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Mechanism of Gentisic Acidon rheumatoid arthritis BasedonmiR-19b-3p/RAF1 Axis

Chinese Journal of Integrative Medicine 2023年第6期29卷 508-516页

作者： DING Dou ZHANG Qi ZENG Fu-jia CAI Ming-xing GAN Yuan DONG Xiao-jun Department of Traditional Chinese Medicine Zunyi Medical and Pharmaceutical CollegeZunyi(563006)Guizhou ProvinceChina

Objective To investigate the therapeutic effect of gentisic acid(GA)on rheumatoid arthritis(RA)based on the miR-19b-3p/RAF1 *** The cell counting kit-8 method was used to detect the growth inhibitory effect of different concentrations of GA on MH7A cells,and the drug concentration of GA was determined in the *** quantificational real-time polymerase chain reaction(qRT-PCR)was used to detect the expression of miR-19b-3p and ***1,extracellular regulated protein kinases1/2(ERK1/2)and phospho-ERK1/2(p-ERK1/2)were examined by Western *** methods(dual-luciferase assay,qRT-PCR and Western blot analysis)were used to verify miR-19b-3p targeting *** cytometry was performed to detect MH7A cell *** and wound healing assays were used to determine the invasion and migration capacities of MH7A *** The growth of MH7A cells was gradually inhibited with increasing GA *** the GA concentration exceeded 80 mmol/L,GA was significantly cytotoxic to MH7A cells,so the half maximal inhibitory concentration of GA for MH7A cells was calculated as 67.019 mmol/*** upregulated miR-19b-3p expression,downregulated RAF1 expression,inhibited ERK1/2 phosphorylation,induced MH7A cell apoptosis and suppressed MH7A cell invasion and migration(P<0.05 or P<0.01).RAF1 was identified as the target of miR-19b-3p and reversed inhibitory effects on miR-19b-3p expression(P<0.05 or P<0.01).The miR-19b-3p inhibitor upregulated RAF1 expression and ERK1/2 phosphorylation,suppressed MH7A cell apoptosis and induced MH7A cell invasion and migration(P<0.01).Conclusion GA regulated miR-19b-3p/RAF1 axis to mediate ERK pathway and inhibit the development of RA.

关键词： gentisic acid rheumatoid arthritis miR-19b-3p RAF1 MAPK/ERK

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Effect of sustained intensive therapy with disease modifying anti-rheumatic drugs in rheumatoid arthritis:a 5-year real-world consecutive study

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Chinese Medical Journal 2020年第12期133卷 1397-1403页

作者： Yue-Ming Cai Ru Li Hua Ye Jing He Xiao-Lin Sun Jia-Yang Jin Jia-Jia Liu Yu-Zhou Gan Xu-Jie You Jing Xu Lian-Jie Shi Gong Cheng Qing-Wen Wang Zhan-Guo Li Department of Rheumatology and Immunology Peking University People’s HospitalBeijing 100044China Department of Rheumatology and Immunology Peking University Shenzhen HospitalShenzhenGuangdong 518035China Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis(BZ0135) Beijing 100044China Peking-Tsinghua Center for Life Sciences Peking UniversityBeijing 100044China Department of Rheumatology and Immunology Peking University International HospitalBeijing 102206China

Background:Intensive therapy with disease modifying anti-rheumatic drugs(DMARDs)has been reported to improve the outcomes of rheumatoid arthritis(RA).However,real-world study on the effect of intensive therapy on RA sustained remission is still *** study aimed to investigate the outcome of sustained intensive DMARD therapy(SUIT)for RA in a real-world 5-year consecutive ***:Based on a consecutive cohort of 610 out-patients with RA,remission of RA was assessed in 541 patients from 2012 to 2017,by dividing into SUIT,non-SUIT,and intermittent SUIT(Int-SUIT)*** in the disease activity scores were evaluated by 28-joint disease activity score based on erythrocyte sedimentation rate(DAS28-ESR),28-joint disease activity score based on C-reactive protein(DAS28-CRP),and clinical deep remission criteria(CliDR).Cumulative remission rates between different groups were compared using Kaplan-Meier curves and predictive factors of sustained remission were identified by univariate and multivariate logistic regression ***:The remission rates of the SUIT group decreased from 12.0%(65/541)to 5.6%(20/359)based on DAS28-ESR,from 14.0%(76/541)to 7.2%(26/359)based on DAS28-CRP,and from 8.5%(46/541)to 3.1%(11/359)based on CliDR,respectively,with a gradually decreasing trend during the 5 *** SUIT regimen led to a significantly higher cumulative remission rate than non-SUIT regimen based on DAS28-ESR(39.7%vs.19.5%,P=0.001),DAS28-CRP(42.0%vs.19.6%,P=0.001),and CliDR(24.5%vs.8.7%,P=0.001).The cumulative remission rates of patients treated with SUIT regimen were significantly higher than those treated with Int-SUIT regimen based on DAS28-ESR(39.7%vs.25.7%,P=0.043)and CliDR(24.5%vs.14.2%,P=0.047),but there was no significant difference between the two groups based on DAS28-CRP(42.0%vs.27.4%,P=0.066).Multivariate logistic regression analysis showed that the use of SUIT regimen was an independent favorable predictor according to different remission d

关键词： rheumatoid arthritis Remission Sustained intensive therapy Cohort study

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Tartrate-resistant acid phosphatase 5b is a potential biomarker for rheumatoid arthritis： a pilot study in Han Chinese

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Chinese Medical Journal 2014年第16期127卷 2894-2899页

作者： Cheng Tao Wang Mingjun Chen Zhiwei Robert A Eisenberg Zhang Yu Zou Yaohong Deng Yingsu Wang Mian Zhou Ling Department of Rheumatology First AffiliatedHospital of Soochow University Suzhou Jiangsu 215000 China Department of Nephrology First AffiliatedHospital of Soochow University Suzhou Jiangsu 215000 China Department of Rheumatology University of Pennsylvania Philadelphia 19104 USA Department of Hematology Subei People's Hospital YangzhouJiangsu 225001 China Department of Rheumatology Wuxi First People's Hospital WuxiJiangsu 214043 China School of Public HealS Central South University Changsha Hunan 410083 China

Background Bone damage around the joints is one of the major pathophysiological mechanisms that leads to rheumatoid arthritis （RA） chronic *** tartrate-resistant acid phosphatase 5b （TRACP-5b） is secreted by osteoclasts,its activity can be used as a clinically relevant bone resorption *** aim of this study was to test whether the measurement of serum levels of TRACP-5b in patients with RA would correlate with measures of disease activity and with responses to *** Fifty-six patients were randomly assigned to receive recombinant human cytotoxic tlymphocyte-associated antigen-4 immunoglobulin （RhCTLA4-lg）,infliximab or methotrexate （MTX）.The clinical and serologic indicators of RA activity were evaluated at baseline and at 24 *** TRACP-5b was measured by Enzyme-linked Immunosorbent Assay （ELISA） at 0,12 and 24 *** X-rays were obtained at *** At baseline,the levels of TRACP-5b correlated with the severity of X-ray damage,disease duration （r=0.332,P=0.012）,and tender joint count （r=0.408,P=0.002）.The 24 weeks values of TRACP-5b for RhCTLA4-lg group and infliximab group differed significantly from the baseline values in each group （P 〈0.05; P 〈0.05）,whereas only the value for RhCTLA4-lg group differed significantly from the 24 weeks value for the MTX group （P 〈0.01）.Considering the two biologics-treated groups together,the TRACP-5b levels at 24 weeks differed significantly from the baseline values only in those patients who reached an ACR70 level （P 〈0.05）.Conclusions Measurement of serum TRACP-5b in RA patients reflects clinical and radiological measures of disease activity,treatment with certain biologics,and degree of response to ***-5b should be investigated further as a potential biomarker to predict response to therapy,including slowing of radiographic progression.

关键词： tartrate-resistant acid phosphatase 5b rheumatoid arthritis Chinese osteoclast biologic agent

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Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4417-4441页

作者： Yuyi Xu Ming Zhao Jinxue Cao Ting Fang Jian Zhang Yanli Zhen Fangling Wu Xiaohui Yu Yaming Liu Ji Li Dongkai Wang Department of Pharmaceutics School of PharmacyShenyang Pharmaceutical UniversityShenyang 110016China

rheumatoid arthritis is a chronic,systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity *** drugs have been used for the treatment of rheumatoid arthritis,but their use is limited by suboptimal bioavailability,serious adverse effects,and nonnegligible first-pass *** contrast,transdermal drug delivery systems(TDDSs)can avoid these drawbacks and improve patient compliance,making them a promising option for the treatment of rheumatoid arthritis(RA).Of course,TDDSs also face unique challenges,as the physiological barrier of the skin makes drug delivery somewhat *** overcome this barrier and maximize drug delivery efficiency,TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology,and different generations of TDDSs have been derived,which have significantly improved transdermal efficiency and even achieved individualized controlled drug *** this review,we summarize the different generations of transdermal drug delivery systems,the corresponding transdermal strategies,and their applications in the treatment of RA.

关键词： rheumatoid arthritis Transdermal drug delivery systems Different generations Enhancement strategies Drug therapy Transdermal delivery mechanism Advanced devices Microneedles

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Nanomedicines for the treatment of rheumatoid arthritis:State of art and potential therapeutic strategies

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Acta Pharmaceutica Sinica B 2021年第5期11卷 1158-1174页

作者： Qin Wang Xianyan Qin Jiyu Fang Xun Sun Key Laboratory of Advanced Technologies of Materials Ministry of Education and School of Materials Science and EngineeringSouthwest Jiaotong UniversityChengdu 610031China Advanced Materials Processing and Analysis Center and Department of Materials Science and Engineering University of Central FloridaOrlandoFL 32816USA Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of EducationWest China School of PharmacySichuan UniversityChengdu 610041China

Increasing understanding of the pathogenesis of rheumatoid arthritis(RA)has remarkably promoted the development of effective therapeutic regimens of ***,the inadequate response to current therapies in a proportion of patients,the systemic toxicity accompanied by longterm administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability,are still unsettled problems lying across the full remission of *** far,these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment.A variety of versatile nanocarriers with controllable physicochemical properties,tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA *** review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance,pro-resolving therapy or regulating the immunometabolism for RA treatments.

关键词： Nanomedicines rheumatoid arthritis Targeted drug delivery Liposome Micelle Stimulus-responsive delivery systems Immune tolerance Inflammation resolution

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Data Mining Study on Prescription Patterns of Different Dosage Forms of Chinese Herbal Medicines for Treating and Improving Immune-Inflammatory Indices in Patients with rheumatoid arthritis

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Chinese Journal of Integrative Medicine 2022年第3期28卷 215-222页

作者： HUANG Dan LIU Jian XIN Ling XIE Jin-gui ZHU Qiang CHEN Pei-sheng SHEN Zhi-bin MENG Qing-he WANG Hai-yan Department of Rheumatology First Affiliated Hospital of Anhui University of Chinese MedicineHefei(230031)China The School of Management University of Science and Tech no logy of ChinaHefei(230026)China An hui Jiren Pharmaceutical Co. Ltd.BozhouAnhui Provinee(236800)China Department of Acupuncture Huangshan Hospital of Chinese MedicineHuangshanAnhui Province(245000)China Department of Internal Medicine Bozhou Hospital of Chinese MedicineBozhouAnhui Province(236800)China

Objective:To explore the prescription patterns of different dosage forms of Chinese herbal medicines(CHMs)for the treatment of rheumatoid arthritis(RA)and their effects on immune-inflammatory ***:Clinical data were collected from patients with RA in 4 hospitals(3 Class A comprehensive hospitals and 1 Class B comprehensive hospital)in Anhui Province,China,from August 2012 to June 2018 via the electronic medical record gathering *** extraction of prescription information,each prescribed herb was quantified and standardized according to the knowledge base to establish a database of RA treatment *** medical records were divided into the granules group and decoction pieces *** herbs and their combination patterns were obtained from the two groups of cases using Liquorice *** in immune-inflammatory and hepatic and renal function indices were compared between the two groups using SPSS 23.0 *** Aprior module of SPSS Clementine 11.1 software was applied to analyse the correlation between CHMs and improvement in ***,the ORACLE 10 g tool was used to evaluate the random walk model of the immune-inflammatory indices between the two ***:(1)We retrospectively analysed 35,898 prescriptions for 6,829 patients with RA who received CHM *** were 3,816 patients in the granules group and 3,013 in the decoction pieces group.(2)The core herbs were Pi(Spleen)-strengthening and dampness-resolving drugs,blood-activating and stasis-resolving drugs,wind/dampness-dispelling drugs and heatclearing and detoxifying drugs.(3)Both dosage forms could improve immune-inflammatory indices in RA patients,with similar efficacy and no influence on hepatic or renal function.(4)Herba Siegesbeckiae and Oldenlandia had a stronger association with immune-inflammatory indices in the two groups.(5)The immune-inflammatory indices showed obvious improvement after treatment with granules and decoction pieces of CHMs,and

关键词： rheumatoid arthritis Chinese heral medicine granules decoction pieces data mining

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Osteoimmunology research in rheumatoid arthritis:From single-cell omics approach

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Chinese Medical Journal 2023年第14期136卷 1642-1652页

作者： Nan Hu Jing Wang Bomiao Ju Yuanyuan Li Ping Fan Xinxin Jin Xiaomin Kang Shufang Wu Department of Rheumatology The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxi 710061China Department of Physiology and Pathophysiology School of Basic Medical SciencesXi’an Jiaotong University Health Science CenterXi’anShaanxi 710061China Center for Translational Medicine The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxi 710061China

Cellular immune responses as well as generalized and periarticular bone loss are the key pathogenic features of rheumatoid arthritis(RA).Under the pathological conditions of RA,dysregulated inflammation and immune processes tightly interact with skeletal system,resulting in pathological bone damage via inhibition of bone formation or induction of bone *** omics technologies are revolutionary tools in the field of modern biological *** enable the display of the state and function of cells in various environments from a single-cell resolution,thus making it conducive to identify the dysregulated molecular mechanisms of bone destruction in RA as well as the discovery of potential therapeutic targets and ***,we summarize the latest findings of single-cell omics technologies in osteoimmunology research in *** results suggest that single-cell omics have made significant contributions to transcriptomics and dynamics of specific cells involved in bone remodeling,providing a new direction for our understanding of cellular heterogeneity in the study of osteoimmunology in RA.

关键词： rheumatoid arthritis Osteoimmunology Single-cell omics Single-cell RNA sequencing scATAC-seq

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Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts

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Cellular & Molecular Immunology 2022年第10期19卷 1185-1195页

作者： Ruby J.Siegel Anil K.Singh Paul M.Panipinto Farheen S.Shaikh Judy Vinh Sang U.Han H.Mark Kenney Edward M.Schwarz Cynthia S.Crowson Sadik A.Khuder Basil S.Khuder David A.Fox Salahuddin Ahmed Department of Pharmaceutical Sciences Washington State University College of Pharmacy and Pharmaceutical SciencesSpokaneWAUSA Department of Pathology and Laboratory Medicine University of Rochester Medical CenterRochesterNYUSA Center for Musculoskeletal Research University of Rochester Medical CenterRochesterNYUSA Department of Quantitative Health Sciences and Division of Rheumatology Mayo ClinicRochesterMNUSA Department of Medicine and Public Health University of ToledoToledoOHUSA Department of Pathology and Laboratory Medicine Phoenix Children’s HospitalPhoenixAZUSA Department of Medicine Division of Rheumatology and Clinical Autoimmunity Center of ExcellenceUniversity of Michigan Medical SystemAnn ArborMIUSA Division of Rheumatology University of Washington School of MedicineSeattleWAUSA

Extracellular sulfatase-2(Sulf-2)influences receptor-ligand binding and subsequent signaling by chemokines and growth factors,yet Sulf-2 remains unexplored in inflammatory cytokine signaling in the context of rheumatoid arthritis(RA).In the present study,we characterized Sulf-2 expression in RA and investigated its potential role in TNF-α-induced synovial inflammation using primary human RA synovial fibroblasts(RASFs).Sulf-2 expression was significantly higher in serum and synovial tissues from patients with RA and in synovium and serum from hTNFtg *** sequencing analysis of TNF-α-stimulated RASFs showed that Sulf-2 siRNA modulated~2500 genes compared to scrambled *** Pathway Analysis of RNA sequencing data identified Sulf-2 as a primary target in fibroblasts and macrophages in *** blot,ELISA,and qRT‒PCR analyses confirmed that Sulf-2 knockdown reduced the TNF-α-induced expression of ICAM1,VCAM1,CAD11,PDPN,CCL5,CX3CL1,CXCL10,and *** studies identified the protein kinase C-delta(PKCδ)and c-Jun N-terminal kinase(JNK)pathways as key in the TNF-α-mediated induction of proteins related to cellular adhesion and *** of Sulf-2 abrogated TNF-α-induced RASF ***-2 knockdown with siRNA and inhibition by OKN-007 suppressed the TNF-α-induced phosphorylation of PKCδand JNK,thereby suppressing the nuclear translocation and DNA binding activity of the transcription factors AP-1 and NF-κBp65 in human ***,Sulf-2 expression positively correlated with the expression of TNF receptor 1,and coimmunoprecipitation assays demonstrated the binding of these two proteins,suggesting they exhibit crosstalk in TNF-α*** study identified a novel role of Sulf-2 in TNF-αsignaling and the activation of RA synoviocytes,providing the rationale for evaluating the therapeutic targeting of Sulf-2 in preclinical models of RA.

关键词： Sulfatase-2 TNF-α rheumatoid arthritis Synovial fibroblasts Signal transduction

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A high-fiber diet synergizes with Prevotella copri and exacerbates rheumatoid arthritis

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Cellular & Molecular Immunology 2022年第12期19卷 1414-1424页

作者： Lingjuan Jiang Mengmeng Shang Shengnan Yu Yudong Liu Hui Zhang Yangzhong Zhou Min Wang Tingting Wang Hui Li Zhihua Liu Xuan Zhang Department of Medical Research Center National Science and Technology Key Infrastructure on Translational MedicinePeking Union Medical College HospitalDepartment of RheumatologyBeijing HospitalNational Center of GerontologyInstitute of Geriatric MedicineChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100730China State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100730China Department of Rheumatology Beijing HospitalNational Center of GerontologyInstitute of Geriatric MedicineClinical Immunology CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100730China Department of Pathology Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100730China Department of Internal Medicine Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100730China Key Laboratory of Infection and Immunity Institute of BiophysicsChinese Academy of SciencesBeijing100101China Institute for Immunology School of MedicineTsinghua UniversityBeijing100084China Tsinghua-Peking Center for Life Sciences Beijing100084China

Both preclinical and established rheumatoid arthritis(RA)patients display alterations in the gut *** *** preferentially enriched in a subset of RA ***,we isolated a Prevotella strain,*** RA,from the feces of RA patients and showed that colonization of *** RA exacerbated arthritis in a collagen-induced arthritis(CIA)*** the presence of *** RA colonization,a high-fiber diet exacerbated arthritis via microbial alterations and intestinal *** of *** together with a high-fiber diet enabled the digestion of complex fiber,which led to the overproduction of organic acids,including fumarate,succinate and short-chain fatty *** promoted proinflammatory responses in macrophages,and supplementation with succinate exacerbated arthritis in the CIA *** findings highlight the importance of dysbiosis when evaluating the effects of dietary interventions on RA pathogenesis and provide new insight into dietary interventions or microbiome modifications to improve RA management.

关键词： rheumatoid arthritis Dysbiosis Prevotella copri High-fber diet Microbiota-derived metabolites

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Screening disease-associated proteins from sera of patients with rheumatoid arthritis： a comparative proteomic study

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Chinese Medical Journal 2010年第5期123卷 537-543页

作者： LI Tian-wang ZHENG Ben-rong HUANG Zhi-xiang LIN Qu ZHAO Li-ke LIAO Ze-tao ZHAO Ji-jun LIN Zhi-ming GU Jie-ruo Department of Rheumatology Third Affiliated Hospital of Sun Yat-sen University Guangzhou Guangdong 510630 China Department of Rheumatology Beijing Hospital Beijing 100730 China

Background rheumatoid arthritis （RA） is an autoimmune disease characterized by chronic inflammation at the synovial membrane. Although great progress has been made recently in exploring the etiology and pathogenesis of RA, its molecular pathological mechanism remains to be further defined and it is still a great challenge in determining the diagnosis and in choosing the appropriate therapy in early patients. This study was performed to screen candidate RA-associated serum proteins by comparative proteomics to provide research clues to early diagnosis and treatment of RA. Methods Sera isolated from 6 RA patients and 6 healthy volunteers were pooled respectively and high-abundance proteins were depleted by Plasma 7 Multiple Affinity Removal System. The protein expression profiles between the two groups were then compared by two-dimensional gel electrophoresis （2-DE） and the proteins over/under-expressed by more than 3-fold were identified by mass spectrometry analysis. To validate the differential expression levels of the identified proteins between the two groups, ELISA was performed in two of the identified proteins in individual sera from 32 RA patients and 32 volunteers. Results Eight proteins which over/under-expressed in sera of RA patients were identified. Among them, chain A of transthyretin （TTR） was under-expressed, while serum amyloid A protein, apolipoprotein A （ApoA）-IV, ApoA-IV precursor, haptoglobin 2, ceruloplasmin （Cp）, immunoglobulin superfamily 22 and HT016 were over-expressed. ELISA test confirmed that Cp expressed remarkably higher while TTR obviously lower in RA group compared with volunteer group. Conclusion There were 8 identified proteins differentially expressed between RA group and volunteer group, which might be candidate RA-associated proteins and might be promising diagnostic indicators or therapeutic targets for RA.

关键词： rheumatoid arthritis serum proteomics gel electrophoresis, two-dimensional

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