Dihydromyricetin alleviates carbon tetrachloride-induced acute liver injury via JNK-dependent mechanism in mice

AIM: To assess the effects of dihydromyricetin(DHM) as a hepatoprotective candidate in reducing hepatic injury and accelerating hepatocyte proliferation after carbon tetrachloride(CCl4) treatment.METHODS: C57 BL/6 mice were used in this study. Mice were orally administered with DHM(150 mg/kg) for 4...

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Published in:World journal of gastroenterology : WJG 2015-05, Vol.21 (18), p.5473-5481
Main Authors: Xie, Jun, Liu, Jie, Chen, Tu-Ming, Lan, Qing, Zhang, Qing-Yu, Liu, Bin, Dai, Dong, Zhang, Wei-Dong, Hu, Li-Ping, Zhu, Run-Zhi
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - pharmacology
Basic Study
Biomarkers - blood
Carbon Tetrachloride
Caspase Inhibitors - pharmacology
Cell Proliferation - drug effects
Chemical and Drug Induced Liver Injury - blood
Chemical and Drug Induced Liver Injury - drug therapy
Chemical and Drug Induced Liver Injury - enzymology
Chemical and Drug Induced Liver Injury - pathology
Cytochromes c - metabolism
Dihydromyricetin
Disease Models, Animal
factor-α
Flavonols - pharmacology
Inflammation Mediators - blood
JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases - metabolism
Liver
Liver - drug effects
Liver - enzymology
Liver - pathology
Liver Failure, Acute - blood
Liver Failure, Acute - chemically induced
Liver Failure, Acute - drug therapy
Liver Failure, Acute - enzymology
Liver Failure, Acute - pathology
Liver Regeneration - drug effects
Male
Mice, Inbred C57BL
Mitochondria, Liver - drug effects
Mitochondria, Liver - enzymology
Mitochondria, Liver - pathology
necrosis
Protein Kinase Inhibitors - pharmacology
regeneration
Signal Transduction - drug effects
Time Factors
Tumor
Tumor Necrosis Factor-alpha - blood
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Summary:AIM: To assess the effects of dihydromyricetin(DHM) as a hepatoprotective candidate in reducing hepatic injury and accelerating hepatocyte proliferation after carbon tetrachloride(CCl4) treatment.METHODS: C57 BL/6 mice were used in this study. Mice were orally administered with DHM(150 mg/kg) for 4 d after CCl4 treatment. Serum and liver tissue samples were collected on days 1, 2, 3, 5 and 7 after CCl4 treatment. The anti-inflammatory effect of DHM was assessed directly by hepatic histology detection and indirectly by serum levels of aspartate aminotransferase(AST), alanine aminotransferase(ALT), albumin, and superoxide dismutase(SOD). Inflammatory cytokines, such as interleukin(IL)-1β, IL-6 and tumor necrosis factor-α(TNF-α), were detected using ELISA kits. Proliferating cell nuclear antigen(PCNA) staining was used to evaluate the role of DHM in promoting hepatocyte proliferation. Hepatocyte apoptosis wasmeasured by TUNEL assay.Furthermore,apoptosis proteins Caspases-3,6,8,and 9 were detected by Western blot.SP600125 were used to confirm whether DHM regulated liver regeneration through JNK/TNF-αpathways.RESULTS:DHM showed a strong anti-inflammatory effect on CCl4-induced liver injury in mice.DHM could significantly decrease serum ALT,AST,IL-1β,IL-6 and TNF-αand increase serum albumin,SOD and liver SOD compared to the control group after CCl4 treatment(P<0.05).PCNA results indicated that DHM could significantly increase the number of PCNA positive cells compared to the control(348.9±56.0 vs 107.1±31.4,P<0.01).TUNEL assay showed that DHM dramatically reduced the number of apoptotic cells after CCl4 treatment compared to the control(365.4±99.4 vs 90.5±13.8,P<0.01).Caspase activity detection showed that DHM could reduce the activities of Caspases-8,3,6 and 9 compared to the control(P<0.05).The results of Western blot showed that DHM increased the expression of JNK and decreased TNF-αexpression.However,DHM could not affect TNF-αexpression after SP600125 treatment.Furthermore,DHM could significantly improve the survival rate of acute liver failure(ALF)mice(73.3%vs 20.0%,P<0.0001),and SP600125 could inhibit the effect of DHM.CONCLUSION:These findings demonstrate that DHM alleviates CCl4-induced liver injury,suggesting that DHM is a promising candidate for reversing liver injury and ALF.
ISSN:1007-9327
2219-2840
DOI:10.3748/wjg.v21.i18.5473