Rheumatoid arthritis (RA) is an incurable systemic autoimmune disease. Disease progression leads to joint deformity and associated loss of function, which significantly impacts the quality of life for sufferers and adds to losses in the labor force. In the past few decades, RA has attracted increased attention from researchers, the abnormal signaling pathways in RA are a very important research field in the diagnosis and treatment of RA, which provides important evidence for understanding this complex disease and developing novel RA-linked intervention targets. The current review intends to provide a comprehensive overview of RA, including a general introduction to the disease, historical events, epidemiology, risk factors, and pathological process, highlight the primary research progress of the disease and various signaling pathways and molecular mechanisms, including genetic factors, epigenetic factors, summarize the most recent developments in identifying novel signaling pathways in RA and new inhibitors for treating RA. therapeutic interventions including approved drugs, clinical drugs, pre-clinical drugs, and cutting-edge therapeutic technologies. These developments will hopefully drive progress in new strategically targeted therapies and hope to provide novel ideas for RA treatment options in the future. 

/pdf/signaling-pathways-in-rheumatoid-arthritis-implications-for-wgohdlk9.pdf

Signaling pathways in rheumatoid arthritis: implications for targeted therapy

Angiogenesis as a potential treatment strategy for rheumatoid arthritis.

This study aimed to investigate the molecular mechanisms of Compound Sidaxue (SX), a prescription of Chinese Miao medicine, in treating rheumatoid arthritis (RA) using network pharmacology and in vivo experimental approaches.Network pharmacology was adopted to detect the active components of four Traditional Chinese herbal medicine (TCM) of SX, and the key targets and signaling pathways in the treatment of RA were predicted, and the key components and targets were screened for molecular docking. The predicted targets and pathways were validated in bovine type II collagen and incomplete Freund's adjuvant emulsifier-induced rat RA model.In this study, we identified 33 active components from SX, predicted to act on 44 RA-associated targets by network pharmacology. PPI network demonstrated that TNF-α, VEGF-A, IL-2, IL-6, AKT, PI3K, STAT1 may serve as the key targets of SX for the treatment of RA. The main functional pathways involving these key targets include PI3K-AKT signaling pathway, TNF signaling pathway, NF-κB signaling pathway. Molecular docking analysis found that the active components β-amyrin, cajanin, eleutheroside A have high affinity for TNF-α, VEGFA, IL-2, AKT, and PI3K, etc. SX can improve joint swelling in Collagen-induced arthritis (CIA) rats, reduce inflammatory cell infiltration and angiogenesis in joint synovial tissue, and down-regulate IL-2, IL-6, TNF-α, VEGF, PI3K, AKT, p-AKT, NF-κBp65, the expression of p-NF-κBp65, STAT1, and PTGS2 are used to control the exacerbation of inflammation and alleviate the proliferation of synovial pannus, and at the same time play the role of cartilage protection to achieve the effect of treating RA.Through a network pharmacology approach and animal study, we predicted and validated the active compounds of SX and their potential targets for RA treatment. The results suggest that SX can markedly alleviate CIA rat by modulating the VEGF/PI3K/AKT signaling pathway, TNF-α signaling pathway, IL/NF-κB signaling pathway. 

/pdf/network-pharmacology-and-molecular-docking-study-of-the-118oweg8.pdf

Network Pharmacology and Molecular Docking Study of the Chinese Miao Medicine Sidaxue in the Treatment of Rheumatoid Arthritis

The VEGF/SphK1/S1P pathway is closely related to angiogenesis in rheumatoid arthritis (RA), but the precise underlying mechanisms are unclear at present. Here, we explored the involvement of the VEGF/SphK1/S1P cascade in RA models and determined the effects of GE intervention. Our results showed abnormal expression of proteins related to this pathway in RA synovial tissue. Treatment with GE effectively regulated the signal axis, inhibited angiogenesis, and alleviated RA symptoms. In vitro, TNF-ɑ enhanced the VEGF/SphK1/S1P pathway in a co-culture model of fibroblast-like synoviocytes (FLS) and vascular endothelial cells (VEC). GE induced downregulation of VEGF in FLS, restored the dynamic balance of pro-/antiangiogenic factors, and suppressed SphK1/S1P signaling in VEC, resulting in lower proliferation activity, migration ability, tube formation ability, and S1P secretion ability of VEC cells. Additionally, SphK1-specific small interfering RNA (siRNA) blocked the VEGF/SphK1/S1P cascade, which can effectively alleviate the stimulatory effect of FLS on VEC and further enhanced the therapeutic effect of GE. Taken together, our results demonstrate that GE suppresses the VEGF/SphK1/S1P pathway and alleviates the stimulation of VEC by FLS, thereby preventing angiogenesis and promoting therapeutic effects against RA.

Geniposide downregulates the VEGF/SphK1/S1P pathway and alleviates angiogenesis in rheumatoid arthritis in vivo and in vitro

Background This study aims to systematically evaluate the effect of moxibustion on the level of inflammatory cytokines in animal models with rheumatoid arthritis (RA) and to provide evidence for the clinical application of moxibustion to the treatment of RA and related basic researches. Methods The databases employed in this study include PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Database (VIP), SinoMed, and Wanfang Data Information Site. The retrieval time was from the establishment of these databases to March 2020. The reviewers made use of the CAMARADES 10-item checklist to evaluate the quality of each included study. The inflammatory cytokines were considered as the outcome measure. The Revman 5.3 software was used to conduct meta-analysis on the outcome indicators of the studies included. Results A total of 648 articles were retrieved and 18 animal experiments were included in this study. The quality scores of the studies ranged from two to eight with a mean of 5.8. Compared with the effect of the control group, moxibustion reduced the expression of TNF-α (SMD 2.95, 95% CI: 1.99-3.92, P < 0.00001), IL-1β (SMD 4.10, 95% CI: 2.37-5.84, P < 0.00001), IFN-γ (MD 25, 95% CI: 16.17-33.82, P < 0.00001), IL-6 (MD 11.83, 95% CI: 6.22-17.44, P < 0.0001), and IL-17 (MD 99.3, 95% CI: 86.83-111.76, P < 0.00001). At the same time, the level of IL-2 (SMD 8.89, 95% CI: 0.93-16.86, P=0.03), IL-4 (MD 1.79, 95% CI: 0.26-3.32, P=0.02), and IL-10 (MD 5.93, 95% CI: 1.37-10.49, P=0.01) increased after moxibustion treatment. Asymmetric funnel plots indicated that there was publication bias. Conclusion The findings of the present review indicate that moxibustion can protect the synovium of joint in animal models with RA by upregulation of the level of anti-inflammatory cytokines and downregulation of the level of proinflammatory cytokines. Moxibustion has the potential to relieve inflammation of RA.

/pdf/effect-of-moxibustion-on-inflammatory-cytokines-in-animals-45e8vq5cbm.pdf

Effect of Moxibustion on Inflammatory Cytokines in Animals with Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Background. Moxibustion has a therapeutic effect of reducing swelling and relieving pain in patients with rheumatoid arthritis (RA) but its mechanism is uncertain. Objective. To evaluate the effect of moxibustion on serum levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in patients with RA and to explore the possible mechanism of moxibustion. Methods. This study involved 46 RA patients who had fulfilled the inclusion criteria and were randomly assigned to a treatment group and a control group in an equal ratio. The control group was treated with methotrexate or leflunomide, while the treatment group received methotrexate or leflunomide and moxibustion at ST 36 (Zusanli), BL 23 (Shenshu), and Ashi points. Patients’ clinical symptoms, RA-associated serum markers, and serum levels of TNF-α, IL-1β, HIF-1α, and VEGF were compared in the two groups before and after intervention. Statistical analysis was performed using SPSS 21.0 statistical software. Results. 37 of 46 RA patients eventually completed the whole treatment course. Compared with the control group, the treatment group significantly improved the clinical symptoms ( ) but with no significant differences in RA-associated serum markers ( ). There were significant differences in TNF-α and IL-1β among the groups after 8 weeks of treatment ( ). HIF-1α and VEGF were decreased in the treatment group after therapy ( ). VEGF was reduced in the control group ( ), while HIF-1α was not significantly improved ( ). The reductions of HIF-1α and VEGF in the treatment group were superior to the control group ( ). Conclusions. Moxibustion enhanced the anti-inflammatory and analgesic effects of conventional medicine and can enhance the effect of conventional medicine, downregulating HIF-1α/VEGF contents to inhibit angiogenesis.

/pdf/effect-of-moxibustion-on-hif-1a-and-vegf-levels-in-patients-2c3kojspkq.pdf

Effect of Moxibustion on HIF-1α and VEGF Levels in Patients with Rheumatoid Arthritis.

Moxibustion for primary dysmenorrhea

Effectiveness of grain-sized moxibustion for rheumatoid arthritis: Study protocol for a randomized controlled trial

Effect of chrono-moxibustion and its influence on circadian rhythm for rheumatoid arthritis: A study protocol for a randomized controlled trial

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Papers

Effect of Moxibustion on HIF-1α and VEGF Levels in Patients with Rheumatoid Arthritis.

Moxibustion for primary dysmenorrhea

Effectiveness of grain-sized moxibustion for rheumatoid arthritis: Study protocol for a randomized controlled trial

Effect of chrono-moxibustion and its influence on circadian rhythm for rheumatoid arthritis: A study protocol for a randomized controlled trial