四甲基吡嗪类似物 T-006 通过 PI3K/AKT/mTOR 和 Nrf2 信号传导保护神经元和内皮细胞免受氧化应激影响

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Guiliang Zhang, Zirong Liang, Yuqiang Wang, Zaijun Zhang, Pui-Man Hoi
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引用次数: 0

摘要

背景:T-006是四甲基吡嗪(TMP)的一种新型神经保护衍生物,具有多功能神经保护特性。研究表明,T-006 可改善缺血性中风和神经退行性疾病动物模型的神经和行为功能。本研究旨在进一步阐明T-006对谷氨酸或缺氧诱导的氧化损伤具有保护作用的机制:方法:用小鼠海马HT22细胞评估T-006对谷氨酸诱导的损伤的神经保护作用,用小鼠脑内皮细胞bEnd.3评估T-006对氧-葡萄糖剥夺后再灌注(OGD/R)诱导的损伤的脑血管保护作用。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四氮唑(MTT)测定法和流式细胞术用于测量细胞活力和氧化应激。蛋白表达的 Western 印迹和免疫荧光分析用于研究细胞信号通路:结果:T-006在两种氧化损伤模型中都表现出明显的保护作用。在HT22细胞中,T-006通过上调mTOR和核因子红细胞2相关因子2/血氧合酶-1(Nrf2/HO-1)信号转导,减少了细胞死亡并增强了抗氧化能力。同样,在bEnd.3细胞中,T-006通过上调Nrf2/HO-1减少了氧化损伤并保护了紧密连接的完整性。这些作用受到磷酸肌醇3-激酶(PI3K)抑制剂LY294002的抑制:结论:T-006可能通过调节PI3K/AKT介导的通路,促进下游mTOR和Nrf2信号转导,从而提高细胞存活率和抗氧化防御能力,发挥其神经保护和脑血管保护作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tetramethylpyrazine Analogue T-006 Protects Neuronal and Endothelial Cells Against Oxidative Stress via PI3K/AKT/mTOR and Nrf2 Signaling.

Background: T-006, a novel neuroprotective derivative of tetramethylpyrazine (TMP), exhibits multifunctional neuroprotective properties. T-006 has been shown to improve neurological and behavioral functions in animal models of ischemic stroke and neurodegenerative diseases. The present study aims to further elucidate the mechanisms underlying the protective effects of T-006 against oxidative injuries induced by glutamate or hypoxia.

Methods: Mouse hippocampal HT22 cells were used to evaluate the neuroprotective effects of T-006 against glutamate-induced injuries, while mouse brain endothelial bEnd.3 cells were used to evaluate the cerebrovascular protective effects of T-006 against oxygen-glucose deprivation followed by reperfusion (OGD/R)-induced injuries. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry were used to measure cell viability and oxidative stress. Western blot and immunofluorescence analyses of protein expression were used to study cell signaling pathways.

Results: T-006 exhibited significant protective effects in both oxidative injury models. In HT22 cells, T-006 reduced cell death and enhanced antioxidant capacity by upregulating mTOR and nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 (Nrf2/HO-1) signaling. Similarly, in bEnd.3 cells, T-006 reduced oxidative injuries and preserved tight junction integrity through Nrf2/HO-1 upregulation. These effects were inhibited by LY294002, a Phosphoinositide 3-kinase (PI3K) inhibitor.

Conclusions: T-006 may exert its neuroprotective and cerebrovascular protective effects via the regulation of PI3K/AKT-mediated pathways, which facilitate downstream mTOR and Nrf2 signaling, leading to improved cell survival and antioxidant defenses.

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来源期刊
Antioxidants
Antioxidants Biochemistry, Genetics and Molecular Biology-Physiology
CiteScore
10.60
自引率
11.40%
发文量
2123
审稿时长
16.3 days
期刊介绍: Antioxidants (ISSN 2076-3921), provides an advanced forum for studies related to the science and technology of antioxidants. It publishes research papers, reviews and communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files and software regarding the full details of the calculation or experimental procedure, if unable to be published in a normal way, can be deposited as supplementary electronic material.
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