{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:10:14Z","timestamp":1790187014932,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2017,7,21]],"date-time":"2017-07-21T00:00:00Z","timestamp":1500595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National 12th Five Year Major Projects in China","award":["No. 2014ZX09508007"],"award-info":[{"award-number":["No. 2014ZX09508007"]}]},{"DOI":"10.13039\/501100012246","name":"Priority Academic Program Development of Jiangsu Higher Education Institutions","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the National Science and Technology Major Projects of New Drugs in China","award":["No. 2012ZX09103301-004"],"award-info":[{"award-number":["No. 2012ZX09103301-004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>At present, the early phenomenon of inflammatory angiogenesis is rarely studied in Rheumatoid arthritis (RA). Previous research found that PEG-HM-3, an integrin inhibitor, possessed anti-angiogenesis and anti-rheumatic activity. In this study, the advantages of inhibiting angiogenesis and immune cell adhesion and migration, as well as the benefits of anti-arthritis effects, were evaluated using a combination of PEG-HM-3 and methotrexate (MTX). In vitro, spleen cell proliferation and the levels of tumor necrosis factor \u03b1 (TNF-\u03b1) in macrophage supernatant were assessed. Hind paw edema, arthritis index, clinical score, body weight and immunohistochemistry (IHC) of the spleen, thymus, and joint cavity were evaluated in vivo in adjuvant-induced arthritis rats. Joints of the left hind paws were imaged by X-ray. The expression of the toll-like receptor 4 (TLR-4) protein was assessed in lipopolysaccharide (LPS)-induced synoviocytes. PEG-HM-3 combined with MTX significantly reduced primary and secondary swelling of the hind paws, the arthritis index, the clinical score and bone erosion. The results of IHC showed that the levels of interleukin-6 (IL-6) in spleens and the levels of TNF-\u03b1, CD31 (cluster of differentiation 31), and CD105 in the joint cavity were decreased. The body weight of rats was maintained during combination therapy. Ankle cavity integrity, and bone erosion and deformity were improved in combination treatment. The expression of TLR-4 was significantly reduced with combination treatment in rat synoviocytes. Co-suppression of both inflammation and angiogenesis in arthritis was achieved in this design with combination therapy. The activity of nuclear transcription factor (NF-\u03baB) and the expression of inflammatory factors were down regulated via integrin \u03b1v\u03b23 and TLR-4 signaling pathways. In the future, the application of this combination can be a candidate in early and mid-term RA therapy.<\/jats:p>","DOI":"10.3390\/ijms18071538","type":"journal-article","created":{"date-parts":[[2017,7,21]],"date-time":"2017-07-21T10:45:48Z","timestamp":1500633948000},"page":"1538","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Combination Therapy of PEG-HM-3 and Methotrexate Retards Adjuvant-Induced Arthritis"],"prefix":"10.3390","volume":"18","author":[{"given":"Jingchao","family":"Hao","sequence":"first","affiliation":[{"name":"The Engineering Research Centre of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing 210009, China"},{"name":"School of Pharmaceutical Sciences &amp; Yunnan Provincial Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Wu","sequence":"additional","affiliation":[{"name":"The Engineering Research Centre of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarra","family":"Setrerrahmane","sequence":"additional","affiliation":[{"name":"The Engineering Research Centre of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Qian","sequence":"additional","affiliation":[{"name":"School of Life Science, Huzhou University, Huzhou 313000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueying","family":"Hou","sequence":"additional","affiliation":[{"name":"XiangYa School of Medicine, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liting","family":"Yu","sequence":"additional","affiliation":[{"name":"The Engineering Research Centre of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyu","family":"Lin","sequence":"additional","affiliation":[{"name":"The Engineering Research Centre of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Wu","sequence":"additional","affiliation":[{"name":"The Engineering Research Centre of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanmei","family":"Xu","sequence":"additional","affiliation":[{"name":"The Engineering Research Centre of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing 210009, China"},{"name":"State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/nrrheum.2015.8","article-title":"Rheumatoid arthritis therapy reappraisal: Strategies, opportunities and challenges","volume":"11","author":"Smolen","year":"2015","journal-title":"Nat. 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