{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T19:42:28Z","timestamp":1789846948418,"version":"4.0.1"},"reference-count":52,"publisher":"American Physiological Society","issue":"12","funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI-22931"],"award-info":[{"award-number":["AI-22931"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR068833"],"award-info":[{"award-number":["AR068833"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000980","name":"Arthritis Foundation","doi-asserted-by":"publisher","award":["5997"],"award-info":[{"award-number":["5997"]}],"id":[{"id":"10.13039\/100000980","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["ULTR000130"],"award-info":[{"award-number":["ULTR000130"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"USC Norris Comprehensive Cancer Center","award":["CA014089"],"award-info":[{"award-number":["CA014089"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiological Genomics"],"published-print":{"date-parts":[[2019,12,1]]},"abstract":"<jats:p> Rhesus theta defensin-1 (RTD-1), a macrocyclic immunomodulatory host defense peptide from Old World monkeys, is therapeutic in pristane-induced arthritis (PIA) in rats, a model of rheumatoid arthritis (RA). RNA-sequence (RNA-Seq) analysis was used to interrogate the changes in gene expression in PIA rats, which identified 617 differentially expressed genes (DEGs) in PIA synovial tissue of diseased rats. Upstream regulator analysis showed upregulation of gene expression pathways regulated by TNF, IL1B, IL6, proinflammatory cytokines, and matrix metalloproteases (MMPs) involved in RA. In contrast, ligand-dependent nuclear receptors like the liver X-receptors NR1H2 and NR1H3 and peroxisome proliferator-activated receptor gamma (PPARG) were downregulated in arthritic synovia. Daily RTD-1 treatment of PIA rats for 1\u20135 days following disease presentation modulated 340 of the 617 disease genes, and synovial gene expression in PIA rats treated 5 days with RTD-1 closely resembled the gene signature of naive synovium. Systemic RTD-1 inhibited proinflammatory upstream regulators such as TNF, IL1, and IL6 and activated antiarthritic ligand-dependent nuclear receptor pathways, including PPARG, NR1H2, and NR1H3, that were suppressed in untreated PIA rats. RTD-1 also inhibited proinflammatory responses in IL-1\u03b2-stimulated human RA fibroblast-like synoviocytes (FLS) in vitro and diminished expression of human orthologs of disease genes that are induced in rat PIA synovium. Thus, the antiarthritic mechanisms of systemic RTD-1 include homeostatic regulation of arthritogenic gene networks in a manner that correlates temporally with clinical resolution of rat PIA. <\/jats:p>","DOI":"10.1152\/physiolgenomics.00066.2019","type":"journal-article","created":{"date-parts":[[2019,11,25]],"date-time":"2019-11-25T05:40:24Z","timestamp":1574660424000},"page":"657-667","source":"Crossref","is-referenced-by-count":14,"title":["RTD-1 therapeutically normalizes synovial gene signatures in rat autoimmune arthritis and suppresses proinflammatory mediators in RA synovial fibroblasts"],"prefix":"10.1152","volume":"51","author":[{"given":"Prasad","family":"Tongaonkar","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasu","family":"Punj","sequence":"additional","affiliation":[{"name":"Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshay","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dat Q.","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California"},{"name":"Oryn Therapeutics, LLC, Vacaville, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie K.","family":"Trinh","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin B.","family":"Schaal","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresina","family":"Laragione","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mt. Sinai, New York, New York and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 J.","family":"Ouellette","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California"},{"name":"USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Percio S.","family":"Gulko","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mt. Sinai, New York, New York and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7152-4739","authenticated-orcid":false,"given":"Michael E.","family":"Selsted","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California"},{"name":"Oryn Therapeutics, LLC, Vacaville, California"},{"name":"USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780390919"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2010-11-10-r106"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/art.22167"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00111-18"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00154-17"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkv301"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1385\/1-59259-805-6:295"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00108.2013"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2741\/1817"},{"key":"B10","first-page":"600","volume":"22","author":"Chikanza IC","year":"1995","journal-title":"J Rheumatol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1136\/ard.62.suppl_2.ii68"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/art.11351"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1053\/joca.2001.0485"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1242\/dev.150136"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01100-08"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.12.7199"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601988"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-6737-7_1"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2016-0428OC"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nm820"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0564"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.pathophys.2005.07.011"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1101\/gad.268714.115"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt703"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2012.00173"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.10319"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/j.1699-0463.1997.tb00567.x"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1004965"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4439(00)00056-9"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-011-0200-z"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2003.07.023"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.90897.2008"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-015-0284-5"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2017.05.023"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2011.06303.x"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000793"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0051337"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0187868"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1186\/ar2110"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/ni1206"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.4137\/CMAMD.S5951"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.2741\/s53"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5439.498"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0910535"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.3A0315-102R"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01090-07"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109117200"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0155936"},{"key":"B50","first-page":"1675","volume":"149","author":"Vingsbo C","year":"1996","journal-title":"Am J Pathol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01363-09"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2002.01876.x"}],"container-title":["Physiological Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/physiolgenomics.00066.2019","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,12,13]],"date-time":"2019-12-13T09:32:03Z","timestamp":1576229523000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/physiolgenomics.00066.2019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,1]]},"references-count":52,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2019,12,1]]}},"alternative-id":["10.1152\/physiolgenomics.00066.2019"],"URL":"https:\/\/doi.org\/10.1152\/physiolgenomics.00066.2019","relation":{},"ISSN":["1094-8341","1531-2267"],"issn-type":[{"value":"1094-8341","type":"print"},{"value":"1531-2267","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,1]]}}}