Analysis of the role of PANoptosis in intervertebral disk degeneration via integrated bioinformatics analysis and experimental validation.

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2024-11-17 DOI:10.1016/j.intimp.2024.113528

Daqian Zhou, Jiale Lv, Yongliang Mei, Chao Song, Tao Liu, Kang Cheng, Weiye Cai, Siling Gao, Yang Zhou, Zhongwei Xiong, Zongchao Liu

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Abstract

Intervertebral disc degeneration (IVDD) is an age-related orthopedic degenerative disease characterized by recurrent episodes of lower back pain, and death of nucleus pulposus cells (NPCs) has been identified as a key factor in the pathophysiological process of IVDD episodes. Recent studies have shown that " PANapoptosis ", a newly characterized form of cell death, has emerged as an important factor contributing to the development of several diseases. However, studies on the specific mechanisms of its role in the development of IVDD are lacking. The aim of this study was to explore the characterization of PANoptosis in IVDD and to identify potential biomarkers and therapeutic targets as well as therapeutic agents. We constructed a PANoptosis gene set, based on the GEO database, and used weighted gene co-expression network analysis (WGCNA) and differential expression analysis to identify PANoptosis genes associated with the pathophysiological process of IVDD episodes by Gene Set Enrichment Analysis (GSEA), immune infiltration, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to explore the underlying biological mechanisms of PANoptosis and its role in IVDD. Comprehensive bioinformatics analysis showed that seven key genes (APAF1, MEFV, NLRP3, TNF, GSDMD, AIM2, and IRF1) of PANoptosis have good diagnostic value. In addition, we predicted potential therapeutic agents, among which Andrographolide (AG) had the highest correlation and binding affinity to the target. Finally, we performed Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) assays, molecular docking, and cell flow to validate the expression of PANoptosis-related genes and the therapeutic effect of AG. We further divided SD rats into sham-operated, IVDD model, and Andrographolide-treated groups, administered AG at 50 mg/kg via gavage for one month, and observed significant therapeutic effects through HE staining. This study identifies key PANoptosis genes and demonstrates the potential of AG as a therapeutic agent for IVDD.

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通过综合生物信息学分析和实验验证，分析 PANoptosis 在椎间盘退变中的作用。

椎间盘退行性变（IVDD）是一种与年龄有关的骨科退行性疾病，其特征是反复发作的下背痛，髓核细胞（NPC）的死亡已被确定为 IVDD 病理生理过程中的一个关键因素。最近的研究表明，"髓核凋亡 "这种新表征的细胞死亡形式已成为导致多种疾病发生的重要因素。然而，有关其在 IVDD 发展过程中作用的具体机制的研究还很缺乏。本研究旨在探索 IVDD 中 PAN 细胞凋亡的特征，并确定潜在的生物标记物、治疗靶点和治疗药物。我们基于 GEO 数据库构建了 PANoptosis 基因集，并利用加权基因共表达网络分析（WGCNA）和差异表达分析，通过基因组富集分析（GSEA）、免疫浸润、基因本体（GO）和京都基因与基因组百科全书（KEGG）等方法鉴定了与 IVDD 发病病理生理过程相关的 PANoptosis 基因，以探索 PANoptosis 的潜在生物学机制及其在 IVDD 中的作用。综合生物信息学分析表明，PANoptosis的七个关键基因（APAF1、MEFV、NLRP3、TNF、GSDMD、AIM2和IRF1）具有良好的诊断价值。此外，我们还预测了潜在的治疗药物，其中穿心莲内酯（AG）与靶点的相关性和结合亲和力最高。最后，我们进行了 Western 印迹和定量实时聚合酶链反应（qRT-PCR）检测、分子对接和细胞流式实验，以验证 PANoptosis 相关基因的表达和 AG 的治疗效果。我们进一步将SD大鼠分为假手术组、IVDD模型组和穿心莲内酯治疗组，以50 mg/kg的剂量灌胃AG一个月，并通过HE染色观察其显著的治疗效果。本研究发现了关键的泛凋亡基因，证明了AG作为IVDD治疗药物的潜力。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.