The NRF2 transcriptional target, OSGIN1, contributes to monomethyl fumarate-mediated cytoprotection in human astrocytes
The NRF2 transcriptional target, OSGIN1, contributes to monomethyl fumarate-mediated cytoprotection in human astrocytes
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DOI：
10.1038/srep42054
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发表时间：
2017-02-09
影响因子：
4.6
通讯作者：
Scannevin, Robert H.
中科院分区：
文献类型：
--
作者：
Brennan, Melanie S.;Matos, Maria F.;Scannevin, Robert H.
富马酸二甲酯（DMF）适用于治疗复发性多发性硬化症，可能通过激活核因子（红细胞衍生2）样2（NRF 2）途径发挥治疗作用。经口DMF给药后，中枢神经系统（CNS）组织主要暴露于富马酸单甲酯（MMF），DMF的生物活性代谢产物，可稳定NRF 2并诱导抗氧化基因表达;然而，由MMF调节的导致细胞保护的详细NRF 2依赖性机制尚不清楚。我们的数据确定了人星形胶质细胞中MMF介导的细胞保护机制，该机制以OSGIN 1依赖性方式发挥作用，特别是通过上调OSGIN 1 -61 kDa亚型。NRF 2依赖性OSGIN 1表达诱导P53核转位后，MMF管理，导致细胞周期抑制和细胞保护氧化的挑战。这项研究提供了在人CNS衍生细胞中通过NRF 2，OSGIN 1和P53对DMF介导的细胞保护作用的机制见解，并有助于我们了解DMF如何在临床上改善神经退行性疾病的病理过程。
Dimethyl fumarate (DMF) is indicated for the treatment of relapsing multiple sclerosis and may exert therapeutic effects via activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway. Following oral DMF administration, central nervous system (CNS) tissue is predominantly exposed to monomethyl fumarate (MMF), the bioactive metabolite of DMF, which can stabilize NRF2 and induce antioxidant gene expression; however, the detailed NRF2-dependent mechanisms modulated by MMF that lead to cytoprotection are unknown. Our data identify a mechanism for MMF-mediated cytoprotection in human astrocytes that functions in an OSGIN1-dependent manner, specifically via upregulation of the OSGIN1-61 kDa isoform. NRF2-dependent OSGIN1 expression induced P53 nuclear translocation following MMF administration, leading to cell-cycle inhibition and cell protection against oxidative challenge. This study provides mechanistic insight into MMF-mediated cytoprotection via NRF2, OSGIN1, and P53 in human CNS-derived cells and contributes to our understanding of how DMF may act clinically to ameliorate pathological processes in neurodegenerative disease.