Li Yan, Wang Zhuo, Kong Min, Yong Yuanyuan, Yang Xin, Liu Chongdong
Department of Gynecology and Obstetrics, Affiliated Beijing Chaoyang Hospital of Capital Medical University, Beijing, China.
Department of Gynecology and Obstetrics, General Hospital of Ningxia Medical University, Yinchuan, China.
Front Pharmacol. 2024 Aug 20;15:1447605. doi: 10.3389/fphar.2024.1447605. eCollection 2024.
This study aims to investigate how changes in peripheral blood metabolites in Alzheimer's Disease (AD) patients affect the development of Pelvic Organ Prolapse (POP) using a multi-omics approach. We specifically explore the interactions of signaling pathways, gene expression, and protein-metabolite interactions, with a focus on GZMA and cysteine in age-related diseases. This study utilized multi-omics analysis, including metabolomics and transcriptomics, to evaluate the perturbations in peripheral blood metabolites and their effect on POP in AD patients. Additionally, a comprehensive pan-cancer and immune infiltration analysis was performed on the core targets of AD combined with POP, exploring their potential roles in tumor progression and elucidating their pharmacological relevance to solid tumors. We identified 47 differential metabolites linked to 9 significant signaling pathways, such as unsaturated fatty acid biosynthesis and amino acid metabolism. A thorough gene expression analysis revealed numerous differentially expressed genes (DEGs), with Gene Set Enrichment Analysis (GSEA) showing significant changes in gene profiles of AD and POP. Network topology analysis highlighted central nodes in the AD-POP co-expressed genes network. Functional analyses indicated involvement in critical biological processes and pathways. Molecular docking studies showed strong interactions between cysteine and proteins PTGS2 and GZMA, and molecular dynamics simulations confirmed the stability of these complexes. validation demonstrated that cysteine reduced ROS levels and protected cell viability. GZMA was widely expressed in various cancers, associated with immune cells, and correlated with patient survival prognosis. Multi-omics analysis revealed the role of peripheral blood metabolites in the molecular dynamics of AD and their interactions with POP. This study identified potential biomarkers and therapeutic targets, emphasizing the effectiveness of integrative approaches in treating AD and POP concurrently. The findings highlight the need for in-depth research on novel targets and biomarkers to advance therapeutic strategies.
本研究旨在采用多组学方法，探究阿尔茨海默病（AD）患者外周血代谢物的变化如何影响盆腔器官脱垂（POP）的发展。我们特别探讨了信号通路、基因表达和蛋白质-代谢物相互作用之间的相互作用，重点关注与年龄相关疾病中的GZMA和半胱氨酸。本研究利用包括代谢组学和转录组学在内的多组学分析，评估AD患者外周血代谢物的扰动及其对POP的影响。此外，对AD合并POP的核心靶点进行了全面的泛癌和免疫浸润分析，探索它们在肿瘤进展中的潜在作用，并阐明它们与实体瘤的药理学相关性。我们鉴定出47种与9条重要信号通路相关的差异代谢物，如不饱和脂肪酸生物合成和氨基酸代谢。深入的基因表达分析揭示了众多差异表达基因（DEG），基因集富集分析（GSEA）显示AD和POP的基因谱有显著变化。网络拓扑分析突出了AD-POP共表达基因网络中的中心节点。功能分析表明其参与关键的生物学过程和通路。分子对接研究表明半胱氨酸与蛋白质PTGS2和GZMA之间有强烈的相互作用，分子动力学模拟证实了这些复合物的稳定性。验证表明半胱氨酸降低了ROS水平并保护了细胞活力。GZMA在各种癌症中广泛表达，与免疫细胞相关，并与患者生存预后相关。多组学分析揭示了外周血代谢物在AD分子动力学中的作用及其与POP的相互作用。本研究确定了潜在的生物标志物和治疗靶点，强调了综合方法同时治疗AD和POP方法的有效性。研究结果强调了对新靶点和生物标志物进行深入研究以推进治疗策略的必要性。
