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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription.
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Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription.

机译:通过Nrf2介导的转录在体外和体内对线粒体复合物II抑制的保护作用。

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摘要

Complex II inhibitors 3-nitropropionic acid (3NP) and malonate cause striatal damage reminiscent of Huntington's disease and have been shown to involve oxidative stress in their pathogenesis. Because nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent transcriptional activation by means of the antioxidant response element is known to coordinate the up-regulation of cytoprotective genes involved in combating oxidative stress, we investigated the significance of Nrf2 in complex II-induced toxicity. We found that Nrf2-deficient cells and Nrf2 knockout mice are significantly more vulnerable to malonate and 3NP and demonstrate increased antioxidant response element (ARE)-regulated transcription mediated by astrocytes. Furthermore, ARE preactivation by means of intrastriatal transplantation of Nrf2-overexpressing astrocytes before lesioning conferred dramatic protection against complex II inhibition. These observations implicate Nrf2 as an essential inducible factor in the protection against complexII inhibitor-mediated neurotoxicity. These data also introduce Nrf2-mediated ARE transcription as a potential target of preventative therapy in neurodegenerative disorders such as Huntington's disease.
机译:复合物II抑制剂3-硝基丙酸(3NP)和丙二酸酯会引起纹状体损伤,使人联想到亨廷顿舞蹈病,并已证明其发病机理涉及氧化应激。由于已知通过抗氧化剂响应元件来激活核因子类红细胞2相关因子2(Nrf2)依赖的转录激活来协调参与抗氧化应激的细胞保护性基因的上调,因此我们研究了Nrf2在复杂II-中的意义。诱导毒性。我们发现,Nrf2缺陷细胞和Nrf2敲除小鼠明显更容易受到丙二酸和3NP的刺激,并证明星形胶质细胞介导的抗氧化反应元件(ARE)调节的转录增加。此外,通过在损伤前通过纹状体内Nrf2过表达星形胶质细胞的移植预激活ARE,可显着保护复合物II。这些观察结果表明,Nrf2是抵抗复合物II抑制剂介导的神经毒性的重要诱导因子。这些数据还介绍了Nrf2介导的ARE转录,作为神经退行性疾病(如亨廷顿氏病)的预防性治疗的潜在目标。

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