补骨脂酚对多柔比星心脏毒性的拮抗作用及其机制

Protective effects of bakuchiol against doxorubicin-induced cardiotoxicity and its underlying mechanism

目的 观察补骨脂酚(BAK)对多柔比星(DOX)引起的心脏毒性的保护作用并探究其可能的分子机制。方法 将60只雄性C57小鼠随机均分为4组:正常组(control组),多柔比星组(DOX组),补骨脂酚处理组(DOX+BAK组),抑制剂加补骨脂酚处理组(3-TYP+DOX+BAK组)。采用腹腔一次性注射多柔比星(15 mg/kg)建立小鼠多柔比星心脏毒性急性模型。DOX建模后每日经腹腔给予补骨脂酚20 mg/(kg·d)注射给药5 d。DOX注射前3 d每日经腹腔给予SIRT3特异性阻断剂3-TYP 50 mg/(kg·d)注射3 d。各组小鼠药物处理完成后检测其心脏收缩舒张功能、心脏组织病理改变、血清LDH水平、心肌组织氧化应激水平和心肌细胞凋亡情况。结果 与control组相比,DOX组小鼠早期心脏功能明显受损,血清内LDH水平明显升高(P<0.05);小鼠心肌细胞出现明显“空泡化”现象;小鼠心肌组织ROS的产生及MDA的生成明显增加,并且心肌组织SOD的活性显著降低(P<0.05);小鼠心肌细胞凋亡水平显著升高(P<0.05);同时小鼠心肌细胞SIRT3/SOD2信号通路明显被抑制(P<0.05)。与DOX组相比,DOX+BAK组小鼠心脏功能损伤显著减轻,血清内LDH水平明显降低(P<0.05);小鼠心肌细胞“空泡化”现象显著改善;小鼠心肌组织ROS的产生及MDA的生成明显被抑制,并心肌组织SOD的活性显著升高(P<0.05);小鼠心肌细胞凋亡水平显著降低(P<0.05);同时小鼠心肌细胞SIRT3/SOD2信号通路明显被激活(P<0.05)。然而补骨脂酚的上述保护效果均可被SIRT3特异性阻断剂3-TYP显著逆转(P<0.05)。结论 补骨脂酚可通过激活SIRT3/SOD2信号通路发挥抑制氧化应激损伤和细胞凋亡的作用,进而减轻了多柔比星心脏毒性。

Objective To observe the effects of bakuchiol(BAK)on the cardiotoxicity caused by doxorubicin(DOX)and its molecular mechanism.Methods Sixty male mice were randomly divided into 4 groups:control group,DOX group,DOX+BAK group and 3-TYP+DOX+BAK group.An acute model of doxorubicin-induced cardiotoxicity in mice was established by intraperitoneal injection of doxorubicin(15 mg/kg).BAK 20 mg/(kg·d)was administered intraperitoneally following DOX treatment for 5 d.The mice in 3-TYP+DOX+BAK group were intraperitoneally given SIRT3-specific inhibitor 3-TYP 50 mg/(kg·d)once a day for 3 d before DOX administration.Cardiac systolic and diastolic function,cardiac histopathological changes,serum LDH level,oxidative stress in myocardial tissue and apoptosis of cardiomyocytes were examined after all medication was conducted.Results Compared with control group,the early cardiac function was significantly impaired in DOX group,the serum LDH level was markedly increased(P<0.05),and the myocardial tissue showed a significant“vacuolar degeneration”phenomenon.Compared with control group,ROS production and MDA content were dramatically elevated,and SOD activity was effectively inhibited in DOX group(P<0.05).Meanwhile,the apoptosis of cardiomyocytes was increased after DOX treatment(P<0.05),along with the down-regulation of SIRT3/SOD2 signaling pathway(P<0.05).Compared with DOX group,the impaired cardiac function was significantly alleviated,the serum LDH level was markedly decreased in DOX+BAK group(P<0.05),and the vacuolar degeneration in the cardiomyocytes was significantly ameliorated(P<0.05).Besides,ROS production and MDA content in the myocardium were effectively inhibited after BAK administration,and SOD activity was increased(P<0.05).Compared with DOX group,the apoptosis of cardiomyocytes was ameliorated in DOX+BAK group,accompanied by the activation of SIRT3/SOD2 signaling pathway(P<0.05).However,the above protective effects of BAK were all significantly reversed by SIRT3 specific inhibitor 3-TYP(all P<0.05).Conclusion BAK may alleviate the doxorubicin-induced cardiotoxicity by exhibiting its anti-oxidative stress and anti-apoptosis effects via activating the SIRT3/SOD2 signaling pathway.