Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis

Liu, Shuang; Ma, Hongxu; Zhang, Huaxi; Deng, Chengjie; Xin, Ping

doi:10.1016/j.clim.2021.108793

Cited by 114 publications

(83 citation statements)

References 96 publications

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“…Particularly, according to the above-mentioned network pathway analyses and published literature, it was found that the critical core proteins or pathways are related to cell physiological processes or inflammation ( Chen et al, 2020 ; Ney et al, 2020 ; Liu et al, 2021 ). For instance, PI3K/AKT, Rap1, and Ras signaling pathways have a strong relationship with the occurrence and development of inflammation progressing, which can regulate the balance of pro-inflammatory and anti-inflammatory factors, along with perpetuation or mitigation of inflammation in tissues ( Shah et al, 2018 ; Liu et al, 2021 ). Thus, it is reckoned that ARF relieved RA by anti-inflammatory effects; therefore, the five key targets were selected for the next experiment to validate this point.…”

Section: Resultsmentioning

confidence: 99%

Gaultheria leucocarpa var. yunnanensis for Treating Rheumatoid Arthritis—An Assessment Combining Machine Learning–Guided ADME Properties Prediction, Network Pharmacology, and Pharmacological Assessment

et al. 2021

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Background: Dianbaizhu (Gaultheria leucocarpa var. yunnanensis), a traditional Chinese/ethnic medicine (TC/EM), has been used to treat rheumatoid arthritis (RA) for a long time. The anti–rheumatic arthritis fraction (ARF) of G. yunnanensis has significant anti-inflammatory and analgesic activities and is mainly composed of methyl salicylate glycosides, flavonoids, organic acids, and others. The effective ingredients and rudimentary mechanism of ARF remedying RA have not been elucidated to date.Purpose: The aim of the present study is to give an insight into the effective components and mechanisms of Dianbaizhu in ameliorating RA, based on the estimation of the absorption, distribution, metabolism, and excretion (ADME) properties, analysis of network pharmacology, and in vivo and in vitro validations.Study design and methods: The IL-1β–induced human fibroblast-like synoviocytes of RA (HFLS-RA) model and adjuvant-induced arthritis in the rat model were adopted to assess the anti-RA effect of ARF. The components in ARF were identified by using UHPLC-LTQ-Orbitrap-MSn. The quantitative structure–activity relationship (QSAR) models were developed by using five machine learning algorithms, alone or in combination with genetic algorithms for predicting the ADME properties of ARF. The molecular networks and pathways presumably referring to the therapy of ARF on RA were yielded by using common databases and visible software, and the experimental validations of the key targets conducted in vitro.Results: ARF effectively relieved RA in vivo and in vitro. The five optimized QSAR models that were developed showed robustness and predictive ability. The characterized 48 components in ARF had good biological potency. Four key signaling pathways were obtained, which were related to both cytokine signaling and cell immune response. ARF suppressed IL-1β–induced expression of EGFR, MMP 9, IL2, MAPK14, and KDR in the HFLS-RA .Conclusions: ARF has good druggability and high exploitation potential. Methyl salicylate glycosides and flavonoids play essential roles in attuning RA. ARF may partially attenuate RA by regulating the expression of multi-targets in the inflammation–immune system. These provide valuable information to rationalize ARF and other TC/EMs in the treatment of RA.

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Section: Resultsmentioning

confidence: 99%

Gaultheria leucocarpa var. yunnanensis for Treating Rheumatoid Arthritis—An Assessment Combining Machine Learning–Guided ADME Properties Prediction, Network Pharmacology, and Pharmacological Assessment

et al. 2021

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“…Peripheral blood cells, cytokines and inflammatory molecules play important roles in the perpetuation of the autoimmune process in RA [ 21 ]. These may change according to the clinical activity of each patient.…”

Section: Discussionmentioning

confidence: 99%

Canonical (CD74/CD44) and Non-Canonical (CXCR2, 4 and 7) MIF Receptors Are Differentially Expressed in Rheumatoid Arthritis Patients Evaluated by DAS28-ESR

Sánchez-Zuno

Bucala

Hernández‐Bello

et al. 2021

JCM

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Macrophage migration inhibitory factor (MIF) significantly contributes to rheumatoid arthritis (RA) pathogenesis. We aimed to evaluate the canonical (CD74/CD44) and non-canonical MIF receptors (CXCR2,4 and 7) expression and sCD74 to establish their association with RA clinical activity according to DAS28-ESR. Methodology: 101 RA patients with different clinical activities (remission (n = 27), low (n = 16), moderate (n = 35) and high (n = 23)) and 9 control subjects (CS) were included. Expression was evaluated by flow cytometry and levels of soluble CD74 (sCD74) by ELISA. Data analysis was performed with FlowJov10.0, STATAv12.0, and GraphPad Prism v7.0. Results: According to disease activity, CXCR7 expression (percentage of expression and mean fluorescence intensity (MFI)) was higher in granulocytes from patients in remission, while the expression of CXCR4 was higher in patients with high disease activity (p < 0.05). The expression of CD74 was higher in B cells (p < 0.05) and monocytes (p < 0.01) from patients in remission. Regarding sCD74 levels these were higher in patients with high disease activity when compared to those in remission (p <0.05). Conclusions: The results support the need for further study of the role of sCD74 as a soluble MIF decoy receptor, sequestering it to negatively regulate MIF signaling though its membrane receptors. The expression patterns of CXCR4 and CXCR7 show that the latter is a scavenger-type receptor that prevents endocytosis and even degradation of CXCR4 under inflammatory conditions.

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“…Interactions of pro-inflammatory cytokines can phosphorylate JAK and then recruit and activate STATs proteins involved in signal transduction ( Wang et al, 2020 ). Activation of JAK/STAT signaling pathway stimulates the expression of pro-inflammatory cytokines, induces FLS to proliferate and erodes cartilage in synovium, promotes synovium cell proliferation, and participates in cartilage lesions ( Liu et al, 2021 ). Clinical trials have demonstrated the efficacy of JAK2 and JAK3 inhibitors in the treatment of RA ( Wang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Herbal Formula Longteng Decoction Promotes the Regression of Synovial Inflammation in Collagen-Induced Arthritis Mice by Regulating Type 2 Innate Lymphocytes

et al. 2021

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The etiology and pathogenesis of rheumatoid arthritis (RA) have not yet been fully elucidated, with greater adverse drug effects in traditional treatment of RA. It is particularly necessary to develop and study Chinese herbal formula as a supplement and alternative drug for the treatment of RA. The traditional Chinese medicine compound Longteng Decoction (LTD), as an empirical prescription in the treatment of RA in Dongzhimen Hospital of Beijing University of Chinese Medicine, has been widely used in clinic. Type 2 innate lymphocytes (ILC2s) have specific transcription factors and signature cytokines that are very similar to Th cells, which have been proved to be necessary in addressing RA inflammation, and are potential targets for RA prevention and treatment. Our previous studies have confirmed that LTD can intervene in the differentiation of peripheral blood Th17 and Treg cells, reduce joint pain index and swelling degree, shorten the time of morning stiffness, reduce ESR, and inhibit joint inflammation. However, it is unclear whether LTD can promote the regression of RA synovial inflammation by regulating the immune response mechanism of ILC2s.Therefore, our team established a collagen-induced arthritis mouse model and conducted an experimental study with LTD as the intervention object. The results showed that joint swelling, synovial inflammatory infiltration, and articular cartilage destruction were alleviated in CIA mice after intervention with LTD. The proliferation and differentiation of Th17 inflammatory cells and the secretion of proinflammatory cytokines (IL-17 and IFN-γ) were inhibited. In addition, LTD can also activate ILC2s to secrete the anti-inflammatory cytokine IL-4, activate the STAT6 signaling pathway, and act synergistic with Treg cells to inhibit the infiltration of type M1 macrophages in synovial tissue and promote its transformation to M2 phenotype. Taken together, these results confirm that LTD can be used as an adjunct or alternative to RA therapy by modulating the ILC2s immune response network and slowing down the inflammatory process of synovial tissue.

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Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis

Cited by 114 publications

References 96 publications

Gaultheria leucocarpa var. yunnanensis for Treating Rheumatoid Arthritis—An Assessment Combining Machine Learning–Guided ADME Properties Prediction, Network Pharmacology, and Pharmacological Assessment

Gaultheria leucocarpa var. yunnanensis for Treating Rheumatoid Arthritis—An Assessment Combining Machine Learning–Guided ADME Properties Prediction, Network Pharmacology, and Pharmacological Assessment

Canonical (CD74/CD44) and Non-Canonical (CXCR2, 4 and 7) MIF Receptors Are Differentially Expressed in Rheumatoid Arthritis Patients Evaluated by DAS28-ESR

Herbal Formula Longteng Decoction Promotes the Regression of Synovial Inflammation in Collagen-Induced Arthritis Mice by Regulating Type 2 Innate Lymphocytes

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