Aliskiren, tadalafil, and cinnamaldehyde alleviate joint destruction biomarkers; MMP-3 and RANKL; in complete Freund's adjuvant arthritis model: Downregulation of IL-6/JAK2/STAT3 signaling pathway

Abstract

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.

Recent advances in diverse nanosystems for nitric oxide delivery in cancer therapy

“…Understanding the antitumor properties of NO is of great significance for exploiting its role in tumor biology. This review comprehensively explains the antitumor mechanisms of NO from the following aspects ( Table 1 ) 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 .…”

“… Role of NO Mechanism of NO activity Ref. Causes genotoxicity Depolarization through mitochondria, caspase-3 activation and DNA fragmentation 55 , 56 , 57 , 58 , 59 , 60 Suppression of cellular respiration and shifts in iron metabolism Generation of oxygen free radicals Inactivation certain key enzymes in cell metabolism Promotes cancer cell apoptosis Decrease in BCL-2 expression 61 , 62 , 63 , 64 , 65 Promotion of the production of ceramide Macrophage activation P53 accumulation Inhibits cancer cell metastasis Decrease in galectin-3 expression Inhibition of platelet aggregation and tumor metastasis 66 , 68 , 69 Improves the efficacy of other drugs Upregulation of MMP-2 and 9 to loose tumor tissue structure 67 , 72 Destruction of the cell membrane to inhibit multidrug resistance Inhibition of the ATPase activity of P-gp to inhibit multidrug resistance Normalization of blood vessels at tumor sites to increase the penetration of chemotherapy drugs Reverses MDR Decreased expression of P-gp and MRP 70 , 71 , 73 Depletion of GSH Regulation of NF- κ B and HIF GSH, glutathione; HIF, hypoxia-induced factors; MDR, multidrug resistance; MRP, multidrug resistance related protein; NO, nitric oxide; P-gp, P-glycoprotein. …”

“…NO produced from donor spermine-NONOate or ONOO − of SIN-1 has been shown to inhibit MMP-9 through a mechanism involving caveolin-1 at the interface of human non-small cell lung cancer cells and endothelial cells in co-culture expression and activation 67 . However, some indirect evidences suggest that ONOO − produced by NO· and superoxide (O 2 - ·) under pathological conditions may activate proMMPs to MMPs in tumors 68 . Another possible mode of action of NO in controlling the cancer metastasis is via inhibition of galectin-3 69 , 104 .…”

Network pharmacology-based analysis of the mechanism of Saposhnikovia divaricata for the treatment of type I allergy

“…IL-6 is a multifunctional cytokine, can promote inflammatory reaction through IL-6/JAK2/STAT3 signalling pathway (Azouz et al. 2020 ). CXCL8 can bind to IL8RA and IL8RB, which are chemokine receptors of CXCL8.…”

Integrated Experimental Approach, Phytochemistry, and Network Pharmacology to Explore the Potential Mechanisms of Cinnamomi Ramulus for Rheumatoid Arthritis

“…There are many effective antiarthritis prescriptions containing CR in the Chinese Pharmacopoeia, and some studies on the anti-inflammatory and antiarthritic effects of CR in animal models of RA have been published. Notably, in addition to CR volatile oil and its extracts significantly alleviating inflammation and pain in CFA-induced chronic arthritis rats, active components such as cinnamaldehyde in CR volatile oil could also reduce RA symptoms by ameliorating oxidative stress and the release of inflammatory factors [ 14 , 15 ]. However, due to the complex chemical composition of CR, its potential active components and the exact pharmacological mechanism for the treatment of RA remain difficult to elucidate.…”