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硫氧还蛋白相互作用蛋白 (TXNIP) 及其与脑和神经退行性疾病的关系。

Thioredoxin-Interacting Protein (TXNIP) with Focus on Brain and Neurodegenerative Diseases.

机构信息

Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 525-0072, Shiga, Japan.

出版信息

Int J Mol Sci. 2020 Dec 8;21(24):9357. doi: 10.3390/ijms21249357.

DOI:10.3390/ijms21249357
PMID:33302545
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7764580/
Abstract

The development of new therapeutic approaches to diseases relies on the identification of key molecular targets involved in amplifying disease processes. One such molecule is thioredoxin-interacting protein (TXNIP), also designated thioredoxin-binding protein-2 (TBP-2), a member of the α-arrestin family of proteins and a central regulator of glucose and lipid metabolism, involved in diabetes-associated vascular endothelial dysfunction and inflammation. TXNIP sequesters reduced thioredoxin (TRX), inhibiting its function, resulting in increased oxidative stress. Many different cellular stress factors regulate TXNIP expression, including high glucose, endoplasmic reticulum stress, free radicals, hypoxia, nitric oxide, insulin, and adenosine-containing molecules. TXNIP is also directly involved in inflammatory activation through its interaction with the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome complex. Neurodegenerative diseases such as Alzheimer's disease have significant pathologies associated with increased oxidative stress, inflammation, and vascular dysfunctions. In addition, as dysfunctions in glucose and cellular metabolism have been associated with such brain diseases, a role for TXNIP in neurodegeneration has actively been investigated. In this review, we will focus on the current state of the understanding of possible normal and pathological functions of TXNIP in the central nervous system from studies of in vitro neural cells and the brains of humans and experimental animals with reference to other studies. As TXNIP can be expressed by neurons, microglia, astrocytes, and endothelial cells, a complex pattern of regulation and function in the brain is suggested. We will examine data suggesting TXNIP as a therapeutic target for neurodegenerative diseases where further research is needed.

摘要

新的治疗方法的发展疾病依赖于确定的关键分子靶点参与放大疾病过程。这样的分子是硫氧还蛋白相互作用蛋白(TXNIP),也称为硫氧还蛋白结合蛋白-2(TBP-2),α-抑制蛋白家族的蛋白质和葡萄糖和脂质代谢的中央调节剂,参与糖尿病相关的血管内皮功能障碍和炎症。TXNIP 隔离还原型硫氧还蛋白(TRX),抑制其功能,导致氧化应激增加。许多不同的细胞应激因素调节 TXNIP 的表达,包括高血糖、内质网应激、自由基、缺氧、一氧化氮、胰岛素和含腺苷的分子。TXNIP 还通过与核苷酸结合域、富含亮氨酸的家族和富含吡喃结构域的 3(NLRP3)炎性小体复合物相互作用直接参与炎症激活。阿尔茨海默病等神经退行性疾病与氧化应激、炎症和血管功能障碍增加有显著的病理关系。此外,由于葡萄糖和细胞代谢的功能障碍与这些脑部疾病有关,因此积极研究 TXNIP 在神经退行性变中的作用。在这篇综述中,我们将重点讨论目前对 TXNIP 在中枢神经系统中的正常和病理功能的理解,参考其他研究,从体外神经细胞和人类及实验动物大脑的研究中进行讨论。由于 TXNIP 可以由神经元、小胶质细胞、星形胶质细胞和内皮细胞表达,因此在大脑中存在复杂的调节和功能模式。我们将研究表明 TXNIP 作为神经退行性疾病治疗靶点的数据,其中需要进一步研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5387/7764580/8f6befab6e17/ijms-21-09357-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5387/7764580/b33bd34bb46b/ijms-21-09357-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5387/7764580/8f6befab6e17/ijms-21-09357-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5387/7764580/b33bd34bb46b/ijms-21-09357-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5387/7764580/8f6befab6e17/ijms-21-09357-g002.jpg

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