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xiaowanzi9新虫 (正式写手)
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[求助]
求助翻译两段话，量大
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Besides well-described actions on the immune system (see earlier), application of dimethyl fumarate led to effects on endogenous cellular antioxidative pathways involving the transcription factor nuclear (erythroid-derived 2) related factor (Nrf2) [26••]. Nrf2 is a redox-sensitive leucine zipper transcription factor, which contains a domain for interaction with the cytoplasmatic protein kelch-like ECH-associated protein (Keap-1) [27]. In vitro, application of dimethyl fumarate resulted in stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity, and expression of NADPH:quinolone oxidoreductase 1 (NQO1) as a prototypic target gene [28]. Furthermore, application of dimethyl fumarate or MMF involved direct modification of Keap-1 [26••]. On a cellular level, the application of MMF enhanced neuronal survival and protected glial cells against oxidative stress. This action of dimethyl fumarate on cellular resistance to oxidative damage in primary cultures of CNS cells was further substantiated in independent studies [29, 30•] where protective effects were abolished in cells with Nrf2 deficiency [30•]. In vivo, increased levels of Nrf2 were detected in the CNS of dimethyl fumarate treated mice with myelin oligodendrocyte glycoprotein induced EAE. In the very late stage of myelin oligodendrocyte glycoprotein induced EAE, dimethyl fumarate ameliorated the disease course and improved preservation of myelin, axons, and neurons. This effect was not seen in Nrf2-deficient mice [26••]. In summary, activation of Nrf2-dependent antioxidative pathways seems to be an important mechanism of action of dimethyl fumarate. Since oxidative stress may play a major role in the pathogenesis of axonal damage and tissue injury inMS [31], the dimethyl fumarate mediated pharmacological modulation of Nrf2-mediated signaling is an interesting and new therapeutic target not only in experimental models, but also in humans. |
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genhunter
至尊木虫 (著名写手)
- 翻译EPI: 387
- 应助: 259 (大学生)
- 金币: 9757.4
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- 注册: 2013-07-22
- 专业: 肿瘤化学药物治疗
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xiaowanzi9: 金币+50, 翻译EPI+1, ★★★★★最佳答案, 谢谢你 2015-05-25 10:38:37
xiaowanzi9: 金币+50, 翻译EPI+1, ★★★★★最佳答案, 谢谢你 2015-05-25 10:38:37
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除了已经很好描述了的对免疫系统的效果之外（见前面），反丁烯二酸二甲酯还可通过细胞核转录 因子(红细胞来源的）相关因子（Nrf2）影响内源性的抗氧化通路。Nrf2是一种对氧化还原敏感的亮氨酸拉链转录因子，它含一个能与细胞质蛋白Kelch-like ECH-associated protein（keap-1）相互作用域[ 27 ]。在 体外实验中，使用反丁烯二酸二甲酯导致Nrf2变得稳定，从而激活Nrf2依赖的转录活性，并表达它的一个 典型的靶基因NADPH：喹诺酮类药物的氧化还原酶1（NQO1）[ 28 ]。此外，应用反丁烯二酸二甲酯或MMF (估计是反丁烯二酸单甲酯)还参与keap-1 的直接修饰。在细胞水平上，使用MMF可以增强神经细胞的存活和保护神经胶质细胞受氧化应激(的损伤)。这种反丁烯二酸二甲酯对原代培养的中枢神经细胞抵抗氧化作用引起的损伤已有独立的研究进一步证实[ 29，30 ]，并且保护作用在没有Nrf2表达的细胞中不存在•[ 30 ]。在体内，在髓鞘少突胶质细胞糖蛋白诱导的EAE模型的小鼠中反丁烯二酸二甲酯处理增加Nrf2的表达。在髓鞘少突胶质细胞糖蛋白诱导的EAE的晚期，反丁烯二酸二甲酯减缓了病程发展及改善了对髓鞘，轴突及神经细胞存活。在Nrf2的基因敲除小鼠内没有这种效果。 总之，Nrf2依赖抗氧化通路的激活似乎是一个反丁烯二酸二甲酯作用的重要机制作用。由于氧化应激可能在轴突损伤和 (MS: multiple sclerosis) 多发性硬化症组织损伤中起主要作用[ 31 ]，由富马酸二甲酯介导的药理调控Nrf2介导的信号转递是一个有趣的和新的治疗靶点不仅在实验动物模型中，而且在人类(治疗中也有意义)。 |
2楼2015-05-21 16:08:51