Pharmacology and Toxicology Department, Faculty of Pharmacy, Port Said University, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Beni-Suef University, Egypt.
Eur J Pharmacol. 2018 Mar 5;822:177-185. doi: 10.1016/j.ejphar.2018.01.009. Epub 2018 Jan 11.
Signaling pathways are interesting fields of study of pathogenesis and treatment trials. We elucidated the possible protective effects of nicorandil (15mg/kg/day) and theophylline (20mg/kg/day) on experimentally-induced RA, focusing on the role of JAK (Janus Kinase) / STAT (Signal Transducer and Activator of Transcription) / RANKL (Receptor Activator of Nuclear factor-Kappa B Ligand) / cytokine signaling pathway. Four sets of experiments were performed. First, effect of test agents on normal animals was evaluated. Second, effect of test agents was evaluated on Complete Freund's Adjuvant (CFA; 0.3ml, s.c.)-induced RA to investigate anti-arthritic effect. Third, effect of test agents was evaluated on growth hormone (GH; 2mg/kg/day, s.c.)-induced stimulation of JAK/STAT/RANKL/cytokine signaling pathway to investigate the role of this signaling pathway in their anti-arthritic effect. Fourth, the effect of test agents was performed on CFA/GH-induced RA. To fulfill this purpose, serum anti-citrullinated peptide antibody (ACPA), interleukin-6 (IL-6), and cartilage oligomeric matrix protein (COMP), together with tissue JAK2, STAT3, RANKL, inducible and endothelial nitric oxide synthases (iNOS and eNOS) as well as macrophage inflammatory protein (MIP) were estimated using ELISA, Western blotting and PCR techniques, confirmed by a histopathological study. Test agents significantly corrected JAK2, STAT3, RANKL and IL-6 values in animals receiving GH. Additionally, test agents could correct ACPA, IL-6, COMP, JAK2, STAT3, RANKL, iNOS, eNOS and MIP levels compared with the respective CFA or CFA/GH controls. These results conclude that nicorandil and theophylline have good anti-arthritic effects related to modulation of JAK/STAT/RANKL signaling pathway. Further clinical trials are claimed.
信号通路是研究发病机制和治疗试验的有趣领域。我们阐明了尼可地尔（15mg/kg/天）和茶碱（20mg/kg/天）对实验性类风湿关节炎的可能保护作用，重点关注 JAK（Janus 激酶）/STAT（信号转导和转录激活因子）/RANKL（核因子-κB 配体受体激活剂）/细胞因子信号通路的作用。进行了四组实验。首先，评估了试验药物对正常动物的影响。其次，评估了试验药物对完全弗氏佐剂（CFA；0.3ml，sc）诱导的类风湿关节炎的影响，以研究其抗关节炎作用。第三，评估了试验药物对生长激素（GH；2mg/kg/天，sc）诱导的 JAK/STAT/RANKL/细胞因子信号通路刺激的影响，以研究该信号通路在其抗关节炎作用中的作用。第四，在 CFA/GH 诱导的类风湿关节炎中进行了试验药物的作用。为此，使用 ELISA、Western 印迹和 PCR 技术评估了血清抗瓜氨酸肽抗体（ACPA）、白细胞介素-6（IL-6）和软骨寡聚基质蛋白（COMP），以及组织 JAK2、STAT3、RANKL、诱导型和内皮型一氧化氮合酶（iNOS 和 eNOS）以及巨噬细胞炎症蛋白（MIP），并通过组织病理学研究进行了验证。试验药物显著纠正了接受 GH 的动物的 JAK2、STAT3、RANKL 和 IL-6 值。此外，与各自的 CFA 或 CFA/GH 对照相比，试验药物可以纠正 ACPA、IL-6、COMP、JAK2、STAT3、RANKL、iNOS、eNOS 和 MIP 水平。这些结果表明，尼可地尔和茶碱具有良好的抗关节炎作用，与 JAK/STAT/RANKL 信号通路的调节有关。需要进一步的临床试验。
