蛛网膜下腔出血中通过 Circodz3/HuR 轴连接褪黑激素、铁凋亡和小胶质细胞极化的新机制

IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemical Research Pub Date : 2024-06-18 DOI:10.1007/s11064-024-04193-x
Yanju Song, Xin Luo, Liping Yao, YingChao Chen, Xinfa Mao
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摘要

蛛网膜下腔出血(SAH)是指蛛网膜下腔出血导致脑损伤,危及生命。越来越多的证据表明,褪黑激素能在蛛网膜下腔出血后提供神经保护。探索褪黑激素介导的神经保护机制有助于其在 SAH 中的临床应用。研究人员收集了 SAH 患者的血浆和脑脊液(CSF),并通过蝶窦前注射建立了 SAH 小鼠。测定了Circodz3的表达、IL-1β和TNF-α的水平、脑含水量、神经系统评分和束光评分。通过分析铁、脂质 ROS、MDA 和 GSH 的水平来评估铁变态反应。通过免疫荧光染色分析了 circodz3 和 Iba-1 的共定位。通过 RNA 拉取和 RNA 免疫沉淀实验确定了 circodz3 和 HuR 的相互作用。在此,我们发现 circodz3 在 SAH 患者和小鼠中含量很高。circodz3和Iba-1在SAH小鼠左半球的共定位提示了circodz3在SAH后调节小胶质细胞活化的作用。褪黑素减轻了SAH小鼠的脑水肿、神经功能损伤和小胶质细胞活化,并抑制了circodz3的表达。此外,褪黑素还能抑制M1极化、氧化应激和铁变态反应,并抑制SAH后原代小胶质细胞中circodz3的表达。circodz3的过表达会削弱这些作用。Circodz3敲除抑制了SAH后BV2小胶质细胞的铁突变和M1极化。Circodz3与HuR相互作用,促进β-Trcp1介导的泛素化和降解,从而抑制SLC7A11和GPX4的表达。总之,褪黑激素通过circodz3/HuR轴抑制铁变态反应和M1极化,从而在SAH后发挥神经保护作用。我们的研究提示了褪黑激素在治疗 SAH 中的潜在应用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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A Novel Mechanism Linking Melatonin, Ferroptosis and Microglia Polarization via the Circodz3/HuR Axis in Subarachnoid Hemorrhage

CircODZ3 is highly abundant in the plasma and cerebrospinal fluid from SAH patients.

Melatonin protects against SAH by inhibiting circodz3 expression.

Silencing of circodz3 inhibits ferroptosis and M1 polarization of BV2 microglia.

Circodz3 interacts with HuR to promote its ubiquitination and degradation.

Circodz3 degrades HuR to reduce SLC7A11 and GPX4 expression.

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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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