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Nrf2 通路激活促进酒精暴露的星形胶质细胞中与谷胱甘肽代谢相关基因的表达。

Nrf2 pathway activation promotes the expression of genes related to glutathione metabolism in alcohol-exposed astrocytes.

机构信息

Department of Neurology, The First Affiliated Hospital of Jiamusi University, Jiamusi, China.

Jiamusi University, Jiamusi, People's Republic of China.

出版信息

PeerJ. 2024 May 31;12:e17541. doi: 10.7717/peerj.17541. eCollection 2024.

DOI:10.7717/peerj.17541
PMID:38832034
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11146317/
Abstract

INTRODUCTION: Oxidative and antioxidant pathways play essential roles in the development of alcohol-induced brain injury. The Nrf2 pathway is an endogenous antioxidant response pathway, but there has been little research on the role of Nrf2 in alcohol-related diseases. Thus, we examined the effects of alcohol and an Nrf2 agonist (TBHQ) on astrocyte function, mRNA expression, and metabolite content to further explore the protective mechanisms of Nrf2 agonists in astrocytes following alcohol exposure. METHODS: CTX TNA2 astrocytes were cultured with alcohol and TBHQ and then subjected to transcriptome sequencing, LC-MS/MS analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and malondialdehyde (MDA) and superoxide dismutase (SOD) activity assays. RESULTS: Alcohol exposure significantly increased malondialdehyde (MDA) levels while decreasing superoxide dismutase (SOD) levels in astrocytes. Treatment with TBHQ effectively reversed these effects, demonstrating its protective role against oxidative stress induced by alcohol. Transcriptome sequencing and qRT-PCR analysis revealed that TBHQ specifically upregulates genes involved in glutathione metabolism, including a notable increase in the expression of the glutathione S-transferase A5 (GSTA5) gene, which was suppressed by alcohol exposure. Additionally, metabolomic analysis showed that TBHQ regulates key components of ether lipid metabolism in alcohol-exposed astrocytes, with significant reductions in the levels of lysophosphatidylcholine (18:0) (LysoPC (18:0)) and 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine, both of which are critical markers in the ether lipid metabolic pathway. DISCUSSION: The findings underscore the role of TBHQ as an Nrf2 agonist in mitigating alcohol-induced oxidative damage in astrocytes by modulating glutathione metabolism and ether lipid metabolism. The regulation of GSTA5 gene expression emerges as a key mechanism through which Nrf2 agonists confer neuroprotection against oxidative stress and lipid oxidation. These insights pave the way for potential therapeutic strategies targeting the Nrf2 pathway to protect astrocytes from alcohol-induced damage.

摘要

简介：氧化和抗氧化途径在酒精引起的脑损伤的发展中起着至关重要的作用。Nrf2 途径是一种内源性抗氧化反应途径，但关于 Nrf2 在与酒精相关的疾病中的作用的研究甚少。因此，我们研究了酒精和 Nrf2 激动剂 (TBHQ) 对星形胶质细胞功能、mRNA 表达和代谢物含量的影响，以进一步探讨 Nrf2 激动剂在酒精暴露后对星形胶质细胞的保护机制。 方法：CTX TNA2 星形胶质细胞用酒精和 TBHQ 培养，然后进行转录组测序、LC-MS/MS 分析、定量逆转录聚合酶链反应 (qRT-PCR) 和丙二醛 (MDA) 和超氧化物歧化酶 (SOD) 活性测定。 结果：酒精暴露显著增加了星形胶质细胞中的丙二醛 (MDA) 水平，同时降低了超氧化物歧化酶 (SOD) 水平。TBHQ 的治疗有效逆转了这些作用，表明其对酒精诱导的氧化应激具有保护作用。转录组测序和 qRT-PCR 分析表明，TBHQ 特异性地上调了谷胱甘肽代谢相关基因，包括谷胱甘肽 S-转移酶 A5 (GSTA5) 基因的表达显著增加，而该基因的表达在酒精暴露时受到抑制。此外，代谢组学分析表明，TBHQ 调节了酒精暴露星形胶质细胞中醚脂代谢的关键成分，其中溶血磷脂酰胆碱 (18:0) (LysoPC (18:0)) 和 2-乙酰-1-烷基-sn-甘油-3-磷酸胆碱的水平显著降低，这两种物质都是醚脂代谢途径中的关键标志物。 讨论：这些发现强调了 TBHQ 作为 Nrf2 激动剂的作用，通过调节谷胱甘肽代谢和醚脂代谢，减轻酒精引起的星形胶质细胞氧化损伤。GSTA5 基因表达的调节是 Nrf2 激动剂对抗氧化应激和脂质氧化引起的神经保护的关键机制。这些发现为针对 Nrf2 途径的潜在治疗策略提供了思路，以保护星形胶质细胞免受酒精引起的损伤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/c219dbe15db4/peerj-12-17541-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/1f8321a48488/peerj-12-17541-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/290e0be81101/peerj-12-17541-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/265c6ddc4d2e/peerj-12-17541-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/b107aa0993d7/peerj-12-17541-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/3fd92d91d9da/peerj-12-17541-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/3c3ffc05d1c0/peerj-12-17541-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/183bea4f28e7/peerj-12-17541-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/c219dbe15db4/peerj-12-17541-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/1f8321a48488/peerj-12-17541-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/290e0be81101/peerj-12-17541-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/265c6ddc4d2e/peerj-12-17541-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/b107aa0993d7/peerj-12-17541-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/3fd92d91d9da/peerj-12-17541-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/3c3ffc05d1c0/peerj-12-17541-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/183bea4f28e7/peerj-12-17541-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e363/11146317/c219dbe15db4/peerj-12-17541-g008.jpg

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本文引用的文献

[1]
Inhibition of the Rho/ROCK pathway promotes the expression of developmental and migration-related genes in astrocytes exposed to alcohol.

Alcohol. 2024-3

[2]
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PeerJ. 2023

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Am J Physiol Cell Physiol. 2023-6-1

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Redox Biol. 2023-2

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Acta Cir Bras. 2021

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Pharmacol Res. 2021-4

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