HSYA靶向ZBP1-166R位点抑制MAVS信号:脑缺血再灌注损伤的潜在治疗策略

IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Hao Sun , Kai Zhu , Yuqin Peng , Xian Zhou , Dennis Chang , Ning Wang , Ping Huang
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引用次数: 0

摘要

背景与目的:z - dna结合蛋白1 (ZBP1)是缺血性脑卒中引起的神经炎症的标志物。羟基红花黄A (HSYA)是红花的主要活性成分,对缺血性脑卒中具有神经保护作用。HSYA是否靶向ZBP1保护线粒体功能对抗脑缺血再灌注损伤(CIRI)尚不清楚。方法:在SD大鼠侧脑室注射针对ZBP1位点的质粒腺相关病毒(AAV)。采用线插法建立了MCAO/R模型,对CIRI进行了仿真。采用激光散斑血流仪和TTC染色对模型进行评价。采用行为学、形态学和影像学技术评估HSYA对CIRI的脑保护作用。蛋白对接和共免疫沉淀(CO-IP)实验证实了ZBP1与MAVS之间的相互作用。随后,在HT22细胞中建立氧葡萄糖剥夺/再氧化(OGD/R)模型。ELISA法检测炎症标志物和ATP水平,Western blot法检测信号通路蛋白表达。结果:成功建立的大鼠脑血流量明显减少。HSYA降低神经行为评分和脑指标,改善ZBP1病理分布,抑制细胞凋亡。HSYA可显著提高氧糖剥夺/再氧化(OGD/R)处理后的细胞活力,显著降低细胞凋亡率。此外,HSYA在MCAO/R损伤后,通过下调ZBP1和MAVS表达,上调TBK1表达,增强线粒体功能,抑制炎症因子释放。ZBP1位点突变后,HSYA的保护作用减弱。此外,ZBP1和MAVS表现出显著的相互作用。结论:我们的研究揭示了HSYA抗MCAO/R的机制可能与ZBP1 - A166R位点有关,为设计新的ZBP1拮抗剂治疗与ZBP1相关的各种疾病提供了模板。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
HSYA targets the ZBP1–166R site to inhibit MAVS signaling: A potential therapeutic strategy for cerebral ischemia-reperfusion injury

Background and purpose

Z-DNA-binding protein 1 (ZBP1) is a marker of neuroinflammation caused by ischemic stroke. Hydroxylsafflower Yellow A (HSYA), the main active component of safflower, has neuroprotective effects in ischemic stroke. Whether HSYA targets ZBP1 to protect mitochondrial function against cerebral ischemia-reperfusion injury (CIRI) remains unclear.

Methods

This study involves lateral ventricle injection of plasmid adeno-associated virus (AAV) targeting the ZBP1 locus in SD rats. The MCAO/R model is established using the line plug method to simulate CIRI. Laser speckle blood flow meter and TTC staining are used to evaluate the model. Behavioral, morphological, and imaging techniques were employed to assess the cerebro-protective effects of HSYA against CIRI. Protein-protein docking and co-immunoprecipitation (CO-IP) experiments confirmed the interaction between ZBP1 and MAVS. Subsequently, an oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in HT22 cells. The levels of inflammatory markers and ATP were measured using ELISA, and the expression of signaling pathway proteins was analyzed by Western blot.

Results

The cerebral blood flow in rats with a successfully established model was significantly decreased. HSYA reduces neurobehavioral scores and cerebral indices, improves ZBP1 pathologic distribution, and inhibits cell apoptosis. HSYA significantly enhanced cell viability and markedly decreased the apoptosis rate of cells following oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. Additionally, HSYA enhances mitochondrial function and suppresses inflammatory factor release by down-regulating ZBP1 and MAVS expression while up-regulating TBK1 expression, after MCAO/R injury. The protective effect of HSYA is weakened after ZBP1 site mutation. Moreover, ZBP1 and MAVS exhibit a significant interaction.

Conclusion

Our study reveals the mechanism of HSYA resisting MCAO/R may be associated with ZBP1 - A166R locus, and to design new ZBP1 antagonist treatment of various diseases associated with ZBP1 provides a template.
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来源期刊
Cellular signalling
Cellular signalling 生物-细胞生物学
CiteScore
8.40
自引率
0.00%
发文量
250
审稿时长
27 days
期刊介绍: Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.
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