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Science China(Life Sciences) 2022年第5期65卷 953-968页

作者： Xiaoyu Zhang Wenxiang Zhao Yihan Zhao Zeda Zhao Zhangsheng Lv Zhen Zhang Hua Ren Qin Wang Mingyao Liu Min Qian Bing Du Juliang Qin Changning Maternity and Infant Health Hospital and School of Life Sciences Shanghai Key Laboratory of Regulatory BiologyEast China Normal UniversityShanghai 200241China Department of Orthopedics The Eighth Affiliated HospitalSun Yat-sen UniversityShenzhen 510275China Joint Center for Translational Medicine Fengxian District Central HospitalShanghai 201499China

rheumatoid arthritis(RA)is a chronic autoimmune disease that primarily affects the joints and is associated with excessive immune cell ***,the complex interactions between the immune cell populations in the RA synovium remain ***,we demonstrate that inflammatory macrophages in the synovium exacerbate neutrophil-driven joint damage in RA through ADP/P2Y_(1)*** show that extracellular ADP(e ADP)and its receptors are obviously increased in synovial tissues of RA patients as well as collagen-induced arthritis(CIA)mice,and e ADP enhances neutrophil infiltration into joints through macrophages producing the chemokine CXCL2,aggravating disease ***,the arthritis mouse model had more neutrophils in inflamed joints following ADP injection,whereas P2Y_(1)deficiency and pharmacologic inhibition restored arthritis severity to basal levels,suggesting a dominant role of ADP/P2Y_(1)signaling in RA ***,cellular activity of ADP/P2Y_(1)-mediated CXCL2 production was dependent on the G_(αq)/Ca^(2+)-NF-κB/NFAT pathway in ***,this study reveals a non-redundant role of e ADP as a trigger in the pathogenesis of RA through neutrophil recruitment and disrupted tissue homeostasis and function.

关键词： extracellular ADP P2Y_(1) macrophage joint inflammation rheumatoid arthritis

Chinese registry of rheumatoid arthritis(CREDIT)V:sex impacts rheumatoid arthritis in Chinese patients

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Chinese Medical Journal 2022年第18期135卷 2210-2217页

作者： Nan Jiang Qin Li Hongbin Li Yongfei Fang Lijun Wu Xinwang Duan Jian Xu Cheng Zhao Zhenyu Jiang Yanhong Wang Qian Wang Xiaomei Leng Mengtao Li Xinping Tian Xiaofeng Zeng CREDIT Co-Authors Department of Rheumatology and Clinical Immunology Peking Union Medical College Hospital(PUMCH)Chinese Academy of Medical Sciences and Peking Union Medical CollegeNational Clinical Research Center for Dermatologic and Immunologic Diseases(NCRC-DID)Ministry of Science and TechnologyState Key Laboratory of Complex Severe and Rare DiseasesKey Laboratory of Rheumatology and Clinical ImmunologyMinistry of EducationBeijing 100730China Department of Rheumatology the First People’s Hospital of Yunnan ProvinceKunmingYunnan 650032China Department of Rheumatology the Affiliated Hospital of Inner Mongolia Medical CollegeHohhotInner Mongolia 010050China Department of Rheumatology Southwest HospitalThird Military Medical UniversityChongqing 400038China Department of Rheumatology and Immunology People’s Hospital of Xinjiang Uygur Autonomous RegionUrumqiXinjiang 830001China Department of Rheumatology The Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi 330006China Department of Rheumatology and Immunology First Affiliated Hospital of Kunming Medical UniversityKunmingYunnan 650032China Department of Rheumatology The First Affiliated Hospital of Guangxi Medical UniversityManningGuangxi 530021China Department of Rheumatology The First Hospital of Jilin UniversityChangchunJilin 130021China Department of Epidemiology and Bio-Statistics Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China. 不详

Background: The impact of sex on the clinical manifestations of rheumatoid arthritis (RA) were diversely reported in the literature. The Chinese Registry of rheumatoid arthritis provides a platform for the investigation of this issue in Chinese ***: Demographic and clinical parameters were collected from all enrolled patients with RA and from patients with early RA (disease duration ≤6 months). The differences in data regarding disease activity, comorbidities, and medications for RA were compared between men and women. The proportions of patients who achieved remission and low disease activity were compared at enrollment and during 3-, 6-, and 12-month follow-up ***: A total of 11,564 patients were enrolled, 83.6% of whom were female. In all the enrolled patients and patients with early RA, C-reactive protein (CRP, 12.0vs. 6.7 mg/L), pain visual analogue scale (4.8vs. 4.5), patient’s and physician’s global assessment (4.9vs. 4.5 and 4.9vs. 4.5), 28-joint disease activity score using DAS28-CRP (4.3vs. 4.0) simplified disease activity index (21.9vs. 19.9), and clinical disease activity index (19.3vs. 18.0) were significantly higher in men than in women. Additionally, the swollen joint count/tender joint count and DAS28 using erythrocyte sedimentation rate were higher in male patients than in female patients with early RA. More female patients with early RA reached the treatment target at baseline than male patients (23.4%vs. 18.2%, assessed by CDAI). At 3 months, 6 months, and 12 months, the proportion of remission and treatment target achievement was similar in both sexes. Coronary artery disease (CAD) and stroke were more frequent in men than in ***: In Chinese patients with RA, men were found to have more active disease, as well as more cases of CAD and stroke. Therefore, sex should be carefully considered during the personalization of RA treatment.

关键词： rheumatoid arthritis Sex Disease activity Treatment target Comorbidities

Prevalence and Factors Associated with Concomitant Chinese Medicine Use by rheumatoid arthritis Patients in A Multi-Ethnic Asian Population

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Chinese Journal of Integrative Medicine 2022年第3期28卷 223-228页

作者： HUANG You-yi XIN Xiao-hui Rehena Sultana Julian Thumboo FONG Kok Yong Duke-NUS Medical School Singapore Department of Rheumatology and Immunology Singapore General HospitalSingapore Medicine Academic Clinical Program Division of MedicineSingapore General HospitalSingapore Centre for Quantitative Medicine Duke-NUS Medical SchoolSingapore

Objective:To determine the prevalence,factors associated with and patterns of concomitant Chinese medicine(CM)with Western treatment use among patients with rheumatoid arthritis(RA)in a tertiary referral centre(Singapore General Hospital)in ***:We conducted a cross-sectional intervieweradministered survey of a consecutive sample of patients with RA in Singapore General Hospital centre regarding their CM use including data on patient demographics,disease characteristics,concomitant use of CM and reasons,concerns and disclosure patterns from March to August *** and multivariate logistic regression analyses were performed to determine the associations of CM ***:Prevalence of CM use among the 258 patients surveyed(male:female 42:216;Chinese:Malay:Indian 191:29:34;mean age:61 years;mean duration of RA:10 years)was 46.1%(119/258).On muutivariate analysis,Chinese ethnicity(OR,95%CI:4.11,1.49-11.36),Chinese speakers(OR,95%CI:2.35,1.03-5.54),middle-income group(OR,95%CI:2.53,1.01-6.31)and greater learned helplessness(OR,95%CI:1.13,1.04-1.22)were significantly associated with CM *** CM users disclosed their CM use to CM physicians(87.3%,96/110),sought advice from them on treatment interactions(59.4%,57/96)and how best to combine treatments(49.0%,47/96)than did so with rheumatologists(42.0%,50/119;40.0%,20/50;and 42.0%,21/50,respectively).Forty-two percentage(29/69)of patients who concealed CM use from rheumatologists because their rheumatologists did not specifically enquire about CM ***:Concomitant CM use among patients with RA treated in a tertiary referral centre in Singapore is high but voluntary disclosure is *** associations identified can help doctors identify and enquire about CM use,minimizing potential adverse interactions.

关键词： pevalence rheumatoid arthritis Chinese medicine complementary therapies

A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway

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Acta Pharmaceutica Sinica B 2023年第3期13卷 1093-1109页

作者： Sae-Bom Yoon Hyowon Hong Hee-Jong Lim Ji Hye Choi Yoon Pyo Choi Seong Wook Seo Hyuk Woo Lee Chong Hak Chae Woo-Kyu Park Hyun Young Kim Daeyoung Jeong Tran Quang De Chang-Seon Myung Heeyeong Cho Therapeutics&Biotechnology Division Korea Research Institute of Chemical TechnologyYuseong-guDaejeon 34114Republic of Korea Department of Pharmacology Chungnam National University College of PharmacyYuseong-guDaejeon 34134Republic of Korea Future Medicine Co. Ltd.Rm616 LH-Business Growth CenterSeongnamGyeonggido 13449Republic of Korea Department of Chemistry College of Natural SciencesCan Tho UniversityCan Tho city 9000Viet Nam

Interleukin-1 receptor-associated kinase 4(IRAK4)is a pivotal enzyme in the Toll-like receptor(TLR)/MYD88 dependent signaling pathway,which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma(ABC-DLBCL).Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of ***,proviral integration site for Moloney murine leukemia virus 1(PIM1)functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib *** developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction in vitro and in *** rheumatoid arthritis mouse models,treatment with KIC-0101 significantly ameliorated cartilage damage and ***-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in *** addition,KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-κB pathway and PIM1 *** results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.

关键词： Drug discovery IRAK4 PIM1 NF-κB pathway rheumatoid arthritis ABC-DLBCL Ibrutinib resistance Dual inhibitor

Moxibustion regulates T-regulatory/T-helper 17 cell balance by modulating the microRNA-221/suppressor of cytokine signaling 3 axis in a mouse model of rheumatoid arthritis

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Journal of Integrative Medicine 2022年第5期20卷 453-462页

作者： Chuang Zhao Xiao-yan Li Zun-yuan Li Miao Li Zhi-dan Liu Department of Acupuncture Baoshan Branch of Shuguang HospitalShanghai University of Traditional Chinese MedicineShanghai 201999China Department of Acupuncture Baoshan Hospital of Integrated Traditional Chinese Medicine and Western MedicineShanghai 201999China

Objective rheumatoid arthritis(RA)progression is associated with the balance of T-regulatory(Treg)and T-helper 17(Th17)cells,while the role of microRNAs(miRs)in regulating Treg/Th17 cell balance has not been *** study aimed to assess whether moxibustion could regulate Treg/Th17 cell balance by modulating the miR-221/suppressor of cytokine signaling 3(SOCS3)axis in the RA mouse *** A mouse model of collagen-induced arthritis(CIA)was established in male DBA/1J ***-two days after CIA induction,the mice received daily treatment with moxibustion for 12 *** scores were assessed according to the levels of synovial *** expression levels of cytokines interleukin(IL)-1β,IL-6,tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ),IL-17 and IL-10 were analyzed in serum by enzyme-linked immunosorbent *** cluster of differentiation 4(CD4+)splenocytes was analyzed by fluorescence-activated cell *** expression levels of RA-related miRs and target genes were subsequently detected,and the target of miR-221 was confirmed by the dual-luciferase reporter *** It was revealed that moxibustion treatment decreased the pathological scores and downregulated the expression levels of IL-1β,IL-6,TNF-α,IFN-γand IL-17,while upregulated the expression level of *** Treg/Th17 cell balance was regulated by moxibustion *** expression level of miR-221 was suppressed by moxibustion ***,SOCS3 was found as the direct target of miR-221,which mediated the function of moxibustion by regulating the Treg/Th17 cell *** Moxibustion therapy regulated the Treg/Th17 cell balance by modulating the miR-221/SOCS3 axis in the RA mouse model.

关键词： rheumatoid arthritis Moxibustion MicroRNA-221 Suppressor of cytokine signaling 3 T-regulatory/T-helper 17 cell balance

Reactive oxygen species and nitric oxide scavenging nanoparticles alleviating rheumatoid arthritis through adjusting the seeds and growing soils

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Acta Pharmaceutica Sinica B 2023年第12期13卷 5016-5029页

作者： Peng Hua Ruifeng Liang Yanbei Tu Yuying Yin Man-Kay Law Meiwan Chen State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao SARChina State Key Laboratory of Analog and Mixed-Signal VLSI IME and FST-ECEUniversity of MacaoMacao SARChina

Normalizing inflamed soils including reactive oxygen species(ROS),nitric oxide(NO),cellfree DNA,and regulating infammation-related seeds such as macrophages,neutrophils,fibroblasts,represent a promising strategy to maintain synovial tissue homeostasis for rheumatoid arthritis(RA)***,ROS scavenging amphiphilic block copolymer PEGylated bilirubin and NO-scavenging PEGylated o-phenylenediamine were fabricated to self-assemble into a dually responsive nanoparticle loaded with JAK inhibitor notopterol(Not@BR/oPDA-PEG,NBOP NPs).The simultaneous ROS and NO depletion combined with JAK-STAT pathway inhibition could not only promote M2 polarization to reduce further ROS and NO generation,but also decrease cytokines and chemokines to prevent immune cell ***,NBOP NPs responded to high level ROS and NO,and disintegrated to release notopterol in inflamed joints as the hydrophobic heads BR and oPDA were transformed into hydrophilic *** released notopterol could inhibit the JAK-STAT pathway of infammatory cells to reduce the secretion of pro-inflammatory cytokines and *** strategy represented an effective way to regulate RA soils and seeds through breaking the positive feedback loop of inflammation aggravation,achieving an excellent anti-RA efficacy in a collagen-induced arthritis rat *** together,our work offered a reference to adjust RA soils and seeds for enhanced RA treatment.

关键词： Bilirubin o-Phenylenediamine Notopterol ROS and NO scavenging JAK-STATpathway Anti-inflammatory Cartilage protection rheumatoid arthritis

Roles of Serum Amyloid A 1 Protein Isoforms in rheumatoid arthritis

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Engineering 2022年第3期8卷 174-182页

作者： Elaine Laihan Leung Huan-Ling Lai Run-Ze Li Hu-Dan Pan Ze-Bo Jiang Ying Li Fu-Gang Duan Jia-Hui Xu Yi-Zhong Zhang A-Xi Shi Chun-Li Wei Fang-Yuan Zhang Xiao-Jun Yao Liang Liu State Key Laboratory of Quality Research in Chinese Medicine&Macao Institute for Applied Research in Medicine and Health&Faculty of Chinese Medicine Macao University of Science and TechnologyMacao 999078China Department of Pediatrics Pennsylvania State University College of MedicineHersheyPA 17033USA

Secondary amyloid A amyloidosis,a lethal complication,is induced when acute or chronic infection coexists with over-secretion of the serum amyloid A 1(SAA1)protein and deposition in key internal ***,using the whole-exome sequencing method,we identified a novel deleterious mutation SAA1.2 in rheumatoid arthritis(RA)***,the role of SAA1 in RA pathogenesis and its complications remains *** purpose of this study was to determine the pathogenetic roles of SAA1 protein isoforms in RA *** modified an experimental adenovirus infection protocol to introduce SAA1.2 gene alleles into the knee joints of mice and used SAA1.3 and SAA1.5 as *** tomography analysis was applied to determine changes in bone morphology and ***(IHC)analysis,flow cytometry,enzyme-linked immunosorbent assay(ELISA),and real-time polymerase chain reaction(RT-PCR)were used to investigate disease progression and cytokine alterations in the course of adenoviral SAA-induced knee joint inflammation and bone *** found that the arthritis-inducing effect of SAA1.2 transcription in the knee joints and mutant SAA1 protein secretion in blood resulted in the stimulation of immune responses,leading to CD8^(+)T cell and pro-inflammatory cytokine elevation,such as interleukin(IL)-6,IL-22,matrix metalloproteinase(MMP)-3,MMP-9,with subsequent synovial inflammation and bone *** findings indicate that SAA1 protein isoforms,particularly SAA1.2,play a significant role in the induction and progression of RA and may have potential value in the early diagnosis and severity prediction of RA.

关键词： Serum amyloid A 1 rheumatoid arthritis Pathogenetic Intra-articular

Synergistically targeting synovium STING pathway for rheumatoid arthritis treatment

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Bioactive Materials 2023年第6期24卷 37-53页

作者： Haotian Shen Lulu Jin Qiangqiang Zheng Ziqiang Ye Linxiang Cheng Yuxu Wu Honghao Wu Tae Gyong Jon Wenduo Liu Zongyou Pan Zhengwei Mao Yue Wang Department of Orthopedic Surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhou310003China MOE Key Laboratory of Macromolecular Synthesis and Functionalization Department of Polymer Science and EngineeringZhejiang UniversityHangzhou310027China Dr.Li Dak Sum&Yip Yio Chin Center for Stem Cells and Regenerative Medicine Zhejiang University School of MedicineHangzhou310000China International Institutes of Medicine The Fourth Affiliated HospitalZhejiang University School of MedicineN1 Shangchen RoadYiwuZhejiang322000China

rheumatoid arthritis(RA)is a common autoimmune disease leading to pain,disability,and even *** studies have revealed that aberrant activation of STING was implicated in various autoimmune diseases,the role of STING in RA remains *** the current study,we demonstrated that STING activation was pivotal in RA *** the accumulation of dsDNA,a specific stimulus for STING,is a feature of RA,we developed a spherical polyethyleneimine-coated mesoporous polydopamine nanoparticles loaded with STING antagonist C-176(PEI-PDA@C-176 NPs)for treating *** fabricated NPs with biocompatibility had high DNA adsorption ability and could effectively inhibit the STING pathway and inflammation in ***-articular administration of PEI-PDA@C-176 NPs could effectively reduce joint damage in mice models of dsDNA-induced arthritis and collagen-induced arthritis by inhibiting STING *** concluded that materials with synergistic effects of STING inhibition might be an efficacious strategy to treat RA.

关键词： Mesoporous nanoparticles STING Inflammation Drug delivery rheumatoid arthritis

Reprogrammed siTNFα/neutrophil cytopharmaceuticals targeting inflamed joints for rheumatoid arthritis therapy

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Acta Pharmaceutica Sinica B 2023年第2期13卷 787-803页

作者： Yijun Chen Kaiming Li Mengying Jiao Yingshuang Huang Zihao Zhang Lingjing Xue Caoyun Ju Can Zhang State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesCenter of Advanced Pharmaceuticals and BiomaterialsChina Pharmaceutical UniversityNanjing 210009China

rheumatoid arthritis(RA)is an autoimmune disease characterized by severe synovial inflammation and cartilage *** great progress in RA therapy,there still lacks the drugs to completely cure RA ***,we propose a reprogrammed neutrophil cytopharmaceuticals loading with TNFα-targeting-siRNA(siTNFα)as an alternative anti-inflammatory approach for RA *** loaded siTNFαact as not only the gene therapeutics to inhibit TNFαproduction by macrophages in inflamed synovium,but also the editors to reprogram neutrophils to anti-inflammatory *** the active tendency of neutrophils to inflammation,the reprogrammed siTNFα/neutrophil cytopharmaceuticals(siTNFα/TP/NEs)can rapidly migrate to the inflamed synovium,transfer the loaded siTNFαto macrophages followed by the significant reduction of TNFαexpression,and circumvent the pro-inflammatory activity of neutrophils,thus leading to the alleviated synovial inflammation and improved cartilage *** work provides a promising cytopharmaceutical for RA treatment,and puts forward a living neutrophil-based gene delivery platform.

关键词： Neutrophil cytopharmaceuticals siRNA Macrophages rheumatoid arthritis Tumor necrosis factorα Gene delivery Anti-inflammatory Cartilage protection

The Correlation Between Decreased Ornithine Level and Alleviation of rheumatoid arthritis Patients Assessed by a Randomized,Placebo-Controlled,Double-Blind Clinical Trial of Sinomenine

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Engineering 2022年第9期16卷 93-99页

作者： Ying Shi Hu-Dan Pan Jian-Lin Wu Qing-Hua Zou Xin-Yi Xie Hong-Gang Li Hua Zhou Xi-Qing Bian Wen-Fei Leng Can-Jian Wang Ya-Feng Wang Yong-Fei Fang Liang Liu Department of Rheumatology The Southwest Hospital of Army Military Medical UniversityChongqing 400038China State Key Laboratory of Dampness Syndrome Chinese Medicine The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510000China State Key Laboratory of Quality Research in Chinese Medicine&Macao Institute for Applied Research in Medicine and Health Macao University of Science and TechnologyMacao 999078China People’s Hospital of Changshou Chongqing Chongqing 401220China Traditional Chinese Medicine Hospital Dianjiang Chongqing Chongqing 408300China Medical Management Center World Federation of Chinese Medicine SocietiesBeijing 100101China

Sinomenine(SIN)is commonly used as part of rheumatoid arthritis(RA)therapy in China,but there is still no published evidence of the efficacy of SIN *** work investigates the efficacy and safety of SIN in treating RA patients and analyzes the correlation between ornithine level and the alleviation of disease activity in RA *** this 24 week,randomized,placebo-controlled,double-blind clinical trial,people with mild to moderate RA were randomly assigned(1:1:1,stratified by hospital)to receive SIN(120 mg,twice daily),methotrexate(MTX)(10 mg per week),or SIN+MTX *** primary outcome was the proportion of patients who achieved a 50%improvement in the American College of Rheumatology(ACR50)criteria at week 24 and who showed improvement according to the clinical disease activity index(CDAI).In this prospective subgroup analysis,we also assessed whether the 24-week alterations of disease activity in the treatment group were significantly correlated to the levels of blood *** the 135 enrolled participants,38,39,and 36 patients were treated with SIN,MTX,and SIN+MTX,*** the SIN-treated group,52.63%of patients achieved ACR50 after 24-weeks of treatment,which was comparable to the results in the MTX-treated and SIN+MTX-treated *** and gastrointestinal disorders were the main adverse events;however,the ratio of patients suffering from hepatic disorder in the SIN group(1/38)was much lower than that in the MTX(10/39)and SIN+MTX(8/36)groups.A total of 221 serum samples were collected at the four follow-up time points in the three treatments,and the levels of ornithine,citrulline,and arginine were obtained through ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF/MS).The serum ornithine level decreased after the 24-week treatment along with a decrease in disease activity,and may reflect therapeutic responses with a sensitivity value of 80%.In conclusion,SIN revealed a comparabl

关键词： rheumatoid arthritis Sinomenine Efficacy Safety Inflammatory biomarker