Dihydromyricetin protects against liver ischemia/reperfusion induced apoptosis via activation of FOXO3a-mediated autophagy.
Dihydromyricetin protects against liver ischemia/reperfusion induced apoptosis via activation of FOXO3a-mediated autophagy.
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DOI：
10.18632/oncotarget.12894
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发表时间：
2016-11-22
期刊：
影响因子：
--
通讯作者：
Jiang Y
中科院分区：
文献类型：
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作者：
Chen Y;Lv L;Pi H;Qin W;Chen J;Guo D;Lin J;Chi X;Jiang Z;Yang H;Jiang Y
肝脏缺血再灌注损伤的特点是肝脏自噬功能缺陷，同时伴有内源性防御系统的改变。二氢杨梅素（DHM）是一种天然类黄酮，具有广泛的生理功能，并被认为是自噬的调节剂。本研究旨在探讨DHM预处理对缺血再灌注（I/R）所致肝损伤的保护作用及其可能的作用机制。使小鼠经受60分钟的缺血，随后5小时的再灌注。DHM（100 mg/kg bw/天）或溶剂在缺血前7天和再灌注前即刻每天通过管饲法给药。在这项研究中，DHM显着降低血清转氨酶活性和抑制肝I/R刺激的细胞凋亡。此外，DHM通过上调各种必需的自噬相关基因（包括ATG 5，ATG 12，BECN 1和LC 3）的mRNA水平来发挥肝脏保护作用。自噬抑制剂氯喹或Atg 5敲低阻断DHM介导的肝功能升高。具体而言，DHM显著增加FOXO 3a表达，并增强FOXO 3a核转位和Ser 588磷酸化修饰。重要的是，在小鼠中用FOXO 3a-siRNA抑制FOXO 3a减少了DHM诱导的自噬相关基因，并降低了DHM对肝脏I/R损伤的保护作用。综上所述，这些发现将DHM确定为一种新型的肝保护性小分子，其通过提高FOXO 3a表达和核转位、刺激自噬相关基因和抑制肝I/R诱导的细胞凋亡，表明FOXO 3a可能在肝I/R损伤中具有肝细胞保护的治疗价值。
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.