{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:23:15Z","timestamp":1791415395106,"version":"4.3.3"},"reference-count":58,"publisher":"American Association for the Advancement of Science (AAAS)","funder":[{"DOI":"10.13039\/100016696","name":"Special Foundation for Theoretical Physics Research Program of China","doi-asserted-by":"publisher","award":["82104480"],"award-info":[{"award-number":["82104480"]}],"id":[{"id":"10.13039\/100016696","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["spj.science.org"],"crossmark-restriction":true},"short-container-title":["Research"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:p>Rheumatoid arthritis (RA) is an autoimmune disease with features of synovial inflammation, cartilage erosion, bone destruction, and pain and is currently lacking a satisfactory treatment strategy. Dihydroartemisinin (DHA), the active metabolite of artemisinin, has exhibited outstanding suppressive effects on RA without obvious side effects. However, the underlying mechanisms remain unclear, which limits its further clinical application. The purpose of this study is to reveal the pharmacodynamic mechanism of DHA against RA by means of a combination of single-cell RNA sequencing (RNA-seq), proteomics, as well as transcriptomics both in\u00a0vivo and in\u00a0vitro. In our results, DHA effectively reduced the degree of redness, swelling, and pain in RA rats and dramatically changed the synovial tissue microenvironment under the pathological state. Within this microenvironment, fibroblasts, macrophages, B cells, and endothelial cells were the major affected cell types, primarily through DHA targeting the extracellular matrix (ECM) structural constituent signaling pathway. In addition, we confirmed that DHA regulated the ECM by modulating matrix metalloproteinase 2 (MMP2) and MMP3 in the synovial tissue of RA rats. Moreover, DHA induced apoptosis in MH7A cells, further validating the bioinformatics data. In conclusion, DHA effectively reduced the inflammatory response and improved the immune microenvironment in synovial tissue by inhibiting MMP2 and MMP3. Our findings provide a basis for the application of DHA in the treatment of RA.<\/jats:p>","DOI":"10.34133\/research.0459","type":"journal-article","created":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T16:50:24Z","timestamp":1722963024000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":19,"title":["Dihydroartemisinin Regulated the MMP-Mediated Cellular Microenvironment to Alleviate Rheumatoid Arthritis"],"prefix":"10.34133","volume":"7","author":[{"given":"Qiuyan","family":"Guo","sequence":"first","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qixin","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayun","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghong","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianming","family":"Lu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuchang","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin Kwan","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Physiology, Yong Loo Lin School of Medicine, \rNational University of Singapore, Singapore, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueling","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chinese Medical Association, Beijing 100710, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanhao","family":"Dai","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Shen","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanhuan","family":"Pang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Xia","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Qiu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daoyuan","family":"Xie","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Medicine Research, Deyang People\u2019s Hospital of Chengdu University of Traditional Chinese Medicine, Deyang 618000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0575-0105","authenticated-orcid":true,"given":"Jigang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, \rChina Academy of Chinese Medical Sciences, Beijing 100700, China."},{"name":"State Key Laboratory of Antiviral Drugs, School of Pharmacy, \rHenan University, Kaifeng 475004, China."},{"name":"Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, \rSouthern University of Science and Technology), Shenzhen 518020, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2024,9,10]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.34133\/research.0220"},{"issue":"10055","key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen JS","year":"2016","unstructured":"Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023\u20132038.","journal-title":"Lancet"},{"issue":"6","key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1136\/annrheumdis-2019-216655","article-title":"EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update","volume":"79","author":"Smolen JS","year":"2020","unstructured":"Smolen JS, Landew\u00e9 RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, McInnes IB, Sepriano A, van Vollenhoven RF, de Wit M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685\u2013699.","journal-title":"Ann Rheum Dis"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.34133\/research.0003"},{"issue":"1","key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1136\/annrheumdis-2016-209775","article-title":"EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015\/2016 update","volume":"76","author":"Agca R","year":"2017","unstructured":"Agca R, Heslinga SC, Rollefstad S, Heslinga M, McInnes IB, Peters MJ, Kvien TK, Dougados M, Radner H, Atzeni F, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015\/2016 update. Ann Rheum Dis. 2017;76(1):17\u201328.","journal-title":"Ann Rheum Dis"},{"issue":"5","key":"e_1_3_4_7_2","first-page":"S95","article-title":"Side effects and management of side effects of methotrexate in rheumatoid arthritis","volume":"28","author":"Albrecht K","year":"2010","unstructured":"Albrecht K, M\u00fcller-Ladner U. Side effects and management of side effects of methotrexate in rheumatoid arthritis. Clin Exp Rheumatol. 2010;28(5 Suppl 61):S95\u2013S101.","journal-title":"Clin Exp Rheumatol"},{"issue":"5","key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1007\/s00223-017-0335-7","article-title":"Glucocorticoids, inflammation and bone","volume":"102","author":"G\u00fcler-Y\u00fcksel M","year":"2018","unstructured":"G\u00fcler-Y\u00fcksel M, Hoes JN, Bultink IEM, Lems WF. Glucocorticoids, inflammation and bone. Calcif Tissue Int. 2018;102(5):592\u2013606.","journal-title":"Calcif Tissue Int"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.34133\/research.0013"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","DOI":"10.1016\/j.phrs.2020.104901","article-title":"Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases","volume":"158","author":"Cheong DHJ","year":"2020","unstructured":"Cheong DHJ, Tan DWS, Wong FWS, Tran T. Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases. Pharmacol Res. 2020;158: Article 104901.","journal-title":"Pharmacol Res"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","DOI":"10.1016\/j.ijpharm.2020.119178","article-title":"Dimeric artesunate phospholipid-conjugated liposomes as promising anti-inflammatory therapy for rheumatoid arthritis","volume":"579","author":"Zhang Y","year":"2020","unstructured":"Zhang Y, He W, Du Y, Du Y, Zhao C, Zhang Y, Zhang H, Yin L, Li X. Dimeric artesunate phospholipid-conjugated liposomes as promising anti-inflammatory therapy for rheumatoid arthritis. Int J Pharm. 2020;579: Article 119178.","journal-title":"Int J Pharm"},{"issue":"9","key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s11926-018-0764-y","article-title":"Artemisinins\u2014A promising new treatment for systemic lupus erythematosus: A descriptive review","volume":"20","author":"Mu X","year":"2018","unstructured":"Mu X, Wang C. Artemisinins\u2014A promising new treatment for systemic lupus erythematosus: A descriptive review. Curr Rheumatol Rep. 2018;20(9):55.","journal-title":"Curr Rheumatol Rep"},{"issue":"6","key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1080\/08923973.2017.1379087","article-title":"Artemisinin therapeutic efficacy in the experimental model of multiple sclerosis","volume":"39","author":"Khakzad MR","year":"2017","unstructured":"Khakzad MR, Ganji A, Ariabod V, Farahani I. Artemisinin therapeutic efficacy in the experimental model of multiple sclerosis. Immunopharmacol Immunotoxicol. 2017;39(6):348\u2013353.","journal-title":"Immunopharmacol Immunotoxicol"},{"issue":"12","key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"3055","DOI":"10.1038\/s41401-022-00978-4","article-title":"Artemisinin derivative SM934 in the treatment of autoimmune and inflammatory diseases: Therapeutic effects and molecular mechanisms","volume":"43","author":"Tong X","year":"2022","unstructured":"Tong X, Chen L, He SJ, Zuo JP. Artemisinin derivative SM934 in the treatment of autoimmune and inflammatory diseases: Therapeutic effects and molecular mechanisms. Acta Pharmacol Sin. 2022;43(12):3055\u20133061.","journal-title":"Acta Pharmacol Sin"},{"issue":"1","key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s11307-020-01534-4","article-title":"The evaluation of (68)Ga-citrate PET\/CT imaging for dihydroartemisinin in the treatment of rheumatoid arthritis","volume":"23","author":"Wang Z","year":"2021","unstructured":"Wang Z, Hou Y, Cai L, Chen Y. The evaluation of (68)Ga-citrate PET\/CT imaging for dihydroartemisinin in the treatment of rheumatoid arthritis. Mol Imaging Biol. 2021;23(1):30\u201337.","journal-title":"Mol Imaging Biol"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.3389\/fimmu.2018.02762","article-title":"DC32, a Dihydroartemisinin derivative, ameliorates collagen-induced arthritis through an Nrf2-p62-Keap1 feedback loop","volume":"9","author":"Fan M","year":"2018","unstructured":"Fan M, Li Y, Yao C, Liu X, Liu J, Yu B. DC32, a Dihydroartemisinin derivative, ameliorates collagen-induced arthritis through an Nrf2-p62-Keap1 feedback loop. Front Immunol. 2018;9:2762.","journal-title":"Front Immunol"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.intimp.2018.10.015","article-title":"Dihydroartemisinin derivative DC32 attenuates collagen-induced arthritis in mice by restoring the Treg\/Th17 balance and inhibiting synovitis through down-regulation of IL-6","volume":"65","author":"Fan M","year":"2018","unstructured":"Fan M, Li Y, Yao C, Liu X, Liu X, Liu J. Dihydroartemisinin derivative DC32 attenuates collagen-induced arthritis in mice by restoring the Treg\/Th17 balance and inhibiting synovitis through down-regulation of IL-6. Int Immunopharmacol. 2018;65:233\u2013243.","journal-title":"Int Immunopharmacol"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.27041","article-title":"Human cell atlas meeting participants","volume":"6","author":"Regev A","year":"2017","unstructured":"Regev A, Teichmann S, Lander E, Amit I, Benoist C, Birney E, Bodenmiller B, Campbell P, Carninci P, Clatworthy M, et al. Human cell atlas meeting participants. Elife. 2017;6: Article e27041.","journal-title":"Elife"},{"issue":"9","key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1136\/annrheumdis-2018-214783","article-title":"TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: Transcriptomic and epigenomic analysis","volume":"78","author":"Loh C","year":"2019","unstructured":"Loh C, Park S, Lee A, Yuan R, Ivashkiv L, Kalliolias G. TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: Transcriptomic and epigenomic analysis. Ann Rheum Dis. 2019;78(9):1205\u20131214.","journal-title":"Ann Rheum Dis"},{"issue":"2","key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1093\/jnci\/50.2.549","article-title":"Occurrence of a primary liver carcinoma in a rhesus monkey fed aflatoxin B 1","volume":"50","author":"Adamson R","year":"1973","unstructured":"Adamson R, Correa P, Dalgard D. Occurrence of a primary liver carcinoma in a rhesus monkey fed aflatoxin B 1. J Natl Cancer Inst. 1973;50(2):549\u2013553.","journal-title":"J Natl Cancer Inst"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2022-222605"},{"issue":"5","key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1002\/art.41184","article-title":"B cell synovitis and clinical phenotypes in rheumatoid arthritis: Relationship to disease stages and drug exposure","volume":"72","author":"Rivellese F","year":"2020","unstructured":"Rivellese F, Humby F, Bugatti S, Fossati-Jimack L, Rizvi H, Lucchesi D, Lliso-Ribera G, Nerviani A, Hands R, Giorli G, Frias B, Thorborn G, Jaworska E, John C, Goldmann K, Lewis M, Manzo A, Bombardieri, M, Pitzalis C, PEAC-R4RA Investigators. B cell synovitis and clinical phenotypes in rheumatoid arthritis: Relationship to disease stages and drug exposure. Arthritis Rheumatol. 2020;72(5):714\u2013725.","journal-title":"Arthritis Rheumatol"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-00570-2"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","DOI":"10.1016\/j.jaut.2022.102950","article-title":"Tissue-resident memory T cells: The key frontier in local synovitis memory of rheumatoid arthritis","volume":"133","author":"Gao A","year":"2022","unstructured":"Gao A, Zhao W, Wu R, Su R, Jin R, Luo J, Gao C, Li X, Wang C. Tissue-resident memory T cells: The key frontier in local synovitis memory of rheumatoid arthritis. J Autoimmun. 2022;133: Article 102950.","journal-title":"J Autoimmun"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.709178","article-title":"New insights from single-cell sequencing data: Synovial fibroblasts and synovial macrophages in rheumatoid arthritis","volume":"12","author":"Cheng L","year":"2021","unstructured":"Cheng L, Wang Y, Wu R, Ding T, Xue H, Gao C, Li X, Wang C. New insights from single-cell sequencing data: Synovial fibroblasts and synovial macrophages in rheumatoid arthritis. Front Immunol. 2021;12: Article 709178.","journal-title":"Front Immunol"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00793-5"},{"issue":"1","key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1186\/s13075-018-1720-y","article-title":"Induction of chronic destructive arthritis in SCID mice by arthritogenic fibroblast-like synoviocytes derived from mice with antigen-induced arthritis","volume":"20","author":"Frey O","year":"2018","unstructured":"Frey O, H\u00fcckel M, Gajda M, Petrow P, Br\u00e4uer R. Induction of chronic destructive arthritis in SCID mice by arthritogenic fibroblast-like synoviocytes derived from mice with antigen-induced arthritis. Arthritis Res Ther. 2018;20(1):261.","journal-title":"Arthritis Res Ther"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.abb.2018.07.010","article-title":"Aryl hydrocarbon receptor enhances the expression of miR-150-5p to suppress in prostate cancer progression by regulating MAP3K12","volume":"654","author":"Yu J","year":"2018","unstructured":"Yu J, Feng Y, Wang Y, An R. Aryl hydrocarbon receptor enhances the expression of miR-150-5p to suppress in prostate cancer progression by regulating MAP3K12. Arch Biochem Biophys. 2018;654:47\u201354.","journal-title":"Arch Biochem Biophys"},{"issue":"6","key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41584-023-00966-w","article-title":"Matrix metalloproteinases in arthritis: Towards precision medicine","volume":"19","author":"Grillet B","year":"2023","unstructured":"Grillet B, Pereira R, Van Damme J, Abu El-Asrar A, Proost P, Opdenakker G. Matrix metalloproteinases in arthritis: Towards precision medicine. Nat Rev Rheumatol. 2023;19(6):363\u2013377.","journal-title":"Nat Rev Rheumatol"},{"issue":"4","key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s00281-017-0631-3","article-title":"Synovial cellular and molecular markers in rheumatoid arthritis","volume":"39","author":"Asif Amin M","year":"2017","unstructured":"Asif Amin M, Fox D, Ruth J. Synovial cellular and molecular markers in rheumatoid arthritis. Semin Immunopathol. 2017;39(4):385\u2013393.","journal-title":"Semin Immunopathol"},{"issue":"11","key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1136\/ard.61.11.957","article-title":"MMPs and rheumatoid synovial fibroblasts: Siamese twins in joint destruction?","volume":"61","author":"M\u00fcller-Ladner U","year":"2002","unstructured":"M\u00fcller-Ladner U, Gay S. MMPs and rheumatoid synovial fibroblasts: Siamese twins in joint destruction? Ann Rheum Dis. 2002;61(11):957\u2013959.","journal-title":"Ann Rheum Dis"},{"issue":"2","key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/1529-0131(200002)43:2<259::AID-ANR4>3.0.CO;2-W","article-title":"Involvement of receptor activator of nuclear factor kappaB ligand\/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis","volume":"43","author":"Takayanagi H","year":"2000","unstructured":"Takayanagi H, Iizuka H, Juji T, Nakagawa T, Yamamoto A, Miyazaki T, Koshihara Y, Oda H, Nakamura K, Tanaka S. Involvement of receptor activator of nuclear factor kappaB ligand\/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum. 2000;43(2):259\u2013269.","journal-title":"Arthritis Rheum"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.91"},{"issue":"1","key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1080\/14397595.2019.1704976","article-title":"Comparative study of HO-1 expressing synovial lining cells between RA and OA","volume":"31","author":"Yang S","year":"2021","unstructured":"Yang S, Ohe R, Aung N, Kato T, Kabasawa T, Utsunomiya A, Takakubo Y, Takagi M, Yamakawa M. Comparative study of HO-1 expressing synovial lining cells between RA and OA. Mod Rheumatol. 2021;31(1):133\u2013140.","journal-title":"Mod Rheumatol"},{"issue":"1","key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/j.1365-2249.2012.04634.x","article-title":"The role of stromal cells in the persistence of chronic inflammation","volume":"171","author":"Naylor A","year":"2013","unstructured":"Naylor A, Filer A, Buckley C. The role of stromal cells in the persistence of chronic inflammation. Clin Exp Immunol. 2013;171(1):30\u201335.","journal-title":"Clin Exp Immunol"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.2.838"},{"issue":"1","key":"e_1_3_4_37_2","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1074\/jbc.275.1.444","article-title":"Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis","volume":"275","author":"Onodera S","year":"2000","unstructured":"Onodera S, Kaneda K, Mizue Y, Koyama Y, Fujinaga M, Nishihira J. Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis. J Biol Chem. 2000;275(1):444\u2013450.","journal-title":"J Biol Chem"},{"issue":"2","key":"e_1_3_4_38_2","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2017-000471","article-title":"Synovial fibroblasts in 2017","volume":"3","author":"Ospelt C","year":"2017","unstructured":"Ospelt C. Synovial fibroblasts in 2017. RMD Open. 2017;3(2): Article e000471.","journal-title":"RMD Open"},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13036-019-0184-1","article-title":"Long non-coding RNA PVT1 knockdown suppresses fibroblast-like synoviocyte inflammation and induces apoptosis in rheumatoid arthritis through demethylation of sirt6","volume":"13","author":"Zhang C","year":"2019","unstructured":"Zhang C, Wu X, Liu D, Zhou W, Tan W, Fang Y, Zhang Y, Liu Y, Li G. Long non-coding RNA PVT1 knockdown suppresses fibroblast-like synoviocyte inflammation and induces apoptosis in rheumatoid arthritis through demethylation of sirt6. J Biol Eng. 2019;13:60.","journal-title":"J Biol Eng"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.41941"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2016.02.008"},{"key":"e_1_3_4_42_2","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.3389\/fimmu.2018.02228","article-title":"Sinomenine inhibits the progression of rheumatoid arthritis by regulating the secretion of inflammatory cytokines and monocyte\/macrophage subsets","volume":"9","author":"Liu W","year":"2018","unstructured":"Liu W, Zhang Y, Zhu W, Ma C, Ruan J, Long H, Wang Y. Sinomenine inhibits the progression of rheumatoid arthritis by regulating the secretion of inflammatory cytokines and monocyte\/macrophage subsets. Front Immunol. 2018;9:2228.","journal-title":"Front Immunol"},{"issue":"57","key":"e_1_3_4_43_2","doi-asserted-by":"crossref","first-page":"7632","DOI":"10.1039\/c4cc02595d","article-title":"A hyaluronic acid-methotrexate conjugate for targeted therapy of rheumatoid arthritis","volume":"50","author":"Shin J","year":"2014","unstructured":"Shin J, Kim S, Thambi T, You D, Jeon J, Lee J, Chung B, Jo D, Park J. A hyaluronic acid-methotrexate conjugate for targeted therapy of rheumatoid arthritis. Chem Commun (Camb). 2014;50(57):7632\u20137635.","journal-title":"Chem Commun (Camb)"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2017.03.044"},{"key":"e_1_3_4_45_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.biomaterials.2017.01.008","article-title":"Targeting NF-kB signaling with polymeric hybrid micelles that co-deliver siRNA and dexamethasone for arthritis therapy","volume":"122","author":"Wang Q","year":"2017","unstructured":"Wang Q, Jiang H, Li Y, Chen W, Li H, Peng K, Zhang Z, Sun X. Targeting NF-kB signaling with polymeric hybrid micelles that co-deliver siRNA and dexamethasone for arthritis therapy. Biomaterials. 2017;122:10\u201322.","journal-title":"Biomaterials"},{"key":"e_1_3_4_46_2","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.biomaterials.2015.05.028","article-title":"Macrophage repolarization with targeted alginate nanoparticles containing IL-10 plasmid DNA for the treatment of experimental arthritis","volume":"61","author":"Jain S","year":"2015","unstructured":"Jain S, Tran T, Amiji M. Macrophage repolarization with targeted alginate nanoparticles containing IL-10 plasmid DNA for the treatment of experimental arthritis. Biomaterials. 2015;61:162\u2013177.","journal-title":"Biomaterials"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11092"},{"key":"e_1_3_4_48_2","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.coi.2021.05.011","article-title":"BAFF signaling in B cell metabolism","volume":"71","author":"McAllister E","year":"2021","unstructured":"McAllister E, Jellusova J. BAFF signaling in B cell metabolism. Curr Opin Immunol. 2021;71:69\u201374.","journal-title":"Curr Opin Immunol"},{"key":"e_1_3_4_49_2","doi-asserted-by":"crossref","DOI":"10.1155\/2014\/681678","article-title":"B cells in rheumatoid arthritis: From pathogenic players to disease biomarkers","volume":"2014","author":"Bugatti S","year":"2014","unstructured":"Bugatti S, Vitolo B, Caporali R, Montecucco C, Manzo A. B cells in rheumatoid arthritis: From pathogenic players to disease biomarkers. Biomed Res Int. 2014;2014: Article 681678.","journal-title":"Biomed Res Int"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222413675"},{"key":"e_1_3_4_51_2","doi-asserted-by":"crossref","DOI":"10.1016\/j.jep.2020.113039","article-title":"Anti-angiogenic effect of Shikonin in rheumatoid arthritis by downregulating PI3K\/AKT and MAPKs signaling pathways","volume":"260","author":"Liu C","year":"2020","unstructured":"Liu C, He L, Wang J, Wang Q, Sun C, Li Y, Jia K, Wang J, Xu T, Ming R, et al. Anti-angiogenic effect of Shikonin in rheumatoid arthritis by downregulating PI3K\/AKT and MAPKs signaling pathways. J Ethnopharmacol. 2020;260: Article 113039.","journal-title":"J Ethnopharmacol"},{"key":"e_1_3_4_52_2","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.lfs.2019.05.024","article-title":"Vardenafil and cilostazol can improve vascular reactivity in rats with diabetes mellitus and rheumatoid arthritis co-morbidity","volume":"229","author":"Wahba M","year":"2019","unstructured":"Wahba M, Messiha B, El-Daly M, Abo-Saif A. Vardenafil and cilostazol can improve vascular reactivity in rats with diabetes mellitus and rheumatoid arthritis co-morbidity. Life Sci. 2019;229:67\u201379.","journal-title":"Life Sci"},{"issue":"2","key":"e_1_3_4_53_2","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s12013-013-9563-2","article-title":"Antiangiogenic effect of methotrexate and PUVA on psoriasis","volume":"67","author":"Shaker O","year":"2013","unstructured":"Shaker O, Khairallah M, Rasheed H, Abdel-Halim M, Abuzeid O, Tawdi A, Hadidi H, Ashmaui A. Antiangiogenic effect of methotrexate and PUVA on psoriasis. Cell Biochem Biophys. 2013;67(2):735\u2013742.","journal-title":"Cell Biochem Biophys"},{"issue":"8","key":"e_1_3_4_54_2","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.4049\/jimmunol.1800304","article-title":"Therapeutic potential of mesenchymal cell-derived miRNA-150-5p-expressing exosomes in rheumatoid arthritis mediated by the modulation of MMP14 and VEGF","volume":"201","author":"Chen Z","year":"2018","unstructured":"Chen Z, Wang H, Xia Y, Yan F, Lu Y. Therapeutic potential of mesenchymal cell-derived miRNA-150-5p-expressing exosomes in rheumatoid arthritis mediated by the modulation of MMP14 and VEGF. J Immunol. 2018;201(8):2472\u20132482.","journal-title":"J Immunol"},{"key":"e_1_3_4_55_2","doi-asserted-by":"crossref","first-page":"116304","DOI":"10.1016\/j.biopha.2024.116304","article-title":"Glycyrrhetinic acid inhibits non-small cell lung cancer via promotion of Prdx6- and caspase-3-mediated mitochondrial apoptosis","volume":"173","author":"Guo Q","year":"2024","unstructured":"Guo Q, Zhao M, Wang Q, Lu T, Luo P, Chen L, Xia F, Pang H, Shen S, Cheng G, et al. Glycyrrhetinic acid inhibits non-small cell lung cancer via promotion of Prdx6- and caspase-3-mediated mitochondrial apoptosis. Biomed Pharmacother. 2024;173:116304.","journal-title":"Biomed Pharmacother"},{"issue":"11","key":"e_1_3_4_56_2","first-page":"1128","article-title":"Glycyrrhizic acid mitigates Tripterygium-glycoside-tablet-induced acute liver injury via PKM2 regulated oxidative stress","volume":"12","author":"Wang Q","year":"2022","unstructured":"Wang Q, Huang Y, Li Y, Zhang L, Tang H, Zhang J, Cheng G, Zhao M, Lu T, Zhang Q, et al. Glycyrrhizic acid mitigates Tripterygium-glycoside-tablet-induced acute liver injury via PKM2 regulated oxidative stress. Meta. 2022;12(11):1128.","journal-title":"Meta"},{"issue":"1","key":"e_1_3_4_57_2","first-page":"23","article-title":"Recent advances in nano-targeting drug delivery systems for rheumatoid arthritis treatment","volume":"2","author":"Li H","year":"2023","unstructured":"Li H, Gou R, Liao J, Wang Y, Qu R, Tang Q, Gan J, Zou L, Shi S. Recent advances in nano-targeting drug delivery systems for rheumatoid arthritis treatment. Acta Mater Med. 2023;2(1):23\u201341.","journal-title":"Acta Mater Med"},{"key":"e_1_3_4_58_2","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2019.153156","article-title":"Deciphering the chemical profile and pharmacological mechanisms of Baihu-Guizhi decoction using ultra-fast liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry coupled with network pharmacology-based investigation","volume":"67","author":"Li W","year":"2020","unstructured":"Li W, Mao X, Wu H, Guo M, Su X, Lu J, Guo Q, Li T, Wang X, Su W, et al. Deciphering the chemical profile and pharmacological mechanisms of Baihu-Guizhi decoction using ultra-fast liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry coupled with network pharmacology-based investigation. Phytomedicine. 2020;67: Article 153156.","journal-title":"Phytomedicine"},{"issue":"1","key":"e_1_3_4_59_2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41392-020-0160-8","article-title":"Biomolecular network-based synergistic drug combination discovery: A combination of paeoniflorin and liquiritin alleviates neuropathic pain by inhibiting neuroinflammation via suppressing the chemokine signaling pathway","volume":"5","author":"Guo Q","year":"2020","unstructured":"Guo Q, Li W, Wang C, Mao X, Wang X, Chen W, Xu H, Wang Q, Zhang Y, Lin N. Biomolecular network-based synergistic drug combination discovery: A combination of paeoniflorin and liquiritin alleviates neuropathic pain by inhibiting neuroinflammation via suppressing the chemokine signaling pathway. Signal Transduct Target Ther. 2020;5(1):73.","journal-title":"Signal Transduct Target Ther"}],"container-title":["Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/spj.science.org\/doi\/pdf\/10.34133\/research.0459","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T18:07:54Z","timestamp":1725991674000},"score":1,"resource":{"primary":{"URL":"https:\/\/spj.science.org\/doi\/10.34133\/research.0459"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1]]},"references-count":58,"alternative-id":["10.34133\/research.0459"],"URL":"https:\/\/doi.org\/10.34133\/research.0459","relation":{},"ISSN":["2639-5274"],"issn-type":[{"value":"2639-5274","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1]]},"assertion":[{"value":"2024-06-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-22","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"0459"}}