{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:20:55Z","timestamp":1789507255004,"version":"build-2803163510"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2024,6,29]],"date-time":"2024-06-29T00:00:00Z","timestamp":1719619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K05742"],"award-info":[{"award-number":["20K05742"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) belongs to the nuclear receptor superfamily and is involved in the inflammatory process. Previously, we synthesized the ligands of PPAR\u03b3 that possess the hybrid structure of a food-derived cinnamic acid derivative (CA) and GW9662, an irreversible PPAR\u03b3 antagonist. These ligands activate the transcription of PPAR\u03b3 through the covalent bond formation with the Cys285 residue of PPAR\u03b3, whereas their anti-inflammatory effect has not been examined yet. Here, we show the anti-inflammatory effect of the covalent PPAR\u03b3 ligands in RAW264 cells, murine macrophage-like cells. GW9662 suppressed the production of nitric oxide (NO) stimulated by lipopolysaccharide and exerted a synergistic effect in combination with CA. The compounds bearing their hybrid structure dramatically inhibited NO production and transcription of proinflammatory cytokines. A comparison study suggested that the 2-chloro-5-nitrobenzoyl group of the ligands is important for anti-inflammation. Furthermore, we synthesized an alkyne-tagged analogue that becomes an activity-based probe for future mechanistic study.<\/jats:p>","DOI":"10.1093\/bbb\/zbae094","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T16:55:55Z","timestamp":1719593755000},"page":"1136-1143","source":"Crossref","is-referenced-by-count":5,"title":["Anti-inflammatory effect of covalent PPAR\u03b3 ligands that have a hybrid structure of GW9662 and a food-derived cinnamic acid derivative"],"prefix":"10.1093","volume":"88","author":[{"given":"Shinano","family":"Miyazawa","sequence":"first","affiliation":[{"name":"Master's\/Doctoral Program in Life Science Innovation, Graduate School of Comprehensive Human Sciences , University of Tsukuba, Tsukuba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misa","family":"Sakai","sequence":"additional","affiliation":[{"name":"Master's\/Doctoral Program in Life Science Innovation, Graduate School of Comprehensive Human Sciences , University of Tsukuba, Tsukuba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuma","family":"Omae","sequence":"additional","affiliation":[{"name":"School of Integrative and Global Majors, University of Tsukuba , Tsukuba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Ogawa","sequence":"additional","affiliation":[{"name":"College of Agro-Biological Resource Sciences, School of Life and Environmental Sciences , University of Tsukuba, Tsukuba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Shigemori","sequence":"additional","affiliation":[{"name":"Institute of Life and Environmental Sciences , University of Tsukuba, Tsukuba, Japan"},{"name":"Microbiology Research Center for Sustainability , University of Tsukuba, Tsukuba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusaku","family":"Miyamae","sequence":"additional","affiliation":[{"name":"Institute of Life and Environmental Sciences , University of Tsukuba, Tsukuba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,6,29]]},"reference":[{"key":"2024092012355381000_bib1","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/nbt.1531","article-title":"Identification of selective inhibitors of uncharacterized enzymes by high-throughput screening with fluorescent activity-based probes","volume":"27","author":"Bachovchin","year":"2009","journal-title":"Nat Biotechnol"},{"key":"2024092012355381000_bib2","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.biopha.2016.08.069","article-title":"BZ-26, a novel GW9662 derivate, attenuated inflammation by inhibiting the differentiation and activation of inflammatory macrophages","volume":"84","author":"Bei","year":"2016","journal-title":"Biomed Pharmacother"},{"key":"2024092012355381000_bib3","doi-asserted-by":"crossref","first-page":"805","DOI":"10.3390\/ijms22020805","article-title":"PPAR gamma: from definition to molecular targets and therapy of lung diseases","volume":"22","author":"Carvalho","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2024092012355381000_bib4","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/dmrr.790","article-title":"Thiazolidinediones as anti-inflammatory and anti-atherogenic agents","volume":"24","author":"Ceriello","year":"2008","journal-title":"Diabetes Metab Res"},{"key":"2024092012355381000_bib5","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41392-023-01452-1","article-title":"Macrophages in immunoregulation and therapeutics","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"2024092012355381000_bib6","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1146\/annurev.biochem.75.101304.124125","article-title":"Activity-based protein profiling: from enzyme chemistry to proteomic chemistry","volume":"77","author":"Cravatt","year":"2008","journal-title":"Annu Rev Biochem"},{"key":"2024092012355381000_bib7","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1039\/C0CS00004C","article-title":"Activity-based probes: discovering new biology and new drug targets","volume":"40","author":"Heal","year":"2011","journal-title":"Chem Soc Rev"},{"key":"2024092012355381000_bib8","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1016\/S0140-6736(09)60953-3","article-title":"Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial","volume":"373","author":"Home","year":"2009","journal-title":"Lancet North Am Ed"},{"key":"2024092012355381000_bib9","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1038\/ncomms2270","article-title":"PPAR\u03b3 is an E3 ligase that induces the degradation of NF\u03baB\/p65","volume":"3","author":"Hou","year":"2012","journal-title":"Nat Commun"},{"key":"2024092012355381000_bib10","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/34184","article-title":"PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines","volume":"391","author":"Jiang","year":"1998","journal-title":"Nature"},{"key":"2024092012355381000_bib11","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.molmed.2007.09.002","article-title":"Signaling to NF-\u03baB by toll-like receptors","volume":"13","author":"Kawai","year":"2007","journal-title":"Trends Mol Med"},{"key":"2024092012355381000_bib12","doi-asserted-by":"crossref","first-page":"816856","DOI":"10.1155\/2015\/816856","article-title":"Review of the structural and dynamic mechanisms of PPAR\u03b3 partial agonism","volume":"2015","author":"Kroker","year":"2015","journal-title":"PPAR Research"},{"key":"2024092012355381000_bib13","doi-asserted-by":"crossref","first-page":"19649","DOI":"10.1074\/jbc.M200743200","article-title":"T0070907, a selective ligand for peroxisome proliferator-activated receptor gamma, functions as an antagonist of biochemical and cellular activities","volume":"277","author":"Lee","year":"2002","journal-title":"J Biol Chem"},{"key":"2024092012355381000_bib14","doi-asserted-by":"crossref","first-page":"6640","DOI":"10.1021\/bi0159581","article-title":"Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662","volume":"41","author":"Leesnitzer","year":"2002","journal-title":"Biochemistry"},{"key":"2024092012355381000_bib15","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.cell.2010.03.006","article-title":"Inflammation 2010: new adventures of an old flame","volume":"140","author":"Medzhitov","year":"2010","journal-title":"Cell"},{"key":"2024092012355381000_bib16","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1248\/bpb.b21-00263","article-title":"Insights into dynamic mechanism of ligand binding to peroxisome proliferator-activated receptor \u03b3 toward potential pharmacological applications","volume":"44","author":"Miyamae","year":"2021","journal-title":"Biol Pharm Bull"},{"key":"2024092012355381000_bib17","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/ni.3790","article-title":"A guiding map for inflammation","volume":"18","author":"Netea","year":"2017","journal-title":"Nat Immunol"},{"key":"2024092012355381000_bib18","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1021\/acschembio.5b00628","article-title":"Identification of a new type of covalent PPAR\u03b3 agonist using a Ligand-linking strategy","volume":"10","author":"Ohtera","year":"2015","journal-title":"ACS Chem Biol"},{"key":"2024092012355381000_bib19","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/nature03988","article-title":"A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma","volume":"437","author":"Pascual","year":"2005","journal-title":"Nature"},{"key":"2024092012355381000_bib20","doi-asserted-by":"crossref","first-page":"14145","DOI":"10.1074\/jbc.M500901200","article-title":"Alpha,beta-unsaturated ketone is a core moiety of natural ligands for covalent binding to peroxisome proliferator-activated receptor gamma","volume":"280","author":"Shiraki","year":"2005","journal-title":"J Biol Chem"},{"key":"2024092012355381000_bib21","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/j.1574-695X.2007.00329.x","article-title":"The role of nitric oxide in inflammatory reactions","volume":"51","author":"Tripathi","year":"2007","journal-title":"FEMS Immunol Med Microbiol"},{"key":"2024092012355381000_bib22","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.3390\/molecules24102019","article-title":"Importance of the proximity and orientation of ligand-linkage to the design of cinnamate-GW9662 hybrid compounds as covalent PPAR\u03b3 agonists.","volume":"24","author":"Utsugi","year":"2019","journal-title":"Molecules"},{"key":"2024092012355381000_bib23","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1126\/science.aaf7497","article-title":"Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474","volume":"356","author":"van Esbroeck","year":"2017","journal-title":"Science"},{"key":"2024092012355381000_bib24","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.febslet.2008.12.017","article-title":"Atomic structure of mutant PPARgamma LBD complexed with 15d-PGJ2: novel modulation mechanism of PPARgamma\/RXRalpha function by covalently bound ligands","volume":"583","author":"Waku","year":"2009","journal-title":"FEBS Lett"},{"key":"2024092012355381000_bib25","doi-asserted-by":"crossref","first-page":"3395","DOI":"10.1038\/emboj.2010.197","article-title":"The nuclear receptor ppar\u03b3 individually responds to serotonin- and fatty acid-metabolites.","volume":"29","author":"Waku","year":"2010","journal-title":"EMBO J"},{"key":"2024092012355381000_bib26","doi-asserted-by":"crossref","first-page":"29981","DOI":"10.1074\/jbc.M110.110908","article-title":"Opposite action of peroxisome proliferator-activated receptor-gamma in regulating renal inflammation: functional switch by its ligand","volume":"285","author":"Wen","year":"2010","journal-title":"J Biol Chem"},{"key":"2024092012355381000_bib27","doi-asserted-by":"crossref","first-page":"743","DOI":"10.3892\/etm.2021.10175","article-title":"Rosiglitazone alleviates lipopolysaccharide-induced inflammation in RAW264.7 cells via inhibition of NF-\u03bab and in a PPAR\u03b3-dependent manner","volume":"22","author":"Zhou","year":"2021","journal-title":"Exp Ther Med"}],"container-title":["Bioscience, Biotechnology, and Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bbb\/advance-article-pdf\/doi\/10.1093\/bbb\/zbae094\/58703129\/zbae094.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bbb\/article-pdf\/88\/10\/1136\/59210465\/zbae094.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bbb\/article-pdf\/88\/10\/1136\/59210465\/zbae094.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T08:36:02Z","timestamp":1726821362000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bbb\/article\/88\/10\/1136\/7701789"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,29]]},"references-count":27,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,6,29]]},"published-print":{"date-parts":[[2024,9,20]]}},"URL":"https:\/\/doi.org\/10.1093\/bbb\/zbae094","relation":{},"ISSN":["1347-6947"],"issn-type":[{"value":"1347-6947","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,10]]},"published":{"date-parts":[[2024,6,29]]}}}