Prolonged loss of nuclear HMGB1 in neurons following modeled TBI and implications for long-term genetic health

IF 2.7 4区 医学 Q3 NEUROSCIENCES Brain Research Pub Date : 2025-03-11 DOI:10.1016/j.brainres.2025.149559
Laura R. Siracusa , Eugene Park , Elaine Liu , Andrew J. Baker
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Abstract

Under normal physiological conditions high mobility group box protein 1 (HMGB1) stabilizes chromatin, controls transcription, and contributes to DNA repair. Cellular stress or injury results in HMGB1 release from the nucleus acting as a proinflammatory cytokine. The objective of this study was to characterize the temporal progression of nuclear HMGB1 loss up to one week following modeled TBI in 250 g male rats and correlate these changes with the response of DNA damage proteins. HMGB1 was present in the cytoplasm and absent from the nucleus of neurons within 6 h of injury. Quantitative immunohistochemistry and Western blot analysis showed a significant decrease in nuclear HMGB1 expression at 6 and 24 h post-injury compared to controls. Approximately 20 % of neurons were lacking nuclear HMGB1 expression at 7 days post-injury. Cells which were negative for nuclear HMGB1 expression labelled positive for HIF1α, PARP, and γH2AX, indicators of oxidative stress and DNA damage. Nuclear HIF1α expression was detected at 6 h after injury. Nuclear expression of HIF1α, PARP, and γH2AX was observed at 7 days post-injury, suggesting activation of oxidative stress response mechanisms and DNA damage repair pathways. The temporal changes in HMGB1 translocation in conjunction with expression of DNA damage markers suggest a relationship between injury-induced HMGB1 loss in neurons and subsequent DNA damage. These results highlight a potential injury response mechanism with long-term implications in relation to genetic health of surviving neurons.

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在正常生理条件下,高迁移率基团盒蛋白 1(HMGB1)可稳定染色质、控制转录并促进 DNA 修复。细胞应激或损伤会导致 HMGB1 从细胞核中释放出来,成为一种促炎细胞因子。本研究的目的是描述 250 克雄性大鼠模型创伤性脑损伤后一周内核 HMGB1 损失的时间进展,并将这些变化与 DNA 损伤蛋白的反应联系起来。受伤后 6 小时内,HMGB1 出现在神经元的细胞质中,而从细胞核中消失。定量免疫组化和 Western 印迹分析表明,与对照组相比,受伤后 6 小时和 24 小时 HMGB1 的核表达显著下降。大约 20% 的神经元在损伤后 7 天缺乏核 HMGB1 表达。核 HMGB1 表达呈阴性的细胞,其 HIF1α、PARP 和 γH2AX 标记呈阳性,这是氧化应激和 DNA 损伤的指标。损伤后 6 小时检测到核 HIF1α 表达。损伤后7天,观察到HIF1α、PARP和γH2AX的核表达,表明氧化应激反应机制和DNA损伤修复途径被激活。HMGB1转位的时间变化与DNA损伤标记物的表达相结合,表明神经元中损伤诱导的HMGB1丢失与随后的DNA损伤之间存在关系。这些结果突显了一种潜在的损伤反应机制,对存活神经元的遗传健康具有长期影响。
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来源期刊
Brain Research
Brain Research 医学-神经科学
CiteScore
5.90
自引率
3.40%
发文量
268
审稿时长
47 days
期刊介绍: An international multidisciplinary journal devoted to fundamental research in the brain sciences. Brain Research publishes papers reporting interdisciplinary investigations of nervous system structure and function that are of general interest to the international community of neuroscientists. As is evident from the journals name, its scope is broad, ranging from cellular and molecular studies through systems neuroscience, cognition and disease. Invited reviews are also published; suggestions for and inquiries about potential reviews are welcomed. With the appearance of the final issue of the 2011 subscription, Vol. 67/1-2 (24 June 2011), Brain Research Reviews has ceased publication as a distinct journal separate from Brain Research. Review articles accepted for Brain Research are now published in that journal.
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