Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan City, Shandong Province, China.
Department of Hematology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China.
Sci Rep. 2023 Sep 16;13(1):15370. doi: 10.1038/s41598-023-42721-x.
Methazolamide is a carbonic anhydrase (CA) inhibitor with satisfactory safety. Our previous studies have demonstrated the elevation of CA1 expression and the therapeutic effect of Methazolamide in Ankylosing spondylitis (AS). In this study, we explored the pathogenic role of CA1 and the pharmacological mechanism of Methazolamide in AS through Gene Set Enrichment Analysis (GSEA) and network pharmacology. Seven out of twelve CA1 related gene sets were enriched in AS group. CA1 was core enriched in above seven gene sets involving zinc ion binding, arylesterase activity and one carbon metabolic process. Functional analysis of the candidate target genes obtained from the intersection of AS associated genes and Methazolamide target genes indicated that Methazolamide exerts therapeutic effects on AS mainly through inflammatory pathways which regulate the production of tumor necrosis factor, IL-6 and nitric oxide. PTGS2, ESR1, GSK3β, JAK2, NOS2 and CA1 were selected as therapeutic targets of Methazolamide in AS. Molecular docking and molecular dynamics simulations were performed successfully. In addition, we innovatively obtained the intersection of Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and GSEA results, and found that 18 GO terms and 5 KEGG terms were indicated in the pharmacological mechanism of Methazolamide in AS, involving bone mineralization, angiogenesis, inflammation, and chemokine signaling pathways. Nevertheless, validation for these mechanisms is needed in vivo/vitro experiments.
氨苯蝶啶是一种碳酸酐酶（CA）抑制剂，具有良好的安全性。我们之前的研究表明，CA1 的表达升高和氨苯蝶啶在强直性脊柱炎（AS）中的治疗作用。在这项研究中，我们通过基因集富集分析（GSEA）和网络药理学探索了 CA1 在 AS 中的致病作用和氨苯蝶啶的药理机制。在 AS 组中，有 12 个 CA1 相关基因集中的 7 个被富集。CA1 是上述七个基因集中核心富集的基因，这些基因集涉及锌离子结合、芳基酯酶活性和一碳代谢过程。从 AS 相关基因和氨苯蝶啶靶基因的交集获得的候选靶基因的功能分析表明，氨苯蝶啶对 AS 的治疗作用主要通过炎症途径发挥作用，这些途径调节肿瘤坏死因子、IL-6 和一氧化氮的产生。PTGS2、ESR1、GSK3β、JAK2、NOS2 和 CA1 被选为 AS 中氨苯蝶啶的治疗靶点。分子对接和分子动力学模拟成功进行。此外，我们创新性地获得了基因本体论（GO）/京都基因与基因组百科全书（KEGG）分析和 GSEA 结果的交集，并发现 18 个 GO 术语和 5 个 KEGG 术语在 AS 中氨苯蝶啶的药理机制中被指示，涉及骨矿化、血管生成、炎症和趋化因子信号通路。然而，这些机制需要在体内/体外实验中进行验证。
