{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:24:22Z","timestamp":1781105062430,"version":"3.54.1"},"reference-count":18,"publisher":"National Academy of Sciences","issue":"47","license":[{"start":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T00:00:00Z","timestamp":1699833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W91XWH1810681"],"award-info":[{"award-number":["W91XWH1810681"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["RO1HD090214"],"award-info":[{"award-number":["RO1HD090214"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,11,21]]},"abstract":"<jats:p>\n                    To mediate critical host\u2013microbe interactions in the human small intestine, Paneth cells constitutively produce abundant levels of \u03b1-defensins and other antimicrobials. We report that the expression profile of these antimicrobials is dramatically askew in human small intestinal organoids (enteroids) as compared to that in paired tissue from which they are derived, with a reduction of \u03b1-defensins to nearly undetectable levels. Murine enteroids, however, recapitulate the expression profile of Paneth cell \u03b1-defensins seen in tissue. WNT\/TCF signaling has been found to be instrumental in the regulation of \u03b1-defensins, yet in human enteroids exogenous stimulation of WNT signaling appears insufficient to rescue \u03b1-defensin expression. By stark contrast, forkhead box O (FOXO) inhibitor AS1842856 induced the expression of \u03b1-defensin mRNA in enteroids by &gt;100,000-fold, restoring\n                    <jats:italic>DEFA5<\/jats:italic>\n                    and\n                    <jats:italic>DEFA6<\/jats:italic>\n                    to levels comparable to those found in primary human tissue. These results newly identify FOXO signaling as a pathway of biological and potentially therapeutic relevance for the regulation of human Paneth cell \u03b1-defensins in health and disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2312453120","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T15:08:51Z","timestamp":1699888131000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["FOXO inhibition rescues \u03b1-defensin expression in human intestinal organoids"],"prefix":"10.1073","volume":"120","author":[{"given":"Serena J.","family":"Eng","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616"},{"name":"Medical Investigation of Neurodevelopmental Disorders Institute, University of California Davis, Sacramento, CA 95817"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric B.","family":"Nonnecke","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur J.","family":"de Lorimier","sequence":"additional","affiliation":[{"name":"University of California Davis Medical Center, Department of Pediatrics, Sacramento, CA 95817"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed R.","family":"Ali","sequence":"additional","affiliation":[{"name":"University of California Davis Medical Center, Department of Surgery, Sacramento, CA 95817"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9131-6657","authenticated-orcid":false,"given":"Ren\u00e9e M.","family":"Tsolis","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2725-2622","authenticated-orcid":false,"given":"Charles L.","family":"Bevins","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Ashwood","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616"},{"name":"Medical Investigation of Neurodevelopmental Disorders Institute, University of California Davis, Sacramento, CA 95817"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,11,13]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09637"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2546"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12599"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.10.003"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00646"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(99)70052-1"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2021.07.016"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2022.11.001"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.11.016"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0505256102"},{"key":"e_1_3_3_11_2","unstructured":"S. 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Eng \u201cSecretory Function in Human Intestinal Organoids\u201d Doctoral dissertation #29257955 Department of Medical Microbiology and Immunology School of Medicine (University of California Davis ProQuest Dissertations and Theses Global) (2022)."},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202101870R"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1240"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0026898"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.10.005"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27901-5"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.110.065714"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1097\/MIB.0000000000000750"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2312453120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T15:09:35Z","timestamp":1699888175000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2312453120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,13]]},"references-count":18,"journal-issue":{"issue":"47","published-print":{"date-parts":[[2023,11,21]]}},"alternative-id":["10.1073\/pnas.2312453120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2312453120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,13]]},"assertion":[{"value":"2023-07-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2312453120"}}