Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, which is accompanied by progressive joint damage and disability. The intolerability of conventional antirheumatic drugs by some patients necessitates the search for effective antirheumatic agents having better tolerability. In the current work, we aimed to investigate the efficacy of cinnamaldehyde, tadalafil, and aliskiren as potential antirheumatic candidates and to explore their modulatory effects on joint destruction, inflammatory response, and intracellular signaling. Arthritis was induced in female Wistar rats by complete Freund's adjuvant (CFA) 0.4 ml s.c. on days 1, 4, and 7. Treated groups received their respective drugs, starting from day 13, daily for 3 weeks. Methotrexate and prednisolone were the standard antirheumatic drugs, while cinnamaldehyde, tadalafil, and aliskiren were the test agents. Treatment with cinnamaldehyde, tadalafil, or aliskiren reduced serum levels of rheumatoid factor, and pro-inflammatory cytokines; tumor necrosis factor-alpha and interleukin-6 (IL-6), along with elevated level of IL-10 which is an anti-inflammatory cytokine. Besides, cartilage and bone destruction biomarkers; matrix metalloproteinase-3 (MMP-3) and receptor activator of nuclear factor-kappa B ligand (RANKL); were significantly reduced after treatment with the test agents, which was further confirmed by histopathological investigation. The elevated protein expressions of phosphorylated-Janus kinase 2 (p-JAK2), phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), and inducible nitric oxide synthase (iNOS) in articular tissue were markedly attenuated after treatment with cinnamaldehyde, tadalafil, or aliskiren, while that of endothelial nitric oxide synthase (eNOS) was greatly enhanced. In addition, oxidative stress and inflammatory markers such as malondialdehyde, nitric oxide, and myeloperoxidase were reduced in joint tissue after treatment with the test agents, while glutathione content was elevated. Furthermore, the renin inhibitor aliskiren produced effects close to those of the normal and methotrexate, the gold standard antirheumatic drug, in most of the measured parameters.

Collectively, these findings led to the assumption that the downregulation of IL-6/JAK2/STAT3 signaling by cinnamaldehyde, tadalafil, and aliskiren could alleviate joint destruction by MMP-3 and RANKL, reduce iNOS, and enhance eNOS expressions. Moreover, aliskiren could be a promising therapeutic agent for RA, because of its ability to normalize most of the measured parameters after CFA-induced arthritis.

类风湿关节炎（RA）是一种自身免疫性炎性疾病，伴有进行性关节损伤和残疾。一些患者对常规抗风湿药的耐受性使得必须寻找具有更好耐受性的有效抗风湿药。在当前的工作中，我们旨在研究肉桂醛，他达拉非和阿利吉仑作为潜在的抗风湿病药物的功效，并探讨其对关节破坏，炎症反应和细胞内信号传导的调节作用。在第1、4和7天，用完全弗氏佐剂（CFA）0.4 ml sc在雌性Wistar大鼠中诱发关节炎。治疗组从第13天开始每天接受其各自的药物，持续3周。甲氨蝶呤和泼尼松龙是标准的抗风湿药，而肉桂醛，他达拉非，和阿利吉仑是测试代理商。用肉桂醛，他达拉非或阿利吉仑治疗可降低血清类风湿因子和促炎细胞因子的水平；肿瘤坏死因子-α和白介素-6（IL-6），以及作为抗炎细胞因子的IL-10水平升高。此外，软骨和骨破坏生物标志物；基质金属蛋白酶3（MMP-3）和核因子-κB配体的受体激活剂（RANKL）；用受试药物治疗后，血脂显着降低，这已通过组织病理学研究进一步证实。肉桂醛治疗后，关节组织中磷酸化Janus激酶2（p-JAK2），磷酸化信号转导和转录激活子3（p-STAT3）和诱导型一氧化氮合酶（iNOS）的蛋白表达明显减弱，他达拉非或阿利吉仑，而内皮型一氧化氮合酶（eNOS）的含量大大提高。此外，用受试药处理后，关节组织中的氧化应激和炎性标记物（如丙二醛，一氧化氮和髓过氧化物酶）减少，而谷胱甘肽含量升高。此外，在大多数测量参数中，肾素抑制剂阿利吉仑产生的效果均接近于正常和甲氨蝶呤（金标准抗风湿药）的效果。

总的来说，这些发现导致以下假设：肉桂醛，他达拉非和阿利吉仑对IL-6 / JAK2 / STAT3信号的下调可以减轻MMP-3和RANKL的关节破坏，降低iNOS并增强eNOS表达。此外，阿利吉仑可能是RA的有前途的治疗剂，因为它具有使CFA诱发的关节炎后大多数测量参数正常化的能力。