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Folic Acid Deficiency Enhances the Tyr705 and Ser727 Phosphorylation of Mitochondrial STAT3 in In Vivo and In Vitro Models of Ischemic Stroke

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Abstract

Ischemic stroke remains one of the most common causes of death and disability worldwide. The stroke patients with an inadequate intake of folic acid tend to have increased brain injury and poorer prognosis. However, the precise mechanisms underlying the harmful effects of folic acid deficiency (FD) in ischemic stroke is still elusive. Here, we aimed to test the hypothesis that mitochondrial localized STAT3 (mitoSTAT3) expression may be involved in the process of neuronal damage induced by FD in in vivo and in vitro models of ischemic stroke. Our results exhibited that FD increased infarct size and aggravated the damage of mitochondrial ultrastructure in ischemic brains. Meanwhile, FD upregulated the phosphorylation levels of mitoSTAT3 at Tyr705 (Y705) and Ser727 (S727) sites in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model and oxygen-glucose deprivation followed by reperfusion (OGD/R) N2a cells. Furthermore, the inhibition of JAK2 by AG490 led to a significant decrease in FD-induced phosphorylation of Y705, while S727 phosphorylation was unaffected. Conversely, U0126 and LY294002, which respectively inhibited phosphorylation of ERK1/2 and Akt, partially prevented S727 phosphorylation, but had limited effects on the level of pY705, suggesting that phosphorylation of Y705 and S727 is regulated via independent mechanisms in FD-treated brains.

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We declared that materials described in the manuscript, including all relevant raw data, will be freely available to any scientist wishing to use them for non-commercial purposes, without breaching participant confidentiality.

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This work was financially supported by the National Natural Science Foundation of China (Grant No. 81874262).

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Authors and Affiliations

  1. Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, No 22 Qixiangtai Road, Heping District, Tianjin, 300070, China

    Zhiping Dong, Xiaoshan Liang, Huan Liu, Xuan Wang, Na Sai & Xumei Zhang

  2. NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, 300134, China

    Zhiping Dong

  3. Tianjin Key Laboratory of Environment, Nutrition and Public Health, Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin Medical University, Tianjin, 300070, China

    Xiaoshan Liang, Qiang Zhang, Suhui Luo, Huan Liu, Xuan Wang, Na Sai & Xumei Zhang

  4. Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin, 300070, China

    Qiang Zhang

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  1. Zhiping Dong
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Contributions

Study concept and design: Xumei Zhang, Zhiping Dong, and Xiaoshan Liang. Performed research: Zhiping Dong, Xiaoshan Liang, Suihui Luo, Huan Liu, Xuan Wang, and Na Sai. Analysis of data: Zhiping Dong, Qiang Zhang, Huan Liu, and Xuan Wang. Drafting of the manuscript: Xumei Zhang, Zhiping Dong, and Xiaoshan Liang.

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Dong, Z., Liang, X., Zhang, Q. et al. Folic Acid Deficiency Enhances the Tyr705 and Ser727 Phosphorylation of Mitochondrial STAT3 in In Vivo and In Vitro Models of Ischemic Stroke. Transl. Stroke Res. 12, 829–843 (2021). https://doi.org/10.1007/s12975-020-00860-7

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