Ferroptosis in inflammatory arthritis: A promising future.

Ferroptosis is a kind of regulatory cell death (RCD) caused by iron accumulation and lipid peroxidation, which is characterized by mitochondrial morphological changes and has a complex regulatory network. Ferroptosis has been gradually emphasized in the pathogenesis of inflammatory arthritis. In this review, we summarized the relevant research on ferroptosis in various inflammatory arthritis including rheumatoid arthritis (RA), osteoarthritis, gout arthritis, and ankylosing spondylitis, and focused on the relationship between RA and ferroptosis. In patients with RA and animal models of RA, there was evidence of iron overload and lipid peroxidation, as well as mitochondrial dysfunction that may be associated with ferroptosis. Ferroptosis inducers have shown good application prospects in tumor therapy, and some anti-rheumatic drugs such as methotrexate and sulfasalazine have been shown to have ferroptosis modulating effects. These phenomena suggest that the role of ferroptosis in the pathogenesis of inflammatory arthritis will be worth further study. The development of therapeutic strategies targeting ferroptosis for patients with inflammatory arthritis may be a promising future.

Pharmacological Aspects of Natural Quercetin in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to severe joint damage, disability and mortality. Quercetin (QUE) is a natural flavonoid that is ubiquitous in fruits and vegetables. This article reviews the effect of QUE on articular and extra-articular manifestations of RA in vitro and in vivo. In general, for articular manifestations, QUE inhibited synovial membrane inflammation by reducing inflammatory cytokines and mediators, decreasing oxidative stress, inhibiting proliferation, migration and invasion, and promoting apoptosis of fibroblast-like synoviocytes (FLS), regulated autoimmune response through modulating Th17/Treg imbalance and Th17 cells differentiation, reducing autoantibodies levels and regulating ectonucleoside triphosphate diphosphohydrolase (E-NTPDase)/ectoadenosine deaminase (E-ADA) activities, reduced bony damage via lowering matrix metalloproteinase (MMP)-1, MMP-3, receptor activator of nuclear factor kappa B ligand (RANKL) expression and osteoclasts formation. For extra-articular manifestations, QUE could reverse the neurodegenerative processes of the enteric nervous system (ENS) and exhibited cytoprotective, genoprotective and hepatoprotective effects. In addition, we also summarize some contradictory experimental results and explore the possibility for these differences to form a sound basis for the clinical application of QUE for RA.

Ginsenoside compound K- a potential drug for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disease, if prescription of effective delayed, the articular disturbances may lead to disability. Ginsenoside compound K (GCK) is the main degradation product of oral ginsenosides in the human intestine. Numerous researches in vitro and in vivo have recorded the anti-arthritic effect of GCK, we discuss the mechanisms from the following three aspects, including anti-inflammatory, immune-regulatory, and bone-protective, respectively, in this review, and the anti-arthritic mechanism of GCK may be related to the effect on TNF-α-TNFR2, glucocorticoid receptor (GR) and ß-arrestin1/2. We also describe the anti-anemia effect of GCK to open the possibility that GCK can be used as an effective disease-modifying anti-rheumatic drug (DMARD).

Integrating Network Pharmacology with Molecular Docking to Unravel the Active Compounds and Potential Mechanism of Simiao Pill Treating Rheumatoid Arthritis.

OBJECTIVE: To explore the main components and unravel the potential mechanism of simiao pill (SM) on rheumatoid arthritis (RA) based on network pharmacological analysis and molecular docking. METHODS: Related compounds were obtained from TCMSP and BATMAN-TCM database. Oral bioavailability and drug-likeness were then screened by using absorption, distribution, metabolism, and excretion (ADME) criteria. Additionally, target genes related to RA were acquired from GeneCards and OMIM database. Correlations about SM-RA, compounds-targets, and pathways-targets-compounds were visualized through Cytoscape 3.7.1. The protein-protein interaction (PPI) network was constructed by STRING. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed via R packages. Molecular docking analysis was constructed by the Molecular Operating Environment (MOE). RESULTS: A total of 72 potential compounds and 77 associated targets of SM were identified. The compounds-targets network analysis indicated that the 6 compounds, including quercetin, kaempferol, baicalein, wogonin, beta-sitosterol, and eugenol, were linked to ≥10 target genes, and the 10 target genes (PTGS1, ESR1, AR, PGR, CHRM3, PPARG, CHRM2, BCL2, CASP3, and RELA) were core target genes in the network. Enrichment analysis indicated that PI3K-Akt, TNF, and IL-17 signaling pathway may be a critical signaling pathway in the network pharmacology. Molecular docking showed that quercetin, kaempferol, baicalein, and wogonin have good binding activity with IL6, VEGFA, EGFR, and NFKBIA targets. CONCLUSION: The integrative investigation based on bioinformatics/network topology strategy may elaborate on the multicomponent synergy mechanisms of SM against RA and provide the way out to develop new combination medicines for RA.

Proteomic analysis of biomarkers predicting the response to triple therapy in patients with rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) usually receive triple therapy with methotrexate (MTX), leflunomide (LEF) and infliximab (IFX), but nearly one-third of them do not respond to triple therapy. This study aimed to identify biomarkers for predicting the efficacy of triple therapy to optimize personalized treatment of RA. METHODS: All 20 enrolled patients met 2010 ACR/EULAR criteria for RA and were classified into good, moderate and non-responders (GR, MR, NR) for triple therapy. The Responders (R) were defined as the sum of GR and MR. Protein profiles of 4 responders and 4 non-responders were investigated via isobaric tags for relative and absolute quantification (iTRAQ), and differentially expressed proteins (DEPs) with high-confidence peptides were validated in 15 responders and 5 non-responders by parallel response monitoring (PRM). RESULTS: iTRAQ identified 51 DEPs between responders and non-responders (p < 0.05, fold change >±1.2). The top five up-regulated DEPs were B7Z7M2, A0A087WZR4, Q53FL1, P08254 and G3V2V8, while the top five down-regulated proteins were Q6MZX9, B3KP77, P0DJI9, P0DJI8 and P02787. Targeted mass spectrometry by PRM identified 10 candidate biomarkers, and 3 DEPs including fibrinogen beta chain, epididymal secretory protein Li 282 and testicular tissue protein Li 70 were confirmed as predictive biomarkers. CONCLUSION: This study demonstrated the feasibility of exploring biomarkers by applying iTRAQ and PRM mass spectrometry techniques, and a panel of biomarkers were identified to predict clinical response of IFX + MTX + LEF treatment in active RA patients.

miR-124a inhibits the proliferation and inflammation in rheumatoid arthritis fibroblast-like synoviocytes via targeting PIK3/NF-κB pathway.

Abnormal hyperplasia of fibroblast-like synoviocytes (FLS) leads to the progression of rheumatoid arthritis (RA). This study aimed to investigate the role of miR-124a in the pathogenesis of RA. The viability and cell cycle of FLS in rheumatoid arthritis (RAFLS) were evaluated by Cell Counting Kit 8 and flow cytometry assay. The expression of PIK3CA, Akt, and NF-κB in RAFLS was examined by real-time PCR and Western blot analysis. The production of tumour necrosis factor (TNF)-α and interleukin (IL)-6 was detected by ELISA. The joint swelling and inflammation in collagen-induced arthritis (CIA) mice were examined by histological and immunohistochemical analysis. We found that miR-124a suppressed the viability and proliferation of RAFLS and increased the percentage of cells in the G1 phase. miR-124a suppressed PIK3CA 3'UTR luciferase reporter activity and decreased the expression of PIK3CA at mRNA and protein levels. Furthermore, miR-124a inhibited the expression of the key components of the PIK3/Akt/NF-κB signal pathway and inhibited the expression of pro-inflammatory factors TNF-α and IL-6. Local overexpression of miR-124a in the joints of CIA mice inhibited inflammation and promoted apoptosis in FLS by decreasing PIK3CA expression. In conclusion, miR-124a inhibits the proliferation and inflammation in RAFLS via targeting PIK3/NF-κB pathway. miR-124a is a promising therapeutic target for RA.

[Association of short-term efficacy for infliximab in rheumatoid arthritis with plasma concentration and anti-drug antibody].

OBJECTIVE: To investigate the correlation between peripheral concentration of infliximab (IFX) or anti-IFX antibody titers and short-term therapeutic effect of IFX in patients with active rheumatoid arthritis (RA).
 Methods: Twenty patients with active RA were treated with combination of methotrexate (MTX), leflunomide (LEF) with IFX, and the clinical and laboratory index and the side effects were recorded before and after IFX treatment. Twenty healthy subjects were chosen as a control group.
 Results: After 14-week treatment, patients were categorized into good, moderate or no responders according to EULAR remission criteria. There were no significant differences in peripheral IFX concentration, anti-IFX antibody titers and TNF-α levels among the 3 groups, and there were no significant correlations among ΔDAS28-CRP, peripheral IFX concentration, anti-IFX antibody titers and TNF-α levels.
 Conclusion: Peripheral IFX concentration, anti-IFX antibody titers and TNF-α levels can not be used as reliable predictive index for short-term effect of IFX in active RA.

[Clinical effect of tocilizumab on patients with severe active rheumatoid arthritis].

OBJECTIVE: To evaluate therapeutic effects and adverse reactions of tocilizumab on patients with severe active rheumatoid arthritis (RA).
 Methods: Twelve patients with severe refractory RA were treated with tocilizumab. The clinical and laboratory indices and the side effects were recorded after treatment.
 Results: The clinical and laboratory indices and the disease activity score 28 (DAS28) were observed in all patients, which were significantly improved after TCZ therapy (P<0.05), and no obvious adverse reactions were found.
 Conclusion: Tocilizumab can effectively relieve the symptoms and improve the conditions of severe active RA.