School of Clinical Medicine, Jining Medical University, Jining, China.
Department of Intensive Care Unit, Affiliated Jining First People's Hospital of Shandong First Medical University, Jining, Shandong, China.
Sci Rep. 2024 Nov 27;14(1):29466. doi: 10.1038/s41598-024-80865-6.
Currently, the diagnosis of delirium is solely based on clinical observation, lacking objective diagnostic tools, and the regulatory networks and pathological mechanisms behind it are not yet fully understood. Exosomes have garnered considerable interest as potential biomarkers for a variety of illnesses. This research aimed to delineate both the proteomic and metabolomic landscapes inherent to exosomes, assessing their diagnostic utility in postoperative delirium (POD) and understanding the underlying pathophysiological frameworks. Integrated analyses of proteomics and metabolomics were conducted on exosomes derived from plasma of individuals from both the non-postoperative delirium (NPOD) control group and the POD group. Subsequently, the study utilized the Connectivity Map (CMap) methodology for the identification of promising small-molecule drugs and carried out molecular docking assessments to explore the binding affinities with the enzyme MMP9 of these identified molecules. We identified significant differences in exosomal metabolites and proteins between the POD and control groups, highlighting pathways related to neuroinflammation and blood-brain barrier (BBB) integrity. Our CMap analysis identified potential small-molecule therapeutics, and molecular docking studies revealed two compounds with high affinity to MMP9, suggesting a new therapeutic avenue for POD. This study highlights MMP9, TLR2, ICAM1, S100B, and glutamate as key biomarkers in the pathophysiology of POD, emphasizing the roles of neuroinflammation and BBB integrity. Notably, molecular docking suggests mirin and orantinib as potential inhibitors targeting MMP9, providing new therapeutic avenues. The findings broaden our understanding of POD mechanisms and suggest targeted strategies for its management, reinforcing the importance of multidimensional biomarker analysis and molecular targeting in POD intervention.
目前，谵妄的诊断仅基于临床观察，缺乏客观的诊断工具，其调控网络和病理机制尚不完全清楚。外泌体作为多种疾病的潜在生物标志物引起了广泛关注。本研究旨在描绘外泌体固有的蛋白质组学和代谢组学特征，评估其在术后谵妄（POD）中的诊断效用，并了解潜在的病理生理框架。对来自非术后谵妄（NPOD）对照组和 POD 组个体血浆来源的外泌体进行蛋白质组学和代谢组学的综合分析。随后，该研究利用连接图谱（CMap）方法鉴定有前途的小分子药物，并进行分子对接评估，以探索这些鉴定分子与酶 MMP9 的结合亲和力。我们发现 POD 组和对照组之间外泌体代谢物和蛋白质存在显著差异，突出了与神经炎症和血脑屏障（BBB）完整性相关的途径。我们的 CMap 分析确定了潜在的小分子治疗药物，分子对接研究揭示了两种与 MMP9 具有高亲和力的化合物，这表明 POD 有新的治疗途径。这项研究强调了 MMP9、TLR2、ICAM1、S100B 和谷氨酸作为 POD 病理生理学的关键生物标志物，强调了神经炎症和 BBB 完整性的作用。值得注意的是，分子对接表明米林和奥替尼布可能是 MMP9 的潜在抑制剂，为其提供了新的治疗途径。这些发现拓宽了我们对 POD 机制的理解，并为其管理提出了靶向策略，强调了多维生物标志物分析和 POD 干预中分子靶向的重要性。
