{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:07:39Z","timestamp":1789567659131,"version":"build-2803163510"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"36","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010318","name":"University of Manitoba","doi-asserted-by":"publisher","award":["46561"],"award-info":[{"award-number":["46561"]}],"id":[{"id":"10.13039\/100010318","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2017-04967"],"award-info":[{"award-number":["RGPIN-2017-04967"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The calcium-sensing receptor (CaSR) is a nutrient-sensing class C G protein-coupled receptor implicated in intestinal hormone release, yet the signaling pharmacology of the porcine receptor and its relevance to epithelial homeostasis remain poorly defined. Here, a stable Flp-In-293 reporter platform expressing porcine CaSR was combined with structure-based docking, molecular dynamics simulations, secretin tumor cell line-1 (STC-1) enteroendocrine assays, and an STC-1\/IPEC-J2 co-culture system challenged with peptidoglycan. Extracellular Ca2+ activated porcine CaSR through NFAT, SRE, SRF, and cAMP readouts, whereas l-tryptophan and \u03b1-casein (90\u201395) differentially potentiated Ca2+-dependent signaling and docked within the extracellular Venus flytrap domain. Both ligands stimulated CaSR-sensitive glucagon-like peptide-1 (GLP-1) secretion and recruited ERK1\/2, IP1, and cAMP signaling. In co-culture, ligand exposure attenuated inflammatory transcription, preserved selected transporter and tight-junction programs, and improved barrier function under peptidoglycan challenge. Together, these data identify food-derived ligands that couple porcine CaSR signaling to enteroendocrine\u2013epithelial responses.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c06020","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T10:02:09Z","timestamp":1788861729000},"page":"28483-28497","source":"Crossref","is-referenced-by-count":0,"title":["Food-Derived\n                    <scp>l<\/scp>\n                    -tryptophan and \u03b1-Casein\n(90\u201395) Differentially Potentiate Porcine Calcium-Sensing Receptor\nSignaling and Improve Enteroendocrine\u2013Epithelial Responses\nUnder Peptidoglycan Challenge"],"prefix":"10.1021","volume":"74","author":[{"given":"Xiaoya","family":"Zhao","sequence":"first","affiliation":[{"name":"South China Agricultural University , , , ,","place":["Guangzhou, Guangdong, China, 510642"]},{"name":"University of Manitoba , , , ,","place":["Winnipeg, Manitoba, Canada, R3T 2N2"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianru","family":"Hui","sequence":"additional","affiliation":[{"name":"University of Manitoba , , , ,","place":["Winnipeg, Manitoba, Canada, R3T 2N2"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanhuan","family":"Dong","sequence":"additional","affiliation":[{"name":"Jiangxi University of Traditional Chinese Medicine , , ,","place":["Nanchang, Jiangxi, China, 330004"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Azevedo","sequence":"additional","affiliation":[{"name":"University of Manitoba , , , ,","place":["Winnipeg, Manitoba, Canada, R3T 2N2"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karmin","family":"O","sequence":"additional","affiliation":[{"name":"University of Manitoba , , , ,","place":["Winnipeg, Manitoba, Canada, R3T 2N2"]},{"name":"CCARM, St. Boniface Hospital Research Centre , , ,","place":["Winnipeg, Manitoba, Canada, R2H 2A6"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4449-5132","authenticated-orcid":true,"given":"Chengbo","family":"Yang","sequence":"additional","affiliation":[{"name":"University of Manitoba , , , ,","place":["Winnipeg, Manitoba, Canada, R3T 2N2"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"issue":"6","key":"2026091609092661000_cit1","doi-asserted-by":"publisher","first-page":"2402","DOI":"10.1093\/jas\/skz096","article-title":"Distribution and localization of porcine calcium sensing receptor\nin different tissues of weaned piglets","volume":"97","author":"Zhao","year":"2019","journal-title":"J. Anim.\nSci."},{"issue":"11","key":"2026091609092661000_cit2","doi-asserted-by":"publisher","first-page":"2714","DOI":"10.1017\/S1751731119001794","article-title":"Review: Chemosensing of nutrients\nand non-nutrients in the human and porcine gastrointestinal tract","volume":"13","author":"Roura","year":"2019","journal-title":"Animal"},{"issue":"1","key":"2026091609092661000_cit3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/mi.2017.73","article-title":"Enteroendocrine\ncells-sensory sentinels\nof the intestinal environment and orchestrators of mucosal immunity","volume":"11","author":"Worthington","year":"2018","journal-title":"Mucosal Immunol."},{"issue":"2","key":"2026091609092661000_cit4","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.aninu.2016.03.007","article-title":"Amino acid sensing in the gut and its mediation in\ngut-brain signal transduction","volume":"2","author":"Liu","year":"2016","journal-title":"Anim. Nutr."},{"issue":"2","key":"2026091609092661000_cit5","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1210\/endrev\/bnaf040","article-title":"Calcium-sensing\nreceptor-induced regulation of gut hormone release and glucose homeostasis","volume":"47","author":"Anjom-Shoae","year":"2026","journal-title":"Endocr. Rev."},{"issue":"9","key":"2026091609092661000_cit6","doi-asserted-by":"publisher","first-page":"4814","DOI":"10.1073\/pnas.97.9.4814","article-title":"L-Amino acid sensing by the extracellular\nCa2+-sensing receptor","volume":"97","author":"Conigrave","year":"2000","journal-title":"Proc. Natl.\nAcad. Sci. U.S.A."},{"key":"2026091609092661000_cit7","doi-asserted-by":"publisher","DOI":"10.7554\/elife.13662","article-title":"Structural mechanism of ligand activation in human\ncalcium-sensing receptor","volume":"5","author":"Geng","year":"2016","journal-title":"eLife"},{"issue":"3","key":"2026091609092661000_cit8","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1210\/en.2012-1887","article-title":"Impact of clinically relevant mutations on the pharmacoregulation\nand signaling bias of the calcium-sensing receptor by positive and\nnegative allosteric modulators","volume":"154","author":"Leach","year":"2013","journal-title":"Endocrinology"},{"issue":"2","key":"2026091609092661000_cit9","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.ceca.2011.11.009","article-title":"Biased agonism of the calcium-sensing\nreceptor","volume":"51","author":"Thomsen","year":"2012","journal-title":"Cell Calcium"},{"issue":"50","key":"2026091609092661000_cit10","doi-asserted-by":"publisher","first-page":"51739","DOI":"10.1074\/jbc.M406164200","article-title":"The Venus\nflytrap domain of the extracellular Ca2+-sensing receptor\nis required for L-amino acid sensing","volume":"279","author":"Mun","year":"2004","journal-title":"J. Biol.\nChem."},{"issue":"8","key":"2026091609092661000_cit11","doi-asserted-by":"publisher","first-page":"5296","DOI":"10.1074\/jbc.M113.537357","article-title":"Identification of\nan L-phenylalanine binding site enhancing the cooperative responses\nof the calcium-sensing receptor to calcium","volume":"289","author":"Zhang","year":"2014","journal-title":"J. Biol. Chem."},{"issue":"13","key":"2026091609092661000_cit12","doi-asserted-by":"publisher","first-page":"7857","DOI":"10.1021\/acs.jafc.5c01141","article-title":"Casein hydrolysate enhances upper gastrointestinal chemosensing and\ngastric acid secretion in pigs","volume":"73","author":"Mu","year":"2025","journal-title":"J. Agric. Food\nChem."},{"issue":"S1","key":"2026091609092661000_cit13","doi-asserted-by":"publisher","first-page":"S111","DOI":"10.1017\/s0007114500002336","article-title":"Immunoregulatory\npeptides in bovine milk","volume":"84","author":"Gill","year":"2000","journal-title":"Br. J. Nutr."},{"issue":"6","key":"2026091609092661000_cit14","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1080\/1028415X.2018.1521906","article-title":"The role of\ncalcium-sensing receptors in GLP-1 and PYY secretion after acute intraduodenal\nadministration of L-tryptophan in rats","volume":"23","author":"Acar","year":"2020","journal-title":"Nutr.\nNeurosci."},{"issue":"8","key":"2026091609092661000_cit15","doi-asserted-by":"publisher","first-page":"476","DOI":"10.3390\/ani9080476","article-title":"L-Phenylalanine increased\ngut hormone secretion through calcium-sensing\nreceptor in the porcine duodenum","volume":"9","author":"Feng","year":"2019","journal-title":"Animals"},{"issue":"4","key":"2026091609092661000_cit16","doi-asserted-by":"publisher","first-page":"G528","DOI":"10.1152\/ajpgi.00387.2010","article-title":"Amino acids\nstimulate cholecystokinin release through the Ca2+-sensing\nreceptor","volume":"300","author":"Wang","year":"2011","journal-title":"Am. J. Physiol. Gastrointest. Liver\nPhysiol."},{"issue":"2","key":"2026091609092661000_cit17","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1093\/toxsci\/kfv061","article-title":"Deoxynivalenol-induced cholecystokinin and glucagon-like\npeptide-1 release in the STC-1 enteroendocrine cell model is mediated\nby calcium-sensing receptor and transient receptor potential ankyrin-1\nchannel","volume":"145","author":"Zhou","year":"2015","journal-title":"Toxicol. Sci."},{"issue":"5","key":"2026091609092661000_cit18","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1002\/mnfr.201100666","article-title":"Calcium-sensing receptor\nmediates\ndietary peptide-induced CCK secretion in enteroendocrine STC-1 cells","volume":"56","author":"Nakajima","year":"2012","journal-title":"Mol. Nutr. Food Res."},{"key":"2026091609092661000_cit19","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.foodchem.2018.01.107","article-title":"A casein hydrolysate increases GLP-1 secretion and\nreduces food intake","volume":"252","author":"O\u2019Halloran","year":"2018","journal-title":"Food Chem."},{"issue":"4","key":"2026091609092661000_cit20","doi-asserted-by":"publisher","first-page":"skac085","DOI":"10.1093\/jas\/skac085","article-title":"Calcium-sensing receptor\nis not expressed in the absorptive enterocytes of weaned piglets","volume":"100","author":"Zhao","year":"2022","journal-title":"J. Anim. Sci."},{"issue":"3","key":"2026091609092661000_cit21","doi-asserted-by":"publisher","first-page":"1768","DOI":"10.1002\/jcp.30640","article-title":"Citral alleviates peptidoglycan-induced inflammation\nand disruption of barrier functions in porcine intestinal epithelial\ncells","volume":"237","author":"Li","year":"2022","journal-title":"J. Cell. Physiol."},{"issue":"4","key":"2026091609092661000_cit22","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.aninu.2017.06.003","article-title":"Weaning stress and gastrointestinal\nbarrier development: implications for lifelong gut health in pigs","volume":"3","author":"Moeser","year":"2017","journal-title":"Anim. Nutr."},{"issue":"5","key":"2026091609092661000_cit23","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.2527\/jas.2012-6193","article-title":"Potential\napplications of knowledge\nof gut chemosensing in pig production","volume":"91","author":"Liu","year":"2013","journal-title":"J. Anim.\nSci."},{"issue":"4","key":"2026091609092661000_cit24","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis\nof relative gene expression data using real-time\nquantitative PCR and the 2\u2013\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"issue":"2","key":"2026091609092661000_cit25","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1007\/s10753-019-01137-4","article-title":"Inflammatory\nresponses of porcine MoDC and intestinal epithelial cells in a direct-contact\nco-culture system following a bacterial challenge","volume":"43","author":"Loss","year":"2020","journal-title":"Inflammation"},{"issue":"9","key":"2026091609092661000_cit26","doi-asserted-by":"publisher","first-page":"skaa259","DOI":"10.1093\/jas\/skaa259","article-title":"Effects of a microencapsulated formula\nof organic acids and essential\noils on nutrient absorption, immunity, gut barrier function, and abundance\nof enterotoxigenic Escherichia coli F4 in weaned\npiglets challenged with E. coli F4","volume":"98","author":"Choi","year":"2020","journal-title":"J. Anim. Sci."},{"issue":"4","key":"2026091609092661000_cit27","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1124\/mol.117.110890","article-title":"Biased agonism in drug discovery, is it too soon to\nchoose a path?","volume":"93","author":"Michel","year":"2018","journal-title":"Mol. Pharmacol."},{"issue":"7","key":"2026091609092661000_cit28","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1172\/JCI107335","article-title":"Protein digestion\nin human intestine as reflected in\nluminal, mucosal, and plasma amino acid concentrations after meals","volume":"52","author":"Adibi","year":"1973","journal-title":"J. Clin. Invest."},{"issue":"3","key":"2026091609092661000_cit29","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1021\/jf072611h","article-title":"Protein hydrolysates induce CCK release from enteroendocrine\ncells and act as partial agonists of the CCK1 receptor","volume":"56","author":"Foltz","year":"2008","journal-title":"J. Agric. Food Chem."},{"issue":"1\u20133","key":"2026091609092661000_cit30","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.regpep.2012.07.002","article-title":"GLP-2 enhances barrier formation\nand attenuates TNF-\u03b1-induced changes in a Caco-2 cell model\nof the intestinal barrier","volume":"178","author":"Moran","year":"2012","journal-title":"Regul. Pept."},{"issue":"6","key":"2026091609092661000_cit31","doi-asserted-by":"publisher","first-page":"G1249","DOI":"10.1152\/ajpgi.2000.279.6.G1249","article-title":"GLP-2 stimulates\nintestinal growth in premature total\nparenteral nutrition-fed pigs by suppressing proteolysis and apoptosis","volume":"279","author":"Burrin","year":"2000","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"issue":"3","key":"2026091609092661000_cit32","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1093\/jn\/131.3.709","article-title":"Glucagon-like peptide\n2: a nutrient-responsive gut growth factor","volume":"131","author":"Burrin","year":"2001","journal-title":"J. Nutr."},{"key":"2026091609092661000_cit33","doi-asserted-by":"crossref","first-page":"2765","DOI":"10.2741\/3413","article-title":"Mechanism\nof cytokine modulation\nof epithelial tight junction barrier","volume":"14","author":"Al-Sadi","year":"2009","journal-title":"Front.\nBiosci."},{"issue":"2","key":"2026091609092661000_cit34","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1021\/acs.jafc.8b05480","article-title":"Thymol improves barrier\nfunction and attenuates inflammatory responses in porcine intestinal\nepithelial cells during lipopolysaccharide-induced inflammation","volume":"67","author":"Omonijo","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"2026091609092661000_cit35","doi-asserted-by":"publisher","first-page":"715469","DOI":"10.3389\/fphys.2021.715469","article-title":"Capsaicin attenuates lipopolysaccharide-induced inflammation\nand\nbarrier dysfunction in intestinal porcine epithelial cell line-J2","volume":"12","author":"Zhao","year":"2021","journal-title":"Front. Physiol."},{"issue":"3","key":"2026091609092661000_cit36","doi-asserted-by":"publisher","first-page":"629","DOI":"10.3390\/microorganisms10030629","article-title":"Porcine and\nchicken intestinal epithelial\ncell models for screening phytogenic feed additives: chances and limitations\nin use as alternatives to feeding trials","volume":"10","author":"Marks","year":"2022","journal-title":"Microorganisms"}],"container-title":["Journal of Agricultural\nand Food Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jafc.6c06020","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jafcau\/article-pdf\/74\/36\/28483\/68440159\/acs.jafc.6c06020.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jafcau\/article-pdf\/74\/36\/28483\/68440159\/acs.jafc.6c06020.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:31:01Z","timestamp":1789565461000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jafcau\/article\/74\/36\/28483\/5425940\/Food-Derived-l-tryptophan-and-Casein-90-95"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":36,"journal-issue":{"issue":"36","published-online":{"date-parts":[[2026,9,8]]},"published-print":{"date-parts":[[2026,9,16]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jafc.6c06020","relation":{},"ISSN":["0021-8561","1520-5118"],"issn-type":[{"value":"0021-8561","type":"print"},{"value":"1520-5118","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]}}}