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Targeted inhibition of GRK2 kinase domain by CP-25 to reverse fibroblast-like synoviocytes dysfunction and improve collagen-induced arthritis in rats

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Acta Pharmaceutica Sinica B 2021年第7期11卷 1835-1852页

作者： Chenchen Han Yifan Li Yuwen Zhang Yang Wang Dongqian Cui Tingting Luo Yu Zhang Qian Liu Hao Li Chun Wang Dexiang Xu Yang Ma Wei Wei Institute of Clinical Pharmacology Anhui Medical UniversityKey Laboratory of Anti-Inflammatory and Immune Medicine(Anhui Medical University)Ministry of EducationAnhui Collaborative Innovation Center of Antiinflammatory and Immune MedicineHefei 230032China Public Health and Preventive Medicine Postdoctoral Research Station of Anhui Medical University Hefei 230032China

Rheumatoid arthritis(RA)is an autoimmune disease and is mainly characterized by abnormal proliferation of fibroblast-like synoviocytes(FLS).The up-regulated cellular membrane expression of G protein coupled receptor kinase 2(GRK2)of FLS plays a critical role in RA progression,the increase of GRK2 translocation activity promotes dysfunctional prostaglandin E4 receptor(EP4)signaling and FLS abnormal ***,although our group found that paeoniflorin-6’-O-benzene sulfonate(CP-25),a novel compound,could reverse FLS dysfunction via GRK2,little is known as to how GRK2 translocation activity is *** findings revealed that GRK2 expression up-regulated and EP4 expression down-regulated in synovial tissues of RA patients and collagen-induced arthritis(CIA)rats,and prostaglandin E2(PGE2)level increased in ***-25 could down-regulate GRK2 expression,up-regulate EP4 expression,and improve synovitis of CIA ***-25 and GRK2 inhibitors(paroxetine or GSK180736 A)inhibited the abnormal proliferation of FLS in RA patients and CIA rats by down-regulating GRK2 translocation to EP4 *** results of microscale thermophoresis(MST),cellular thermal shift assay,and inhibition of kinase activity assay indicated that CP-25 could directly target GRK2,increase the protein stability of GRK2 in cells,and inhibit GRK2 kinase *** docking of CP-25 and GRK2 suggested that the kinase domain of GRK2 might be an important active pocket for CP-25.G201,K220,K230,A321,and D335 in kinase domain of GRK2 might form hydrogen bonds with ***-directed mutagenesis and co-immunoprecipitation assay further revealed that CP-25 down-regulated the interaction of GRK2 and EP4 via controlling the key amino acid residue of Ala321 of *** data demonstrate that FLS proliferation is regulated by GRK2 translocation to *** inhibition of GRK2 kinase domain by CP-25 improves FLS function and represents an innovative drug for the treatment of RA by targeting G

关键词： CP-25 Rheumatoid arthritis fibroblast-like synoviocyte MH7A G protein coupled receptor kinase 2 Prostaglandin E4 receptor

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Nuciferine alleviates collagen-induced arthritic in rats by inhibiting the proliferation and invasion of human arthritis-derived fibroblast-like synoviocytes and rectifying Th17/Treg imbalance

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Chinese Journal of Natural Medicines 2024年第4期22卷 341-355页

作者： WANG Hao GENG Xiaolong AI Fangbin YU Zhilun ZHANG Yan ZHANG Beibei LV Cheng GAO Ruiyang YUE Bei DOU Wei The MOE Key Laboratory of Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicinesand the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese MedicineInstitute of Chinese Materia MedicaSchool of Traditional Chinese Materia MedicaShanghai University of Traditional Chinese Medicine(SHUTCM)Shanghai 201203China

Rheumatoid arthritis(RA)is a chronic autoimmune disorder marked by persistent synovial inflammation and joint degradation,posing challenges in the development of effective ***,an alkaloid found in lotus leaf,has shown promising anti-inflammatory and anti-tumor effects,yet its efficacy in RA treatment remains *** study investigated the antiproliferative effects of nuciferine on the MH7A cell line,a human RA-derived fibroblast-like synoviocyte,revealing its ability to inhibit cell proliferation,promote apoptosis,induce apoptosis,and cause G1/S phase ***,nuciferine significantly reduced the migration and invasion capabilities of MH7A *** therapeutic potential of nuciferine was further evaluated in a collagen-induced arthritis(CIA)rat model,where it markedly alleviated joint swelling,synovial hyperplasia,cartilage injury,and inflammatory *** also improved collagen-induced bone erosion,decreased pro-inflammatory cytokines and serum immunoglobulins(IgG,IgG1,IgG2a),and restored the balance between T helper(Th)17 and regulatory T cells in the spleen of CIA *** results indicate that nuciferine may offer therapeutic advantages for RA by decreasing the proliferation and invasiveness of FLS cells and correcting the Th17/Treg cell imbalance in CIA rats.

关键词： Rheumatoid arthritis Collagen-induced arthritis fibroblast-like synoviocyte Immune imbalance Nuciferine

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Overexpression of arginine transporter CAT-1 is associated with hypoxia-induced fibroblast-like synoviocytes hyperplasia in rheumatoid arthritis

Overexpression of arginine transporter CAT-1 is associated w...

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第十二届全国免疫学学术大会

作者： Lu Ying Shanghai East Hospital Tongji University School of Medicine

The proliferation of fibroblast-like synoviocytes(FLS) is increased in Rheumatoid arthritis(RA),leading to synovial hyperplasia and articular cartilage *** metabolism and signaling pathways(NOS and ornithine) are closely related with tumor *** is known that FLS have part of cancer cell like *** acid transport protein(CATs) plays a key role on the cellular uptake of arginine,while the characteristics of CATs in RA remains *** this study,we found the enrichment of arginine transporter CAT-1 in FLS of synovial tissue in RA patients,where a 3%O hypoxia environment has been *** order to determine the correlation between the high CAT-1 level and the low oxygen concentration in RA,a hypoxia condition(%O2) in vitro was applied to mimic the RA environment in *** promoted cellular proliferation of rheumatoid arthritis synovial fibroblasts(RASFs),and increased arginine uptake of RASFs,which were accompanied with the increased expression of *** application of CAT-1 loss-of-function assays,we confirmed the requirement of CAT-1 expression for those hypoxia-induced phenotype in *** addition,we demonstrated for the first time that CAT-1 plays key roles in regulating L-arginine-NO signaling pathway to promote FLS proliferation in *** together,we demonstrated a novel pathway regulating hypoxia-induced fibroblast-like synoviocytes hyperplasia in RA mediated by CAT-1.

关键词： rheumatoid arthritis cationic amino acid transporters CAT-1 fibroblast-like synoviocyte

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Involvement of long non-coding RNAs in the pathogenesis of rheumatoid arthritis

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Chinese Medical Journal 2020年第8期133卷 941-950页

作者： Min-Xi Lao Han-Shi Xu Department of Rheumatology and Immunology The First Affiliated HospitalSun Yat-Sen UniversityGuangzhouGuangdong 510080China

Long non-coding RNA (lncRNA) plays a contributory role in rheumatoid arthritis (RA). In this review, we summarized the current findings of lncRNAs in RA, including cellular function and the potential mechanisms. Serum lncRNA levels are associated with serum proinflammatory cytokines and disease activity. LncRNAs regulate proliferation, migration, invasion and apoptosis of RA fibroblast-like synoviocytes (FLSs), modulate the differentiation of T lymphocytes and macrophages, and affect bone formationdestruction balance of chondrocytes. Besides, lncRNAs are involved in inflammation and cell motivation signaling pathways. Indepth research on lncRNAs may help elucidate the pathogenesis of RA and provides clues for novel treatment targets.

关键词： lncRNA Rheumatoid arthritis fibroblast-like synoviocyte Inflammation Invasiveness

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