title: Dihydromyricetin alleviates carbon tetrachloride-induced acute liver injury via JNK-dependent mechanism in mice.
abstract: OBJECTIVE
  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 was measured 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-α pathways.
  
  
  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-α and 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-α expression. However, DHM could not affect TNF-α expression 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.
  
  
  CONCLUSIONS
  These findings demonstrate that DHM alleviates CCl4-induced liver injury, suggesting that DHM is a promising candidate for reversing liver injury and ALF.
authors.affiliation: Jun Xie, Wei-Dong Zhang, Li-Ping Hu, Run-Zhi Zhu, Clinical Research Center, Xuyi People's Hospital, Xuyi 211700, Jiangsu Province, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.affiliation: Jun Xie, Wei-Dong Zhang, Li-Ping Hu, Run-Zhi Zhu, Clinical Research Center, Xuyi People's Hospital, Xuyi 211700, Jiangsu Province, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Jun Xie, Wei-Dong Zhang, Li-Ping Hu, Run-Zhi Zhu, Clinical Research Center, Xuyi People's Hospital, Xuyi 211700, Jiangsu Province, China.
authors.forename: Tu-Ming
authors.initials: TM
authors.lastname: Chen
authors.affiliation: Jun Xie, Wei-Dong Zhang, Li-Ping Hu, Run-Zhi Zhu, Clinical Research Center, Xuyi People's Hospital, Xuyi 211700, Jiangsu Province, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lan
authors.affiliation: Jun Xie, Wei-Dong Zhang, Li-Ping Hu, Run-Zhi Zhu, Clinical Research Center, Xuyi People's Hospital, Xuyi 211700, Jiangsu Province, China.
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: Zhang
authors.affiliation: Jun Xie, Wei-Dong Zhang, Li-Ping Hu, Run-Zhi Zhu, Clinical Research Center, Xuyi People's Hospital, Xuyi 211700, Jiangsu Province, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Jun Xie, Wei-Dong Zhang, Li-Ping Hu, Run-Zhi Zhu, Clinical Research Center, Xuyi People's Hospital, Xuyi 211700, Jiangsu Province, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Dai
authors.affiliation: Jun Xie, Wei-Dong Zhang, Li-Ping Hu, Run-Zhi Zhu, Clinical Research Center, Xuyi People's Hospital, Xuyi 211700, Jiangsu Province, China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Zhang
authors.affiliation: Jun Xie, Wei-Dong Zhang, Li-Ping Hu, Run-Zhi Zhu, Clinical Research Center, Xuyi People's Hospital, Xuyi 211700, Jiangsu Province, China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Hu
authors.affiliation: Jun Xie, Wei-Dong Zhang, Li-Ping Hu, Run-Zhi Zhu, Clinical Research Center, Xuyi People's Hospital, Xuyi 211700, Jiangsu Province, China.
authors.forename: Run-Zhi
authors.initials: RZ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D002251:Carbon Tetrachloride; D061945:Caspase Inhibitors / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D044948:Flavonols / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000097:blood; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D017114:Liver Failure, Acute / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D061945:Caspase Inhibitors; D044948:Flavonols; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D002251:Carbon Tetrachloride; D048031:JNK Mitogen-Activated Protein Kinases; C472036:dihydromyricetin
keywords: Dihydromyricetin; Liver regeneration; Tumor necrosis factor-α