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Ethnopharmacological relevance Clematis chinensis Osbeck / Notopterygium incisum Ting ex H, T-Chang (CN) is a traditional Chinese herb couple with prominent efficacy. The herb couple has been commonly used for clinical treatment of arthralgia syndrome (“Bi Zheng” in Chinese) for centuries in China, including rheumatic arthritis, osteoarthritis and gout in modern medicine. Aim of the study To evaluate the anti-arthritic effect of CN herb couple in a rat model of rheumatoid arthritis (RA). Materials and methods Rats were divided randomly into six groups with eight each. Adjuvant-induced arthritis (AIA) model was established by intradermal injection of complete Freund's adjuvant (CFA). Rats were treated orally with different dosages of CN (0.7 g/kg, 2.1 g/kg, 6.3 g/kg) from day 16 till day 40. Ibuprofen (50.4 mg/kg) served as a positive control. Spontaneous activity, body weight, paw swelling, and arthritis index (AI) were monitored throughout drug treatment. Then serum levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) were determined by enzyme linked immunosorbent assay (ELISA) kits. In addition, histopathological examination and immunohistochemistry were used to assess the severity of arthritis. Results Three dosage of CN significantly ameliorated symptoms of RA via increasing body weight as well as reducing paw swelling (at dose of 6.3 g/kg, p <0.01) in AIA rats. An extremely significant reduction of AI ( p <0.001) was also observed with treatment of CN (6.3 g/kg) compared with model group. In parallel, treatment of CN significantly down-regulated levels of TNF-α, IL-6, and VEGF both in serum ( p <0.01) and in joint synovial compared with model rats. And histopathology revealed noticeable reduction in synovial hyperplasia, cartilage damage, and inflammatory infiltration by CN treatment, especially at dose of 6.3 g/kg. Conclusions To conclude, all results suggest that CN possesses evident anti-arthritic effects in AIA rats. [ABSTRACT FROM AUTHOR]

Alleviating rheumatism by inhibiting synovitis is a routine treatment for rheumatoid arthritis (RA). Baihu Jia Guizhi Decoction (BHJGZ) is a classic prescription and has a long history of application for treating RA with a good anti-inflammatory action. However, the underlying molecular mechanisms have not been fully elucidated. This work aimed to decipher the potential mechanism of BHJGZ against RA focusing on Ras/MEK/ERK pathway. Based on the prediction of network pharmacology, the inhibition action of BHJGZ on Ras/MEK/ERK pathway was firstly validated in vivo and in vitro. Moreover, the affinity with the ingredients of BHJGZ in serum and the targets of Ras/MEK/ERK pathway were evaluated. Finally, the efficacy of BHJGZ for relieving RA was assessed in AA rats. The Ras/MEK/ERK pathway was predicted by network pharmacology as one of important mechanisms of BHJGZ to treat RA. The high expression of Ras protein in synovitis of AA rats was significantly reduced by the treatment with BHJGZ, and the activation of Ras/MEK/ERK pathway in vivo and in vitro was also markedly inhibited (p < 0.05 or p < 0.01). Moreover, the level of p-ERK/ERK, IL-6 and TNF-α in vitro were further suppressed after Ras or MEK was inhibited by mirdametinib or lonafarnib respectively (p < 0.01). Furthermore, the results of molecular docking showed a good affinity and stable binding with the ingredients of BHJGZ in serum and multiple key proteins of the Ras/MEK/ERK pathway. Finally, paw swelling, paw circumference and pathological changes of joint synovitis were significantly reduced by BHJGZ in AA rats (p < 0.05). The inhibition of Ras/MEK/ERK pathway is one of crucial mechanisms of BHJGZ for ameliorating synovitis of RA. [Display omitted] • The therapeutic effect of BHJGZ on rheumatoid arthritis was proved. • It was demonstrated that BHJGZ can alleviate synovitis of rheumatoid arthritis. • It was proved that BHJGZ could inhibit Ras/MEK/ERK signal pathway. • This study provided a new idea for the treatment of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

• CA alleviated inflammation of rheumatoid arthritis in rats by suppressing IL-1β. • CA reduced HIF-1α expression by limiting succinate aggregation and GPR91 activation. • CA inhibited NLRP3 expression through Succinate/GPR91&HIF-1α for IL-1β suppression. Cinnamaldehyde (CA) is an essential component of cinnamon (Cinnamomum cassia Presland), which is often used as a flavoring condiment in beverages, pastries, perfumes, etc. Cinnamon is also used as herbal medicine in China and Southeast Asia to treat rheumatoid arthritis. However, the molecular mechanism is unclear. In this study, we aim to investigate its anti-inflammatory effects against Rheumatoid arthritis (RA) using activated macrophages (Raw246.7) in vitro and adjuvant arthritis rats (AA) in vivo. The results demonstrated that CA significantly reduced synovial inflammation in AA rats, possibly due to suppression of the expressions of pro-inflammatory cytokines, especially the IL-1β. Further investigation found that CA also suppressed the activity of HIF-1α by inhibiting the accumulation of succinate in cytoplasm. As we know, the reduction of HIF-1α nucleation slows down IL-1β production, because HIF-1α activates the expression of NLRP3, which is involved in the assembly of inflammasome and processing of IL-1β. In addition, CA also inhibited the expression of the succinate receptor GPR91, which in turn inhibited the activation of HIF-1α. In conclusions, our results suggested that CA might be a potential therapeutic compound to relieve rheumatoid arthritis progress by suppressing IL-1β through modulating succinate/HIF-1α axis and inhibition of NLRP3. [ABSTRACT FROM AUTHOR]