干扰叉头盒O3介导的ctnna2转录抑制的诱饵寡脱氧核苷酸可预防小鼠术后神经认知障碍

IF 5 1区 医学 Q1 NEUROSCIENCES
Zhixin Wu, Dongkun Xie, Jing Zhao, Jianshuai Zhao, Huiqing Liu, Dong Xing, Tingting Gu, Yaru Guo, Dan Wang, Zhihong Lu, Hailong Dong, Junlong Zhao, Jiao Deng
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Finally, an decoy targeting the Foxo3-ctnna2 interaction was designed and tested for effectiveness in PND.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Our results showed that the SNP rs12472215 is located at a newly defined enhancer region within the <i>ctnna2</i> intron that can be regulated by Foxo3 in the human genome. The rs12472215 A&gt;T mutation potentiates Foxo3's transcriptive inhibitory effect on <i>ctnna2</i>. Experimental laparotomy in mice revealed that hippocampal Foxo3 upregulation and α-N-catenin reduction are involved in PND development. ChIP-PCR deciphered two regulatory sites (R1 and R2) of Foxo3 on <i>ctnna2</i> in the mice that are strengthened by T + I. siAscl1 abolished the rescue effect of carbenoxolone (CBX, Foxo3-specific inhibitor) on α-N-catenin expression in the T + I model, indicating that Foxo3 inhibits <i>ctnna2</i> transcription indirectly through Ascl1. Reduction of Sirt1 increased acetyl-Foxo3, which enhanced its stability in PND. 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引用次数: 0

摘要

围手术期认知障碍(PND)影响高达31%的手术患者。尽管临床研究已经确定了多种风险因素,但还没有制定出有效的预防措施。从我们之前的PND患者队列中,发现了ctnna2上的几个单核苷酸多态性(SNP)位点。本研究旨在破解ctnna2在PND模型中的作用和调控机制,并开发可能预防PND的诱饵寡脱氧核苷酸(decoy)。方法采用小鼠剖腹探查+异氟醚模型和神经元模型(TNFα+异氟醚,T + I)。利用生物信息学方法鉴定ctnna2、foxo3序列的转录活性区域,并预测可能的转录调控因子。利用分子生物学技术分析了Sirt1-foxo3-ctnna2轴在PND发育中的调控机制和特异位点。最后,设计了一个针对Foxo3-ctnna2相互作用的诱饵,并测试了其在PND中的有效性。结果我们的研究结果表明,SNP rs12472215位于人类基因组中ctnna2内含子内一个新定义的增强子区域,该区域可以被Foxo3调节。rs12472215 A>;T突变增强了Foxo3对ctnna2的转录抑制作用。小鼠剖腹实验发现,海马Foxo3上调和α-N-catenin减少参与了PND的发生。ChIP-PCR在T + I增强小鼠的ctnna2上破译了Foxo3的两个调控位点(R1和R2)。siAscl1在T + I模型中消除了carbenoxolone (CBX, Foxo3特异性抑制剂)对α-N-catenin表达的拯救作用,说明Foxo3通过Ascl1间接抑制ctnna2转录。Sirt1的减少增加了乙酰- foxo3,增强了其在PND中的稳定性。Sirt1激活降低了T + I刺激神经元中Foxo3的表达和乙酰-Foxo3水平,并恢复了α-N-catenin的表达。更重要的是,干扰Foxo3-ctnna2相互作用的新诱饵能有效防止PND小鼠α-N-catenin减少、CA1锥体神经元形态改变、电生理功能障碍,改善认知缺陷。结论本研究结果为确定PND的治疗目标和制定干预措施提供了新的思路。该诱饵具有特异性和作用时间短,值得进一步探索临床应用的可能性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A Decoy Oligodeoxynucleotides Disturbing Forkhead Box O3 Mediated ctnna2 Transcriptional Repression Prevents Postoperative Neurocognitive Disorder in Mice

A Decoy Oligodeoxynucleotides Disturbing Forkhead Box O3 Mediated ctnna2 Transcriptional Repression Prevents Postoperative Neurocognitive Disorder in Mice

Background

Perioperative cognitive disorder (PND) affects up to 31% of surgical patients. Although clinical studies have identified a variety of risk factors, no effective prevention has been developed. From our previous cohort of PND patients, several single-nucleotide polymorphism (SNP) sites on ctnna2 were identified. The current study aims to decipher the role and regulatory mechanism of ctnna2 in the PND model and to develop decoy oligodeoxynucleotides (decoy) for the possible prevention of PND.

Methods

Both mice model (exploratory laparotomy+isoflurane) and the neuronal model (TNFα+isoflurane, T + I) for PND were used. Bioinformatic research was utilized to identify transcriptive active areas on ctnna2, foxo3 sequence, and to predict possible transcriptional factors for regulation. Molecular biological techniques were used to decipher the regulatory mechanism and specific sites of the Sirt1-foxo3-ctnna2 axis in the development of PND. Finally, an decoy targeting the Foxo3-ctnna2 interaction was designed and tested for effectiveness in PND.

Results

Our results showed that the SNP rs12472215 is located at a newly defined enhancer region within the ctnna2 intron that can be regulated by Foxo3 in the human genome. The rs12472215 A>T mutation potentiates Foxo3's transcriptive inhibitory effect on ctnna2. Experimental laparotomy in mice revealed that hippocampal Foxo3 upregulation and α-N-catenin reduction are involved in PND development. ChIP-PCR deciphered two regulatory sites (R1 and R2) of Foxo3 on ctnna2 in the mice that are strengthened by T + I. siAscl1 abolished the rescue effect of carbenoxolone (CBX, Foxo3-specific inhibitor) on α-N-catenin expression in the T + I model, indicating that Foxo3 inhibits ctnna2 transcription indirectly through Ascl1. Reduction of Sirt1 increased acetyl-Foxo3, which enhanced its stability in PND. Sirt1 activation reduced Foxo3 expression, acetyl-Foxo3 level, and rescued α-N-catenin expression in T + I stimulated neurons. More importantly, the new decoy disturbing Foxo3-ctnna2 interaction effectively prevents α-N-catenin reduction, CA1 pyramidal neuron morphological change, electrophysiological dysfunction, and improves cognitive deficit in PND mice.

Conclusions

These results provided a new revenue for identifying targets and developing interventions for PND. The decoy, due to its specificity and short acting time, merits further exploration for possible clinical use.

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来源期刊
CNS Neuroscience & Therapeutics
CNS Neuroscience & Therapeutics 医学-神经科学
CiteScore
7.30
自引率
12.70%
发文量
240
审稿时长
2 months
期刊介绍: CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.
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