【作者】 陈龙；

【导师】 董庆华；

【作者基本信息】 浙江大学 ， 肿瘤学， 2015， 硕士

【摘要】 背景和目的：阿霉素是一种临床上广泛使用的广谱抗癌药,但是在使用过程中其心脏毒性严重限制了阿霉素在临床上的应用。之前我们的研究已证实槲皮素可以缓解阿霉素的肝脏毒性,在此基础上,我们研究槲皮素对阿霉素心脏毒性的缓解作用,并探究槲皮素对阿霉素作用下心肌细胞线粒体功能和活性氧产生的影响及相关调控因子Bmi-1的作用,来阐述槲皮素缓解阿霉素心脏毒性的分子作用机制。实验方法和结果：我们选用H9C2大鼠心肌细胞和C57BL/6小鼠进行体内外实验研究。H9C2大鼠心肌细胞用于研究槲皮素对阿霉素作用下细胞凋亡、线粒体功能、氧化应激和相关信号通路变化的影响；C57BL/6小鼠用于研究槲皮素对阿霉素作用下小鼠的心功能、血清酶活性和活性氧水平的影响。体外实验的结果表明,槲皮素有效减少了阿霉素诱导的H9C2大鼠心肌细胞凋亡以及线粒体功能障碍的数量,抑制了细胞内活性氧的产生和DNA双链的断裂。同时,槲皮素下调阿霉素处理后H9C2大鼠心肌细胞内Bid蛋白、p53蛋白和氧化酶(p47和Nox1)的表达,上调Bcl-2和Bmi-1蛋白的表达。在Bmi-1siRNA转染的细胞内,槲皮素的这种心肌保护作用消失了。体内实验的结果显示,槲皮素能够通过降低活性氧含量,抑制脂质过氧化反应,增加Bmi-1蛋白和抗氧化物/超氧化物歧化酶的表达来缓解阿霉素导致的小鼠心功能损伤。结论和意义：我们的实验结果表明：无论在体内还是体外,槲皮素都可以通过上调Bmi-1表达、减少氧化压力来缓解阿霉素的心脏毒性。本研究的实验结果为槲皮素应用于临床预防阿霉素的心脏毒性提供了重要的理论支持。更多还原

【Abstract】 Background and objective:Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity.Methods and results:Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2cardiomyocytes and C57BL/6mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment.In H9c2cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53and oxidase (p47and Noxl) and by increased expression of Bcl-2and Bmi-1. Bmi-1siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1and anti-oxidative superoxide dismutase.Conclusion:Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy.更多还原