The typical pathological changes of Rheumatoid arthritis(RA) are synovitis, the main characteristics of which are the decrease of synovial cell apoptosis, tumor-like growth and the secretion of inflammatory factors. The healthy synovium has an intimal lining that contains macrophage-like synovial cells and fibroblasts-like synovial cells (Fibroblast-like synoviocytes, FLS) and subintimal lining, adipocytes, blood vessels, and dispersed immune cells containing fibroblasts. However, the RA-FLS of fibroblasts-like synovial cells in RA patients has the characteristics of excessive activation and decreased apoptosis. At the same time, the signal transduction network involved in the inflammatory process of RA is very complex. Although it has been gradually uncovered, it has not been fully clarified. Pro-inflammatory cytokines, such as IL-6, IL-8, COX-2 and so on, induce different intracellular transduction events and ultimately regulate the production of a series of cytokines. It has been confirmed that various pathogenic signal transduction pathways in RA are nuclear factor B (NF-κB), mitogen-activated protein kinase. (MAPK), spleen tyrosine kinase (SYK), phosphoinositol 3-kinase (PI3K), Interleukin(IL)-17 and janus kinase-signal transducer and activator of transcription(JAK-STAT).
With Pfizer's oral JAK inhibitor Xeljanz (tofacitinib, tofatinib) approved by Japanese PMDA in March 2013, methotrexate alone or in combination with methotrexate for the treatment of rheumatoid arthritis (RA) , in recent years, many international pharmaceutical companies have devoted themselves to the research and development of JAK inhibitors. At present, the first generation of JAK inhibitor: Ruxolitinib (Rosotinib, Novartis), Tofacitinib and Baricitinib (Barrick Tinib, Lilai), which are characterized by the ability to inhibit multiple JAK subtypes of kinases at the same time. Second generation JAK inhibitors: including Filgotinib, Upadacitinib (Upatinib, Abervi) and Solcitinib selectively inhibit JAK1; Decermotinib and PF06651600 selectively inhibit JAK3; The selective inhibition of tyrosine kinase (Tyk)2, by BMS986165,NDI021232, NDI031407, PF06700841 and SAR20347 is characterized by selective JAK inhibitors designed for different subtypes, among which there are many small molecular compounds with RA as indication.
JAK-STAT signal transduction, originally identified as interferon signal transduction pathway, mediates the immune response of various cytokines and the effects of several growth factors and hormones, and is involved in inflammation and cancer processes. Various strains of JAK and STAT molecules mediate different signals, which leads to different functions. The binding of ligands to their receptors induced the assembly of active receptor complexes and the subsequent phosphorylation of JAK (JAK1,JAK2 and JAK3) and Tyk2 associated with receptors. Phosphorylation activates JAK receptor subunits, including other substrates, and provides docking sites for STAT phosphorylation. The phosphorylated STAT is released from the receptor complex and forms homologous or heterodimer, which is then transferred to the nucleus and binds to the promoter region of the specific target gene, thus regulating the transcription of inflammation-related genes. The continuous activation of JAK/STAT signal transduction in synovial joints of RA patients leads to the increase of matrix metalloprotease gene expression and the frequency of apoptotic cartilage cells, and the most prominent problem in inflamed synovial tissues is "apoptosis resistance". Small molecule JAK inhibitors, represented by topatinib, have a good effect on improving RA, but these drugs are more expensive and many patients are deterred from doing so. The New England Journal reports that patients with RA who have been treated with Barretinib for a long time, in addition to gastrointestinal reactions, also increase the risk of infection, such as herpes zoster infection, resulting in a decrease in high density lipoprotein, increased serum creatinine and transaminase, and so on. Therefore, it is urgent to develop drugs with independent intellectual property rights and more reasonable price, safe and effective treatment of RA, which is in line with the national conditions of our country.
Curcumin is a polyphenolic compound isolated from the roots of Curcuma longa, a plant. It is traditionally used for pain and wound healing. Recent studies have shown that curcumin can improve multiple sclerosis, rheumatoid arthritis, psoriasis and inflammatory bowel disease in human or animal models. Curcumin inhibits these autoimmune diseases by regulating inflammatory cytokines such as IL-1, IL-6, IL-12, TNF-α, IFN-γa and related JAK-STAT, AP-1 and NF-κB signal transduction pathways in immune cells.Curcumin can reduce the expression of HMGB1 in brain tissue after cerebral ischemia and significantly reduce the inflammatory response after cerebral hemorrhage by inhibiting JAK2/STAT3 signaling pathway. It can increase cell adhesion by down-regulating the expression of total proteins of p-JAK, p-STAT3 and STAT3, and inhibit the migration and invasion of melanoma cells and enhance the apoptosis of these cells by regulating multiple pathways, including JAK2/STAT3[12, 13]. It may provide a theoretical basis for the clinical treatment of RA by weakening the phosphorylation of Jak2, down-regulating the transcriptional activities of STAT1 and STAT3 DNA, and inhibiting the proliferation of RA-FLS.
Previous experiments have confirmed that curcumin derivative FM0807 used in experiment has high safety and good anti-arthritis activity in vivo.FM0807 can inhibit the release of inflammatory factors from RAW264.7 cells induced by LPS, and it is more effective on providing protection than curcumin,a equimolar positive control drug.It is speculated that FM0807 may have anti-inflammatory effect mediated by JAK2-STAT3 signal pathway, which is similar to curcumin. It is worth further confirming. The purpose of this chapter is to study the effects of FM0807 on the proliferation, apoptosis and potential molecular mechanism of RA-FLS, in order to elucidate the mechanism and possible targets of anti-experimental arthritis.