Salicylalazine: A novel therapeutic agent targeting TLR4/NLRP3/GSDMD-mediated pyroptosis in rheumatoid arthritis.

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2024-12-11 DOI:10.1016/j.intimp.2024.113778

Sumera Qasim, Fakhria A Al-Joufi, Ambreen Malik Uttra, Hafiza Sara Afzal, Shaimaa R Ahmed

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引用次数: 0

Abstract

Background: Joint pain and functional impairment are hallmarks of arthritis, a painful inflammatory disease. Salicylalazine (SAZ), an anti-inflammatory compound, has demonstrated promise in modulating inflammation, thereby being selected in the current study to unveil its anti-arthritic potential.

Objectives: The aim behind this study was to assess the anti-arthritic properties of salicylalazine via evaluating its impact on paw volume, arthritic scores, oxidative stress indicators, and significant inflammatory mediators.

Methods: The arthritic potential of SAZ was estimated first through the formaldehyde (FA) model to screen the most effective dose of SAZ, followed by the Complete Freund's adjuvant (CFA) model. Over a 28-day period, we monitored parameters such as paw edema, arthritic index, body weight, flexion pain, mobility, and stance score. Oxidative stress markers (GSH, CAT, SOD, MDA), serological markers (CRP, RF, anti-CCP), and gene expression of key inflammatory mediators (TLR4, MyD88, NFκB, NLRP3, ASC, IL-1β, IL-18, caspase-1, GSDMD) were assessed.

Results: SAZ treatment led to a substantial decrease in paw volume in both arthritis models, with the most pronounced effects observed on day 10 for the formaldehyde model and day 28 for the CFA model (p < 0.001). Additionally, SAZ helped to restore the body's weight and considerably relieved the flexion pain, which led to improvements in both mobility and stance. Moreover, SAZ substantially raised the levels of antioxidant enzymes (GSH, CAT, SOD) and decreased MDA levels, suggesting a reduction in oxidative stress. Also with SAZ, there was a substantial (p < 0.001) decrease in the expression of pyroptotic mediators. Serological markers of inflammation, including CRP, RF, and anti-CCP levels, were also restored by SAZ administration.

Conclusion: In a nutshell, SAZ achieved significant anti-arthritic benefits, most likely via the modulation of the TLR4/NLRP3/GSDMD-mediated pyroptosis pathway, lowering oxidative stress, and improvement of clinical findings. Taking into consideration these findings, it seems that SAZ has the potential to be an effective treatment alternative for the management of arthritis.

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水杨酸嗪：针对类风湿性关节炎中 TLR4/NLRP3/GSDMD 介导的脓毒症的新型治疗药物。

背景：关节疼痛和功能障碍是关节炎这种痛苦的炎症性疾病的特征。水杨酸嗪（SAZ）是一种抗炎化合物，在调节炎症方面表现出良好的前景，因此本研究选择了水杨酸嗪来揭示其抗关节炎的潜力：本研究的目的是通过评估水杨酸嗪对爪体积、关节炎评分、氧化应激指标和重要炎症介质的影响来评估其抗关节炎特性：方法：首先通过甲醛（FA）模型估算柳氮的关节炎潜力，以筛选出最有效的柳氮剂量，然后通过完全弗氏佐剂（CFA）模型进行估算。在28天的时间里，我们监测了爪水肿、关节炎指数、体重、屈曲痛、活动度和站立评分等参数。我们还评估了氧化应激标记物（GSH、CAT、SOD、MDA）、血清学标记物（CRP、RF、抗CCP）以及关键炎症介质（TLR4、MyD88、NFκB、NLRP3、ASC、IL-1β、IL-18、caspase-1、GSDMD）的基因表达：结果：在两种关节炎模型中，SAZ治疗都能显著减少爪的体积，在甲醛模型中第10天和在CFA模型中第28天观察到最明显的效果（p 结论：SAZ治疗能显著减少关节炎模型中爪的体积，在甲醛模型中第10天和在CFA模型中第28天观察到最明显的效果：总而言之，SAZ 具有显著的抗关节炎功效，很可能是通过调节 TLR4/NLRP3/GSDMD 介导的热蛋白沉积途径、降低氧化应激和改善临床结果实现的。考虑到这些发现，看来 SAZ 有可能成为治疗关节炎的一种有效替代疗法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.