The anticancer agent adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity, while Salvia miltiorrhiza (SM) is a Chinese herb widely used for the treatment of cardiovascular disorders and its aqueous extract (SMAE) has shown anticancer as well as antioxidant effects. In the current study, we aimed at investigating the synergistic effect and potent molecular mechanisms of SMAE with a focus on the cardioprotective benefit observed under ADR adoption. Histopathological analysis indicated that SMAE could substantially alleviate cardiomyopathy and cell apoptosis caused by ADR. Meanwhile, the two-dimensional electrophoresis (2-DE) oxyblots demonstrated that SMAE treatment could effectively reduce carbonylation of specific proteins associated with oxidative stress response and various metabolic pathways in the presence of ADR. SMAE application also showed protective efficacy against ADR-mediated H9c2 cell death in a dose-dependent manner without causing any cytotoxicity and significantly attenuated the reactive oxygen species production. Particularly, the simultaneous administration of ADR and SMAE could remarkably suppress the growth of breast cancer cells. We also noticed that there was a marked upregulation of detoxifying enzyme system in the presence of SMAE, and its exposure also contributed to an increase in Nrf2 and HO-1 content as well. SMAE also amended the ERK/p53/Bcl-xL/caspase-3 signaling pathways and the mitochondrial dysfunction, which eventually attribute to apoptotic cathepsin B/AIF cascades. Correspondingly, both the ERK1/2 inhibitor (U0126) and pan-caspase inhibitor (Z-VAD-FMK) could at least partially abolish the ADR-associated cytotoxicity in H9c2 cells. Collectively, these results support that ROS apoptosis-inducing molecule release is closely involved in ADR-induced cardiotoxicity while SMAE could prevent or mitigate the causative cardiomyopathy through controlling multiple targets without compromising the efficacy of chemotherapy.

中文翻译：

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功能性氧化还原蛋白质组学揭示丹参水提取物可通过抑制ROS依赖性细胞凋亡减轻阿霉素诱导的心肌病。

长期以来，抗癌药阿霉素（ADR）会引起剂量限制性心脏毒性，而丹参（SM）是一种广泛用于治疗心血管疾病的中草药，其水提取物（SMAE）具有抗癌和抗氧化作用。在当前的研究中，我们旨在研究SMAE的协同效应和有效的分子机制，重点是采用ADR时观察到的心脏保护作用。组织病理学分析表明，SMAE可以大大减轻ADR引起的心肌病和细胞凋亡。同时，二维电泳（2-DE）氧化印迹表明SMAE处理可以有效地减少与ADR存在时与氧化应激反应和各种代谢途径相关的特定蛋白质的羰基化。SMAE的应用还显示出剂量依赖性的抗ADR介导的H9c2细胞死亡的保护功效，而没有引起任何细胞毒性，并且显着减弱了活性氧的产生。特别地，同时施用ADR和SMAE可以显着抑制乳腺癌细胞的生长。我们还注意到在SMAE的存在下，排毒酶系统明显上调，其暴露也导致Nrf2和HO-1含量增加。SMAE还修改了ERK / p53 / Bcl-xL / caspase-3信号传导途径和线粒体功能障碍，最终归因于凋亡的组织蛋白酶B / AIF级联。相应地，ERK1 / 2抑制剂（U0126）和泛半胱天冬酶抑制剂（Z-VAD-FMK）都可以至少部分消除H9c2细胞中ADR相关的细胞毒性。总的来说，这些结果支持ROS凋亡诱导分子释放与ADR诱导的心脏毒性密切相关，而SMAE可以通过控制多个靶标而预防或减轻致病性心肌病，而不会损害化学疗法的效力。