Exploration of Key Genes and Molecular Mechanisms in Mice with Perioperative Neurocognitive Disorders Treated with Remimazolam Based on Transcriptomics and Experimental Verification.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-09-10 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S541958

Shilin Yu, Bo Chen, Mei Zhang, Rong Hu, Jin Luo, Ju Li, Wen Hu, Xiaohua Zou

{"title":"Exploration of Key Genes and Molecular Mechanisms in Mice with Perioperative Neurocognitive Disorders Treated with Remimazolam Based on Transcriptomics and Experimental Verification.","authors":"Shilin Yu, Bo Chen, Mei Zhang, Rong Hu, Jin Luo, Ju Li, Wen Hu, Xiaohua Zou","doi":"10.2147/DDDT.S541958","DOIUrl":null,"url":null,"abstract":"Background: As the number of elderly patients grew, perioperative neurocognitive disorder (PND) from drug - induced anesthesia and surgery drew more attention. Studies showed remimazolam could reduce PND. Thus, exploring key target genes in remimazolam's intervention of PND was crucial.Methods: In this study, behavioral observations were conducted using the PND model. Hippocampal tissues from 15 mice (5 PND, 5 PND, and 5 intervention groups) were collected for total RNA extraction and mRNA sequencing. Candidate genes were identified via differential expression analysis and intersection. Key genes were determined through overlapping three algorithms in protein-protein interaction (PPI) analysis and expression verification. Functional enrichment, immune infiltration, and molecular docking analyses were performed, with their expression levels further validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).Results: There were significant differences in the behavior of mice among different groups. Based on the intersection of up-and down-regulated genes in 357 differentially expressed genes1 (DEGs1) and 323 DEGs2, a total of 38 candidate genes were identified. Finally, we selected Jph3 and Caly as the key genes for subsequent study. Moreover, the PCR results showed that the expression of key genes in the PNG group was nearly twice that of the control group (p < 0.05). In-depth research revealed that pathways like glutamate receptor binding, tau protein binding, and GABA-gated chloride ion channel activity played important roles in disease occurrence. Meanwhile, 5 immune cells (including dendritic cells, macrophages, and gamma delta T cells) showed substantial differences between the model and PND groups, potentially contributing to disease development. Additionally, only Jph3 was regulated by mmu-miR-6969-5p and mmu-miR-186-5p. Both Jph3 and Caly had good binding abilities with remimazolam (< -5.0 kcal/mol), highlighting their potential as therapeutic agents for PND.Conclusion: This study identified 2 validated key genes (Jph3 and Caly), providing potential therapeutic targets for PND patients.","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"8115-8133"},"PeriodicalIF":5.1000,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433651/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/DDDT.S541958","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background: As the number of elderly patients grew, perioperative neurocognitive disorder (PND) from drug - induced anesthesia and surgery drew more attention. Studies showed remimazolam could reduce PND. Thus, exploring key target genes in remimazolam's intervention of PND was crucial.

Methods: In this study, behavioral observations were conducted using the PND model. Hippocampal tissues from 15 mice (5 PND, 5 PND, and 5 intervention groups) were collected for total RNA extraction and mRNA sequencing. Candidate genes were identified via differential expression analysis and intersection. Key genes were determined through overlapping three algorithms in protein-protein interaction (PPI) analysis and expression verification. Functional enrichment, immune infiltration, and molecular docking analyses were performed, with their expression levels further validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

Results: There were significant differences in the behavior of mice among different groups. Based on the intersection of up-and down-regulated genes in 357 differentially expressed genes1 (DEGs1) and 323 DEGs2, a total of 38 candidate genes were identified. Finally, we selected Jph3 and Caly as the key genes for subsequent study. Moreover, the PCR results showed that the expression of key genes in the PNG group was nearly twice that of the control group (p < 0.05). In-depth research revealed that pathways like glutamate receptor binding, tau protein binding, and GABA-gated chloride ion channel activity played important roles in disease occurrence. Meanwhile, 5 immune cells (including dendritic cells, macrophages, and gamma delta T cells) showed substantial differences between the model and PND groups, potentially contributing to disease development. Additionally, only Jph3 was regulated by mmu-miR-6969-5p and mmu-miR-186-5p. Both Jph3 and Caly had good binding abilities with remimazolam (< -5.0 kcal/mol), highlighting their potential as therapeutic agents for PND.

Conclusion: This study identified 2 validated key genes (Jph3 and Caly), providing potential therapeutic targets for PND patients.

Abstract Image

查看原文本刊更多论文

基于转录组学和实验验证的雷马唑仑治疗围手术期神经认知障碍小鼠关键基因和分子机制探索。

背景：随着老年患者数量的增加，药物麻醉和手术引起的围手术期神经认知障碍（PND）越来越受到关注。研究表明，雷马唑仑可以减少PND。因此，探索雷马唑仑干预PND的关键靶基因至关重要。方法：本研究采用PND模型进行行为观察。收集15只小鼠（5个PND组、5个PND组和5个干预组）的海马组织进行总RNA提取和mRNA测序。通过差异表达分析和交叉鉴定候选基因。在蛋白相互作用（PPI）分析和表达验证中，通过重叠三种算法确定关键基因。进行功能富集、免疫浸润和分子对接分析，并通过逆转录-定量聚合酶链反应（RT-qPCR）进一步验证其表达水平。结果：各组小鼠行为差异有统计学意义。通过357个差异表达基因1 （DEGs1）和323个DEGs2中上调和下调基因的交集，共鉴定出38个候选基因。最后，我们选择Jph3和Caly作为后续研究的关键基因。PCR结果显示，PNG组关键基因的表达量几乎是对照组的2倍（p < 0.05）。深入研究发现，谷氨酸受体结合、tau蛋白结合、gaba门控氯离子通道活性等途径在疾病发生过程中发挥了重要作用。同时，5种免疫细胞（包括树突状细胞、巨噬细胞和γ δ T细胞）在模型组和PND组之间表现出显著差异，可能有助于疾病的发展。此外，只有Jph3受到mmu-miR-6969-5p和mmu-miR-186-5p的调控。Jph3和Caly均与雷马唑仑具有良好的结合能力（< -5.0 kcal/mol），显示了它们作为PND治疗剂的潜力。结论：本研究确定了2个已验证的关键基因Jph3和Caly，为PND患者提供了潜在的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.