title: Dihydromyricetin protects against liver ischemia/reperfusion induced apoptosis via activation of FOXO3a-mediated autophagy.
abstract: Liver ischemia and reperfusion (I/R) injury is characterized by defective liver autophagy accompanied by alterations to the endogenous defense system. Dihydromyricetin (DHM) is a natural flavonoid that demonstrates a wide range of physiological functions, and has been implicated as a regulator of autophagy. This study investigates the protective effects of DHM pretreatment on liver injury caused by ischemia/reperfusion (I/R) and elucidates the potential mechanism of DHM-mediated protection. Mice were subjected to 60 minutes of ischemia followed by 5 hours of reperfusion. DHM (100 mg/kg bw/day) or the vehicle was administered daily by gavage 7 days before ischemia and immediately before reperfusion. In this study, DHM markedly decreased serum aminotransferase activity and inhibited liver I/R -stimulated apoptosis. Moreover, DHM exerted hepatoprotective effects by upregulating mRNA levels of various essential autophagy-related genes including ATG5, ATG12, BECN1, and LC3. Autophagy inhibitor chloroquine or Atg5 knockdown blocked DHM -mediated elevation in liver function. Specifically, DHM significantly increased FOXO3a expression, and enhanced FOXO3a nuclear translocation and Ser588 phosphorylation modification. Importantly, the inhibition of FOXO3a with FOXO3a-siRNA in mice decreased DHM-induced autophagy-related genes and diminished the protective effects of DHM against liver I/R injury. In summary, these findings identify DHM as a novel hepatoprotective small molecule by elevating FOXO3a expression and nuclear translocation, stimulating autophagy-related genes and suppressing liver I/R-induced apoptosis, suggesting FOXO3a may have therapeutic value in liver cell protection in liver I/R injury.
authors: Department of Hepatobiliary Surgery, Fuzhou General Hospital of PLA, Fuzhou, Fujian, China.|Department of Hepatobiliary Surgery, Dongfang Hospital of Xiamen University, Fuzhou, Fujian, China.
authors: Yongbiao
authors: Y
authors: Chen
authors: Department of Hepatobiliary Surgery, Fuzhou General Hospital of PLA, Fuzhou, Fujian, China.|Department of Hepatobiliary Surgery, Dongfang Hospital of Xiamen University, Fuzhou, Fujian, China.
authors: Lizhi
authors: L
authors: Lv
authors: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors: Huifeng
authors: H
authors: Pi
authors: The 517th Hospital of PLA, Xinzhou, Shanxi, China.
authors: Weijia
authors: W
authors: Qin
authors: Department of Hepatobiliary Surgery, Fuzhou General Hospital of Fujian Medical University, Fuzhou, Fujian, China.
authors: Jianwei
authors: J
authors: Chen
authors: Department of General Surgery, Mindong Hospital of Fujian Medical University, Fuan, Fujian, China.
authors: Dengfang
authors: D
authors: Guo
authors: Department of Hepatobiliary Surgery, Fuzhou General Hospital of PLA, Fuzhou, Fujian, China.|Department of Hepatobiliary Surgery, Dongfang Hospital of Xiamen University, Fuzhou, Fujian, China.
authors: Jianyu
authors: J
authors: Lin
authors: Department of Hepatobiliary Surgery, Fuzhou General Hospital of PLA, Fuzhou, Fujian, China.|Department of Hepatobiliary Surgery, Dongfang Hospital of Xiamen University, Fuzhou, Fujian, China.
authors: Xiaobing
authors: X
authors: Chi
authors: Department of Hepatobiliary Surgery, Fuzhou General Hospital of PLA, Fuzhou, Fujian, China.|Department of Hepatobiliary Surgery, Dongfang Hospital of Xiamen University, Fuzhou, Fujian, China.
authors: Zhelong
authors: Z
authors: Jiang
authors: Department of Hepatobiliary Surgery, Fuzhou General Hospital of PLA, Fuzhou, Fujian, China.|Department of Hepatobiliary Surgery, Dongfang Hospital of Xiamen University, Fuzhou, Fujian, China.
authors: Hejun
authors: H
authors: Yang
authors: Department of Hepatobiliary Surgery, Fuzhou General Hospital of PLA, Fuzhou, Fujian, China.|Department of Hepatobiliary Surgery, Dongfang Hospital of Xiamen University, Fuzhou, Fujian, China.
authors: Yi
authors: Y
authors: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D044948:Flavonols / Q000494:pharmacology*; D000071316:Forkhead Box Protein O3 / Q000235:genetics* / Q000378:metabolism; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D020011:Protective Agents / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D044948:Flavonols; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D020011:Protective Agents; D053148:Caspase 3; C472036:dihydromyricetin
keywords: FOXO3a; dihydromyricetin; liver ischemia/reperfusion; Autophagy