Protective effects of dimethyl itaconate in mice acute cardiotoxicity induced by doxorubicin.
Protective effects of dimethyl itaconate in mice acute cardiotoxicity induced by doxorubicin.
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衣康酸二甲酯对阿霉素诱导的小鼠急性心脏毒性的保护作用。
DOI：
10.1016/j.bbrc.2019.07.046
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发表时间：
2019-09
影响因子：
3.1
通讯作者：
Lu Xiang
中科院分区：
文献类型：
--
作者：
Shan Qing;Li Xiaoyu;Zheng mei;Lin Xi;Lu Guotao;Su Dongming;Lu Xiang
多柔比星（DOX）是一种广泛应用于血液肿瘤和各种实体瘤的抗肿瘤药物。然而，DOX引起的心脏毒性严重限制了其临床治疗。衣康酸二甲酯（Dimethyl itaconate，DI）是衣康酸的一种常见形式，被认为是预防心脏损伤的潜在靶点。在这里，我们采用野生型和Nrf 2基因敲除小鼠，并通过给予DOX诱导心脏毒性模型，以阐明DI的作用。DI治疗后，通过形态学、LDH水平和心脏重量/体重比的变化，发现其能有效减轻心脏毒性。同时，我们证明DI治疗组中坏死的关键蛋白RIP 3显著降低。此外，我们观察到用DI处理可以通过改变Nrf 2/HO-1来抑制氧化应激。与溶剂组相比，DI可提高组织SOD和GSH水平，降低MDA水平，DHE染色显示DI组ROS水平降低一半。透射电镜（TEM）结果显示，DI处理后线粒体损伤明显减轻。当Nrf 2被阻断后，DI的保护作用消失，SOD、GSH、MDA含量与溶剂组相比无明显变化。本研究为DI治疗对DOX所致心脏毒性的保护作用提供了证据。在机制上，DI通过改变Nrf 2/HO-1通路减轻氧化应激，保护线粒体免受损伤。这些研究结果为DOX相关心脏毒性的治疗提供了新的靶点。
Doxorubicin (DOX) is an antitumor drug widely used in hematological tumors and various solid tumors. However, the cardiotoxicity elicited by DOX severely limits its clinical treatment. Dimethyl itaconate (DI), a common form of itaconate, is found many potential targets for prevent heart injury. Here we employed wild type and Nrf2 knockout mice and induced a cardiotoxicity model by administration of DOX to clarify the effects of DI. After treatment with DI, we found that it could effectively alleviate the cardiotoxicity by analyzing morphology, LDH levels and heart weight/body weight ratio changes. Meanwhile we demonstrated that RIP3, a key protein of necrosis, was significantly decreased in DI treated group. Further we observed that treatment with DI could suppress oxidative stress by altering Nrf2/HO-1. Compared with vehicle group, DI could increase the tissue SOD and GSH, and reduce MDA levels, then DHE staining revealed that the level of ROS in DI group reduced by half. Finally, transmission electron microscope (TEM) data showed that treatment with DI obviously decreased the mitochondrial damage. While Nrf2 was ablated in mice, the protective effects of DI were vanished and SOD, GSH, MDA became unchanged related to vehicle group. This report provides the evidence for the protective effects of DI treatment in cardiotoxicity induced by DOX. On mechanisms, DI could reduce the oxidative stress by altering Nrf2/HO-1 pathway and prevent mitochondrial from damage. Taken together, these findings of this paper will afford the new therapeutic targets in DOX related cardiotoxicity.
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靶向线粒体的小分子有效预防阿霉素引起的心脏毒性
DOI：
10.3390/molecules23061486
发表时间：
2018-06-19
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Shi W;Deng H;Zhang J;Zhang Y;Zhang X;Cui G
通讯作者：
Cui G
影响因子：
7.3
作者：
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通讯作者：
Hsieh, Pei-Wen
Nrf2 缺乏会加剧阿霉素引起的心脏毒性和心脏功能障碍
影响因子：
--
作者：
Li S;Wang W;Niu T;Wang H;Li B;Shao L;Lai Y;Li H;Janicki JS;Wang XL;Tang D;Cui T
通讯作者：
Cui T
DOI：
--
发表时间：
1980-04
期刊：
The American journal of pathology
影响因子：
--
作者：
J. Vleet;V. Ferrans;Walter;E. Weirich
通讯作者：
J. Vleet;V. Ferrans;Walter;E. Weirich