臭氧介导的大脑保护:通过铁变态反应和 NRF2/SLC7A11/GPX4 信号通路揭示机制

IF 2.7 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of chemical neuroanatomy Pub Date : 2024-01-03 DOI:10.1016/j.jchemneu.2023.102387
Farong Zhu , Shengyang Ding , Yu Liu , Xinlei Wang , Zhouquan Wu
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引用次数: 0

摘要

背景脑缺血/再灌注(I/R)损伤的发病机制以过度氧化应激反应导致神经元损失为特征。当细胞中的抗氧化剂和促氧化剂之间的平衡被打破时,就会引发铁氧化反应(一种氧化性细胞死亡)。臭氧是一种天然生物活性分子,具有抗氧化/抗凋亡和促进自噬的特性,已被证明能增强抗氧化系统的能力并改善氧化应激。然而,它在神经元铁凋亡中的作用仍不清楚。因此,我们研究了臭氧在脑缺血再灌注诱导的神经元铁变态反应死亡中的功能和可能机制。结果臭氧预处理减轻了脑缺血再灌注损伤对神经元的损伤,减轻了神经功能缺损的严重程度,降低了大脑中动脉闭塞(MCAO)大鼠的脑梗死体积,并缩小了脑梗死体积。透射电子显微镜、免疫荧光和 Western 印迹显示 MCAO 引起的脑损伤后出现了铁蛋白沉积。MCAO导致神经元线粒体形态损伤、脂质过氧化累积增加和丙二醛(MDA)生成增加。此外,MCAO 还降低了 FTH1 和 GPX4(铁氧化的负调控因子)的水平,增加了 ACSL4(铁氧化的正调控因子)的水平。臭氧预处理通过增加 NRF2 核转位以及 SLC7A11 和 GPX4 的表达,显示出神经保护作用。结论:我们的研究结果表明,臭氧治疗可通过NRF2/SLC7A11/GPX4途径减轻脑缺血再灌注损伤大鼠模型中的铁突变,为臭氧可能用作预防缺血性中风的疗法提供了理论依据。
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Ozone-mediated cerebral protection: Unraveling the mechanism through ferroptosis and the NRF2/SLC7A11/GPX4 signaling pathway

Background

The pathogenesis of brain ischemic/reperfusion (I/R) insult is characterized by neuronal loss due to excessive oxidative stress responses. Ferroptosis, a form of oxidative cell death, can be triggered when the balance between antioxidants and pro-oxidants in cells is disrupted. Ozone, a natural bioactive molecule with antioxidant/anti-apoptotic and pro-autophagic properties, has been shown to enhance the antioxidant system's capacity and ameliorate oxidative stress. However, its role in neuronal ferroptosis remains unclear. Therefore, we investigated the functions and possible mechanisms of ozone in cerebral I/R-induced ferroptotic neuronal death.

Methods

A cerebral ischemia-reperfusion injury model was induced in Sprague-Dawley (SD) rats pre-treated with ozone. Intraperitoneal administration of the NRF2 inhibitor ML385, the SLC7A11 inhibitor Erastin, and the GPX4 inhibitor RSL3 was performed one hour prior to model establishment.

Results

Our results showed that ozone preconditioning mitigated neuronal damage caused by cerebral I/R, reduced the severity of neurological deficits, lowered cerebral infarct volume in middle cerebral artery occlusion (MCAO) rats, and decreased the volume of cerebral infarcts. Transmission electron microscopy, immunofluorescence, and Western blotting indicated ferroptosis following MCAO-induced brain damage. MCAO resulted in morphological damage to neuronal mitochondria, increased lipid peroxidation accumulation, and elevated malondialdehyde (MDA) production. Furthermore, MCAO decreased levels of FTH1 and GPX4 (negative regulators of ferroptosis) and increased ACSL4 levels (a positive regulator of ferroptosis). Ozone preconditioning demonstrated a neuroprotective effect by increasing NRF2 nuclear translocation and the expression of SLC7A11 and GPX4. Treatment with ML385, Erastin, and RSL3 significantly reversed ozone preconditioning's protective effect on neuronal ferroptosis.

Conclusion

Our findings demonstrated that ozone treatment attenuates ferroptosis in a cerebral ischemia/reperfusion injury rat model via the NRF2/SLC7A11/GPX4 pathway, providing a theoretical basis for ozone's potential use as a therapy to prevent ischemic stroke.

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来源期刊
Journal of chemical neuroanatomy
Journal of chemical neuroanatomy 医学-神经科学
CiteScore
4.50
自引率
3.60%
发文量
87
审稿时长
62 days
期刊介绍: The Journal of Chemical Neuroanatomy publishes scientific reports relating the functional and biochemical aspects of the nervous system with its microanatomical organization. The scope of the journal concentrates on reports which combine microanatomical, biochemical, pharmacological and behavioural approaches. Papers should offer original data correlating the morphology of the nervous system (the brain and spinal cord in particular) with its biochemistry. The Journal of Chemical Neuroanatomy is particularly interested in publishing important studies performed with up-to-date methodology utilizing sensitive chemical microassays, hybridoma technology, immunocytochemistry, in situ hybridization and receptor radioautography, to name a few examples. The Journal of Chemical Neuroanatomy is the natural vehicle for integrated studies utilizing these approaches. The articles will be selected by the editorial board and invited reviewers on the basis of their excellence and potential contribution to this field of neurosciences. Both in vivo and in vitro integrated studies in chemical neuroanatomy are appropriate subjects of interest to the journal. These studies should relate only to vertebrate species with particular emphasis on the mammalian and primate nervous systems.
期刊最新文献
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