{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T03:02:37Z","timestamp":1790132557357,"version":"4.0.1"},"reference-count":71,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T00:00:00Z","timestamp":1713398400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T00:00:00Z","timestamp":1713398400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["FDT202204014931"],"award-info":[{"award-number":["FDT202204014931"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR\u201018\u2010CE18\u20100019"],"award-info":[{"award-number":["ANR\u201018\u2010CE18\u20100019"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR\u201020\u2010CE18\u20100024"],"award-info":[{"award-number":["ANR\u201020\u2010CE18\u20100024"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Chymotrypsin is a pancreatic protease secreted into the lumen of the small intestine to digest food proteins. We hypothesized that chymotrypsin activity may be found close to epithelial cells and that chymotrypsin signals to them via protease\u2010activated receptors (PARs). We deciphered molecular pharmacological mechanisms and gene expression regulation for chymotrypsin signalling in intestinal epithelial cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>The presence and activity of chymotrypsin were evaluated by Western blot and enzymatic activity tests in the luminal and mucosal compartments of murine and human gut samples. The ability of chymotrypsin to cleave the extracellular domain of PAR1 or PAR2 was assessed using cell lines expressing N\u2010terminally tagged receptors. The cleavage site of chymotrypsin on PAR1 and PAR2 was determined by HPLC\u2013MS analysis. The chymotrypsin signalling mechanism was investigated in CMT93 intestinal epithelial cells by calcium mobilization assays and Western blot analyses of (ERK1\/2) phosphorylation. The transcriptional consequences of chymotrypsin signalling were analysed on colonic organoids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>We found that chymotrypsin was present and active in the vicinity of the colonic epithelium. Molecular pharmacological studies have shown that chymotrypsin cleaves both PAR1 and PAR2 receptors. Chymotrypsin activated calcium and ERK1\/2 signalling pathways through PAR2, and this pathway promoted interleukin\u201010 (IL\u201010) up\u2010regulation in colonic organoids. In contrast, chymotrypsin disarmed PAR1, preventing further activation by its canonical agonist, thrombin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Our results highlight the ability of chymotrypsin to signal to intestinal epithelial cells via PARs, which may have important physiological consequences in gut homeostasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16341","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T21:59:45Z","timestamp":1713477585000},"page":"2725-2749","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Chymotrypsin activity signals to intestinal epithelium by protease\u2010activated receptor\u2010dependent mechanisms"],"prefix":"10.1111","volume":"181","author":[{"given":"Simon","family":"Guignard","sequence":"first","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Saifeddine","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology University of Calgary Cumming School of Medicine  Calgary Alberta Canada"},{"name":"Department of Medicine University of Calgary Cumming School of Medicine  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichiro","family":"Mihara","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology University of Calgary Cumming School of Medicine  Calgary Alberta Canada"},{"name":"Department of Medicine University of Calgary Cumming School of Medicine  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid","family":"Motahhary","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology University of Calgary Cumming School of Medicine  Calgary Alberta Canada"},{"name":"Department of Medicine University of Calgary Cumming School of Medicine  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magali","family":"Savignac","sequence":"additional","affiliation":[{"name":"Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291\u2014Centre National de la Recherche Scientifique UMR5051, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Guiraud","sequence":"additional","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Sagnat","sequence":"additional","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireille","family":"Sebbag","sequence":"additional","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sokchea","family":"Khou","sequence":"additional","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Rolland","sequence":"additional","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anissa","family":"Edir","sequence":"additional","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Bournet","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Toulouse University Hospital  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Buscail","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Toulouse University Hospital  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Buscail","sequence":"additional","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"},{"name":"Department of Digestive Surgery Toulouse University Hospital  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Alric","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Digestive Diseases Rangueil, Toulouse III University Hospital, University of Toulouse  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Camare","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry Toulouse University Hospital  Toulouse France"},{"name":"University of Toulouse, UMR1297, INSERM\/Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mouna","family":"Ambli","sequence":"additional","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1825-6015","authenticated-orcid":false,"given":"Nathalie","family":"Vergnolle","sequence":"additional","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"},{"name":"Department of Physiology and Pharmacology University of Calgary Cumming School of Medicine  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4070-8786","authenticated-orcid":false,"given":"Morley D.","family":"Hollenberg","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology University of Calgary Cumming School of Medicine  Calgary Alberta Canada"},{"name":"Department of Medicine University of Calgary Cumming School of Medicine  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9013-4592","authenticated-orcid":false,"given":"C\u00e9line","family":"Deraison","sequence":"additional","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3875-492X","authenticated-orcid":false,"given":"Chrystelle","family":"Bonnart","sequence":"additional","affiliation":[{"name":"IRSD, University of Toulouse, INSERM, INRAE, ENVT, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS)  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4,18]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2011.01.003"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16177"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16181"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16181"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3141009"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI103549"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.2001.281.2.G323"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09037-9"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-018-4906-4"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64466-5"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1831452100"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.013159"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15868"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/002215549804600204"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64283-6"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.514.2.9"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms221910711"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.4908"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2744(68)90053-3"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.10.6.477"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12544"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.050658"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.610485"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0270584"},{"key":"e_1_2_13_27_1","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/S0022-3565(24)37961-3","article-title":"Evaluation of proteinase\u2010activated receptor\u20101 (PAR1) agonists and antagonists using a cultured cell receptor desensitization assay: Activation of PAR2 by PAR1\u2010targeted ligands","volume":"288","author":"Kawabata A.","year":"1999","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.16.8884"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00162.2010"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15178"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901220"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.483123"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.115.102723"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.19.11168"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11140-w"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/ibd\/izab244"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjaa229"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00328.2015"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1139\/y03-080"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2021.07.005"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1995.tb20784.x"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.20.9208"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.11.5950"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M513138200"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.4199\/C00026ED1V01Y201102ISP014"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3200335"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00044.2021"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.115.010991"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.201988"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.109.055509"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3615"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10893"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9120(86)80007-8"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.6.1944"},{"key":"e_1_2_13_57_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2006.00851.x"},{"key":"e_1_2_13_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097\u20104652(199808)176:2<365::AID\u2010JCP15>3.0.CO;2\u20102"},{"key":"e_1_2_13_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14430"},{"key":"e_1_2_13_60_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00717"},{"key":"e_1_2_13_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellbi.2008.09.008"},{"key":"e_1_2_13_62_1","first-page":"691\u20104 passim","article-title":"Fecal chymotrypsin and trypsin determinations","volume":"104","author":"Smith J. S.","year":"1971","journal-title":"Canadian Medical Association Journal"},{"key":"e_1_2_13_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700965"},{"key":"e_1_2_13_64_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00096.2009"},{"key":"e_1_2_13_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021\u20109258(18)43615\u20100"},{"key":"e_1_2_13_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2008.10.018"},{"key":"e_1_2_13_67_1","doi-asserted-by":"publisher","DOI":"10.18388\/abp.2005_3452"},{"key":"e_1_2_13_68_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00303.2007"},{"key":"e_1_2_13_69_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2004.048876"},{"key":"e_1_2_13_70_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-309147"},{"key":"e_1_2_13_71_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00001.2002"},{"key":"e_1_2_13_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2020.102281"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.16341","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bph.16341","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.16341","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:40:12Z","timestamp":1790131212000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.16341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,18]]},"references-count":71,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["10.1111\/bph.16341"],"URL":"https:\/\/doi.org\/10.1111\/bph.16341","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.22541\/au.168809502.21259169\/v1","asserted-by":"object"}]},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,18]]},"assertion":[{"value":"2023-06-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}