen species （ROS/RNS） in rats, changes in levels of thiobarbituric acid reactive substance （TBARS）, protein carbonyl, nitrite and nitrate （NOx） and nitrotyrosine （NT） were determined. The activity of inducible nitric oxide synthase （NOS） including iNOS and nNOS was also detected by Western blot.RESULTS：Compared to control animals, cell proliferation in the gastric mucosa of animals subjected to ethanol treatment for 7 days was significant increased （increased to 290% for PCNA density P 〈 0.05, increased to 150 for Cyclin D1 density P 〈 0.05 and 21.6 ± 0.8 vs 42.3 ± 0.7 for PCNA positive cells per view field）, accompanied by an increase in ROS generation （1.298 ± 0.135 μmol vs 1.772 ± 0.078 μmol for TBARS P 〈 0.05; 4.36 ± 0.39 μmol vs 7.48 ± 0.40 μmol for carbonyl contents P 〈 0.05） and decrease in NO generation （11.334 ± 0.467 μmol vs 7.978 ± 0.334 μmol P 〈 0.01 for NOx; 8.986 ± 1.351 μmol vs 6.854 ± 0.460 μmol for nitrotyrosine P 〈 0.01） and nNOS activity （decreased to 43% P 〈 0.05）. This function was abolished by the co-administration of quercetin. CONCLUSION： The antioxidant action of quercetin relies, in part, on its ability to stimulate nNOS and enhance production of NO that would interact with endogenously produced reactive oxygen to inhibit hyper-proliferation of gastric mucosal cells in rats treated with chronic oral ethanol.展开更多
基金Supported by The Dietmar Hopp Foundation and the Manfred Lautenschlger Foundation
文摘Alcoholic liver disease(ALD) and hepatitis C virus(HCV) infection represent, either alone or in combination, more than two thirds of all patients with liver disease in the Western world.This review discusses the epidemiology and combined impact of ALD and HCV on the progres sion of liver disease.ALD and HCV affect the progres sion of liver disease to liver cirrhosis and hepatocellular carcinoma(HCC) in a synergistic manner.Thus, the risk for HCC increases f ive times with a daily alcohol con sumption of 80 g;in the presence of HCV it is increased 20fold, and a combination of both risk factors leads to a more than 100fold risk for HCC development.Alcohol consumption also decreases the response to interferon treatment which is probably due to a lack of compliance than a direct effect on HCV replication.Several molecu lar mechanisms are discussed that could explain the synergistic interaction of alcohol and HCV on disease progression.They include modulation of the immune response and apoptosis, increased oxidative stress via induction of CYP2E1 and the hepatic accumulation of iron.Thus, both HCV and alcohol independently cause hepatic iron accumulation in > 50% of patients probably due to suppression of the liversecreted systemic iron hormone hepcidin.A better understanding of hepcidin regulation could help in developing novel therapeutic approaches to treat the chronic disease in the future.For now, it can be generally concluded that HCVinfect ed patients should abstain from alcohol and alcoholicsshould be encouraged to participate in detoxification programs.
基金Supported by New Research Grant from the University of Nebraska Medical Center, the NIAAA, and Medical Research Funds from the Department of Veterans Affairs, United States
文摘Alcohol-induced fatty liver (steatosis) was believed to result from excessive generation of reducing equivalents from ethanol metabolism, thereby enhancing fat accumulation. Recent findings have revealed a more complex picture in which ethanol oxidation is still required, but specific transcription as well as humoral factors also have important roles. Transcription factors involved include the sterol regulatory element binding protein 1 (SREBP-1) which is activated to induce genes that regulate lipid biosynthesis. Conversely, ethanol consumption causes a general down-regulation of lipid (fatty acid) oxidation, a reflection of inactivation of the peroxisome proliferator- activated receptor-alpha (PPAR-α) that regulates genes involved in fatty acid oxidation. A third transcription factor is the early growth response-1 (Egr-1), which is strongly induced prior to the onset of steatosis. The activities of all these factors are governed by that of the principal regulatory enzyme, AMP kinase. Important humoral factors, including adiponectin, and tumor necrosis factor-α (TNF-α), also regulate alcohol-induced steatosis. Their levels are affected by alcohol consumption and by each other. This review will summarize the actions of these proteins in ethanol-elicited fatty liver. Because steatosis is now regarded as a significant risk factor for advanced liver pathology, an understanding of the molecular mechanisms in its etiology is essential for development of effective therapies.
基金Supported by the HKBU Faculty Research Grant FRG/02-03/Ⅱ-64
文摘AIM: To investigate the protective effects of Astragalus membranaceus(Am) against hapten-induced colitis in male Sprague-Dawley rats as well as its underlying mechanism.METHODS: Experimental colitis was induced in rats by enema administration of 2,4-dinitrobenzene sulfonic acid (DNBS). Rats were either pretreated with Am extract (2 or 4 g/kg, p.o. once daily) starting from 10 d before DNBS enema, or received Am post-treatment (2 or 4 g/kg, p.o.twice daily) on the three consecutive days following DNBS administration. Colonic lesion area and histological damage were determined, while the activities of myeloperoxidase (MPO) and xanthine oxidase, as well as reduced glutathione (GSH) content were measured in the excised colonic tissues. Besides, protein expression of inducible nitrite oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1) and P-selectin was also detected by Western blot analysis.RESULTS: Our findings had shown that both macroscopic lesion area and histological colonic damage induced by DNBS were significantly reduced by both Am pre- and post-treatments. These were accompanied by attenuation of the elevated colonic MPO activity and downregulation of the iNOS, P-selectin, and ICAM-1 protein expression.Besides, deprivation of colonic GSH level under colitis condition was also preserved.CONCLUSION: These results demonstrate that Am possesses both preventive and therapeutic potential in experimental colitis. The anti-inflammatory actions involve anti-oxidation along with inhibition of adhesion molecule synthesis in the colonic tissues.
基金Supported by The CONACYTNo.CB-2011-1-58781 to Ana M Rivas-Estilla(partially)Red CA Fisiopatología de Enfermedades Hepáticas 2015
文摘Hepatitis C virus(HCV) replication is associated with the endoplasmic reticulum, where the virus can induce cellular stress. Oxidative cell damage plays an important role in HCV physiopathology. Oxidative stress is triggered when the concentration of oxygen species in the extracellular or intracellular environment exceeds antioxidant defenses. Cells are protected and modulate oxidative stress through the interplay of intracellular antioxidant agents, mainly glutathione system(GSH) and thioredoxin; and antioxidant enzyme systems such as superoxide dismutase, catalase, GSH peroxidase, and heme oxygenase-1. Also, the use of natural and synthetic antioxidants(vitamin C and E, N-acetylcysteine, glycyrrhizin, polyenylphosphatidyl choline, mitoquinone, quercetin, S-adenosylmethionine and silymarin) has already shown promising results as co-adjuvants in HCV therapy. Despite all the available information, it is not known how different agents with antiviral activity can interfere with the modulation of the cell redox state induced by HCV and decrease viral replication. This review describes an evidence-based consensus on molecular mechanisms involved in HCV replication and their relationship with cell damage induced by oxidative stress generated by the virus itself and cell antiviral machinery. It also describes some molecules that modify the levels of oxidative stress in HCV-infected cells.
文摘Oxidative stress is becoming recognized as a key factor in the progression of chronic liver disease(CLD) and hepatocarcinogenesis. The metabolically important liver is a major reservoir of mitochondria that serve as sources of reactive oxygen species, which are apparently responsible for the initiation of necroinflammation. As a result, CLD could be a major inducer of oxidative stress. Chronic hepatitis C is a powerful generator of oxidative stress, causing a high rate of hepatocarcinogenesis among patients with cirrhosis. Non-alcoholic steatohepatitis is also associated with oxidative stress although its hepatocarcinogenic potential is lower than that of chronic hepatitis C. Analyses of serum markers and histological findings have shown that hepatocellular carcinoma correlates with oxidative stress and experimental data indicate that oxidative stress increases the likelihood of developing hepatocarcinogenesis. However, the results of antioxidant therapy have not been favorable. Physiological oxidative stress is a necessary biological response, and thus adequate control of oxidative stress and a balance between oxidative and anti-oxidative responses is important. Several agents including metformin and L-carnitine can reportedly control mechanistic oxidative stress. This study reviews the importance of oxidative stress in hepatocarcinogenesis and of control strategies for the optimal survival of patients with CLD and hepatocellular carcinoma.
基金State Education Ministry Scientific Research Foundation for the Returned Overseas Chinese Scholars, No. 1999747
文摘AIM： To investigate the effect of quercetin （3,3,4,5, 7-pentahydroxy flavone）, a major flavonoid in human diet, on hyper-proliferation of gastric mucosal cells in rats treated with chronic oral ethanol. METHODS： Forty male Sprague-Dawley rats, weighing 200-250 g, were randomly divided into control group （tap wateradlibitum）, ethanol treatment group （6 mL/L ethanol）, quercetin treatment group （intragastric gavage with 100 mg/kg of quercetin per day）, and ethanol plus quercetin treatment group （quercetin and 6 mL/L ethanol）. Expression levels of proliferating cell nuclear antigen （PCNA）and Cyclin D1 were detected by Western blot to assay gastric mucosal cell proliferation in rats. To demonstrate the influence of quercetin on the production of extra-cellular reactive oxygen species/ nitrogen species （ROS/RNS） in rats, changes in levels of thiobarbituric acid reactive substance （TBARS）, protein carbonyl, nitrite and nitrate （NOx） and nitrotyrosine （NT） were determined. The activity of inducible nitric oxide synthase （NOS） including iNOS and nNOS was also detected by Western blot.RESULTS：Compared to control animals, cell proliferation in the gastric mucosa of animals subjected to ethanol treatment for 7 days was significant increased （increased to 290% for PCNA density P 〈 0.05, increased to 150 for Cyclin D1 density P 〈 0.05 and 21.6 ± 0.8 vs 42.3 ± 0.7 for PCNA positive cells per view field）, accompanied by an increase in ROS generation （1.298 ± 0.135 μmol vs 1.772 ± 0.078 μmol for TBARS P 〈 0.05; 4.36 ± 0.39 μmol vs 7.48 ± 0.40 μmol for carbonyl contents P 〈 0.05） and decrease in NO generation （11.334 ± 0.467 μmol vs 7.978 ± 0.334 μmol P 〈 0.01 for NOx; 8.986 ± 1.351 μmol vs 6.854 ± 0.460 μmol for nitrotyrosine P 〈 0.01） and nNOS activity （decreased to 43% P 〈 0.05）. This function was abolished by the co-administration of quercetin. CONCLUSION： The antioxidant action of quercetin relies, in part, on its ability to stimulate nNOS and enhance production of NO that would interact with endogenously produced reactive oxygen to inhibit hyper-proliferation of gastric mucosal cells in rats treated with chronic oral ethanol.
