通过抑制IL-17/PI3K/AKT/NF-κB活性，帕瑞昔布联合依洛司他对骨关节炎的协同治疗作用

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology Pub Date : 2025-02-10 DOI:10.1016/j.molimm.2025.02.005

Xiaofei Feng , Yao Ma , Yuhao Zhao , Zhenrui Zhao , Zhengdong Song , Li Lin , Wenji Wang

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引用次数: 0

摘要

骨关节炎是一种退行性疾病，目前的药物治疗是给予非甾体类抗炎药来缓解症状。帕瑞昔布和伊洛马司他的抗炎能力已被证实，但联合给药对骨关节炎的协同作用尚不清楚。方法IL-1β刺激小鼠原代软骨细胞培养。采用western blotting、实时定量聚合酶链反应（pcr）和酶联免疫吸附试验（ELISA）检测炎症因子和基质金属蛋白酶的表达水平。采用流式细胞术观察帕瑞昔布和伊洛马司他对软骨细胞凋亡的影响。此外，采用半月板不稳定法建立骨关节炎大鼠模型，在关节内注射帕瑞昔布、依洛司他及两者联合使用后，采用Safranin O-Fast绿色和免疫组化染色监测软骨形态变化及相关分子表达水平。结果体外实验表明，与单药给药相比，帕瑞昔布与伊洛马司他联用能更有效地抑制促炎因子和基质金属蛋白酶的表达。联合用药能更有效地抑制il -1β诱导的软骨细胞凋亡。联合用药可通过抑制IL-17/PI3K/AKT/NF-κB通路缓解骨关节炎的进展。此外，体内实验表明，联合给药可以改善骨关节炎大鼠模型的进一步恶化。结论帕瑞昔布联合伊洛司他抑制IL-17/PI3K/AKT/NF-κB转导有利于降低骨关节炎炎症因子和基质金属蛋白酶的浸润。

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Synergistic therapeutic effect of parecoxib and ilomastat combination in osteoarthritis via inhibition of IL-17/PI3K/AKT/NF-κB activity

Background

Osteoarthritis is a degenerative disease, and current drug treatment is to give nonsteroidal anti-inflammatory drugs to relieve symptoms. The anti-inflammatory ability of parecoxib and ilomastat has been confirmed, but the synergistic effect of combined administration in osteoarthritis has not been clear.

Methods

Mouse primary chondrocytes stimulated with IL-1β were cultured. The expression levels of inflammatory cytokines and matrix metalloproteinases were investigated by western blotting, quantitative real-time polymerase chain reaction and ELISA. The effects of parecoxib and ilomastat on chondrocyte apoptosis were evaluated by flow cytometry. In addition, the rat model of osteoarthritis was established by meniscal instability, and the morphological changes of cartilage and the expression levels of related molecules were monitored using Safranin O-Fast green and immunohistochemical staining after intra-articular injection of parecoxib, ilomastat, and the combination of the two.

Results

In vitro experiments showed that the combined administration of parecoxib and ilomastat more effectively inhibited the expression of proinflammatory factors and matrix metalloproteinases compared with single drug administration. The combined drug treatment could more effectively inhibit IL-1β-induced chondrocyte apoptosis. The combined drug treatment alleviated the progression of osteoarthritis by inhibiting the IL-17/PI3K/AKT/NF-κB pathway. In addition, in vivo experiments showed that the combined administration could improve the further deterioration of the osteoarthritis rat model.

Conclusions

The combined administration of parecoxib and ilomastat to inhibit IL-17/PI3K/AKT/NF-κB transduction is beneficial to reduce the infiltration of inflammatory factors and matrix metalloproteinases in osteoarthritis.

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来源期刊

Molecular immunology 医学-免疫学

CiteScore

6.90

自引率

2.80%

发文量

324

审稿时长

50 days

期刊介绍： Molecular Immunology publishes original articles, reviews and commentaries on all areas of immunology, with a particular focus on description of cellular, biochemical or genetic mechanisms underlying immunological phenomena. Studies on all model organisms, from invertebrates to humans, are suitable. Examples include, but are not restricted to: Infection, autoimmunity, transplantation, immunodeficiencies, inflammation and tumor immunology Mechanisms of induction, regulation and termination of innate and adaptive immunity Intercellular communication, cooperation and regulation Intracellular mechanisms of immunity (endocytosis, protein trafficking, pathogen recognition, antigen presentation, etc) Mechanisms of action of the cells and molecules of the immune system Structural analysis Development of the immune system Comparative immunology and evolution of the immune system "Omics" studies and bioinformatics Vaccines, biotechnology and therapeutic manipulation of the immune system (therapeutic antibodies, cytokines, cellular therapies, etc) Technical developments.