{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T16:35:47Z","timestamp":1772210147222,"version":"3.50.1"},"reference-count":69,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK070878"],"award-info":[{"award-number":["DK070878"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The etiology of necrotizing enterocolitis (NEC) is not known. Alterations in gut microbiome, mucosal barrier function, immune cell activation, and blood flow are characterized events in its development, with stress as a contributing factor. The hormone corticotropin-releasing factor (CRF) is a key mediator of stress responses and influences these aforementioned processes. CRF signaling is modulated by NEC\u2019s main risk factors of prematurity and formula feeding. Using an established neonatal rat model of NEC, we tested hypotheses that: (i) increased CRF levels\u2014as seen during stress\u2014promote NEC in formula-fed (FF) newborn rats, and (ii) antagonism of CRF action ameliorates NEC. Newborn pups were formula-fed to initiate gut inflammation and randomized to: no stress, no stress with subcutaneous CRF administration, stress (acute hypoxia followed by cold exposure\u2014NEC model), or stress after pretreatment with the CRF peptide antagonist Astressin. Dam-fed unstressed and stressed littermates served as controls. NEC incidence and severity in the terminal ileum were determined using a histologic scoring system. Changes in CRF, CRF receptor (CRFRs), and toll-like receptor 4 (TLR4) expression levels were determined by immunofluorescence and immunoblotting, respectively. Stress exposure in FF neonates resulted in 40.0% NEC incidence, whereas exogenous CRF administration resulted in 51.7% NEC incidence compared to 8.7% in FF non-stressed neonates (p&lt;0.001). Astressin prevented development of NEC in FF-stressed neonates (7.7% vs. 40.0%; p = 0.003). CRF and CRFR immunoreactivity increased in the ileum of neonates with NEC compared to dam-fed controls or FF unstressed pups. Immunoblotting confirmed increased TLR4 protein levels in FF stressed (NEC model) animals vs. controls, and Astressin treatment restored TLR4 to control levels. Peripheral CRF may serve as specific pharmacologic target for the prevention and treatment of NEC.<\/jats:p>","DOI":"10.1371\/journal.pone.0246412","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T19:32:36Z","timestamp":1623353556000},"page":"e0246412","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Stress and corticotropin releasing factor (CRF) promote necrotizing enterocolitis in a formula-fed neonatal rat model"],"prefix":"10.1371","volume":"16","author":[{"given":"Robert L.","family":"Bell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ginger S.","family":"Withers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frans A.","family":"Kuypers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Stehr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1334-0517","authenticated-orcid":true,"given":"Aditi","family":"Bhargava","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,6,10]]},"reference":[{"key":"pone.0246412.ref001","doi-asserted-by":"crossref","DOI":"10.1203\/PDR.0b013e3182093280","article-title":"New insights into the pathogenesis and treatment of necrotizing enterocolitis: Toll-like receptors and beyond","volume":"69","author":"A Afrazi","year":"2011","journal-title":"Pediatr Res"},{"issue":"2","key":"pone.0246412.ref002","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1203\/PDR.0b013e31815ed64c","article-title":"Understanding the susceptibility of the premature infant to necrotizing enterocolitis (NEC)","volume":"63","author":"CJ Hunter","year":"2008","journal-title":"Pediatr Res"},{"issue":"10","key":"pone.0246412.ref003","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/nrgastro.2016.119","article-title":"Necrotizing enterocolitis: new insights into pathogenesis and mechanisms","volume":"13","author":"DF Ni\u00f1o","year":"2016","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"4","key":"pone.0246412.ref004","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s00383-009-2344-8","article-title":"Current concepts regarding the pathogenesis of necrotizing enterocolitis","volume":"25","author":"M Petrosyan","year":"2009","journal-title":"Pediatr Surg Int"},{"issue":"3","key":"pone.0246412.ref005","doi-asserted-by":"crossref","first-page":"e18084","DOI":"10.1371\/journal.pone.0018084","article-title":"Gram negative bacteria are associated with the early stages of necrotizing enterocolitis","volume":"6","author":"EM Carlisle","year":"2011","journal-title":"PLoS One"},{"issue":"5","key":"pone.0246412.ref006","doi-asserted-by":"crossref","first-page":"3273","DOI":"10.4049\/jimmunol.177.5.3273","article-title":"The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis","volume":"177","author":"T Jilling","year":"2006","journal-title":"J Immunol"},{"issue":"2","key":"pone.0246412.ref007","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1097\/01.shk.0000239774.02904.65","article-title":"The role of the intestinal barrier in the pathogenesis of necrotizing enterocolitis","volume":"27","author":"RJ Anand","year":"2007","journal-title":"Shock"},{"issue":"1","key":"pone.0246412.ref008","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1053\/j.sempedsurg.2004.10.025","article-title":"Disordered enterocyte signaling and intestinal barrier dysfunction in the pathogenesis of necrotizing enterocolitis","volume":"14","author":"DJ Hackam","year":"2005","journal-title":"Semin Pediatr Surg"},{"issue":"7","key":"pone.0246412.ref009","doi-asserted-by":"crossref","first-page":"4808","DOI":"10.4049\/jimmunol.179.7.4808","article-title":"A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair","volume":"179","author":"CL Leaphart","year":"2007","journal-title":"J Immunol"},{"issue":"2","key":"pone.0246412.ref010","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.jpedsurg.2005.11.003","article-title":"Mechanism of nitric oxide-mediated intestinal barrier failure: insight into the pathogenesis of necrotizing enterocolitis","volume":"41","author":"HR Ford","year":"2006","journal-title":"J Pediatr Surg"},{"issue":"3","key":"pone.0246412.ref011","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.jpedsurg.2006.10.038","article-title":"Neonatal gut barrier and multiple organ failure: role of endotoxin and proinflammatory cytokines in sepsis and necrotizing enterocolitis","volume":"42","author":"R Sharma","year":"2007","journal-title":"J Pediatr Surg"},{"issue":"4","key":"pone.0246412.ref012","doi-asserted-by":"crossref","first-page":"G656","DOI":"10.1152\/ajpgi.00550.2010","article-title":"Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis","volume":"301","author":"SJ McElroy","year":"2011","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"1","key":"pone.0246412.ref013","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s10024-002-0602-z","article-title":"Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts","volume":"6","author":"W Hsueh","year":"2003","journal-title":"Pediatr Dev Pathol"},{"issue":"2","key":"pone.0246412.ref014","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S0022-3468(97)90194-9","article-title":"The role of inflammatory cytokines and nitric oxide in the pathogenesis of necrotizing enterocolitis","volume":"32","author":"H Ford","year":"1997","journal-title":"J Pediatr Surg"},{"issue":"3","key":"pone.0246412.ref015","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1053\/j.sempedsurg.2005.05.002","article-title":"The role of PAF, TLR, and the inflammatory response in neonatal necrotizing enterocolitis","volume":"14","author":"MS Caplan","year":"2005","journal-title":"Semin Pediatr Surg"},{"issue":"4","key":"pone.0246412.ref016","doi-asserted-by":"crossref","first-page":"G757","DOI":"10.1152\/ajpgi.00408.2005","article-title":"Reduction of experimental necrotizing enterocolitis with anti-TNF-alpha","volume":"290","author":"MD Halpern","year":"2006","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"6","key":"pone.0246412.ref017","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.jpedsurg.2011.03.023","article-title":"Altered intestinal microcirculation is the critical event in the development of necrotizing enterocolitis","volume":"46","author":"CD Downard","year":"2011","journal-title":"J Pediatr Surg"},{"issue":"6","key":"pone.0246412.ref018","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.jpeds.2005.01.046","article-title":"Endothelin-1 in human intestine resected for necrotizing enterocolitis","volume":"146","author":"PT Nowicki","year":"2005","journal-title":"J Pediatr"},{"issue":"3","key":"pone.0246412.ref019","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1053\/j.sempedsurg.2005.05.003","article-title":"Ischemia and necrotizing enterocolitis: where, when, and how","volume":"14","author":"PT Nowicki","year":"2005","journal-title":"Semin Pediatr Surg"},{"issue":"2","key":"pone.0246412.ref020","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1203\/pdr.0b013e31802d77db","article-title":"Intestinal microcirculatory dysfunction during the development of experimental necrotizing enterocolitis","volume":"61","author":"Y Ito","year":"2007","journal-title":"Pediatr Res"},{"issue":"3","key":"pone.0246412.ref021","first-page":"CD005496","article-title":"Probiotics for prevention of necrotizing enterocolitis in preterm infants","author":"K Alfaleh","year":"2011","journal-title":"Cochrane Database Syst Rev"},{"issue":"5","key":"pone.0246412.ref022","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1542\/peds.73.5.682","article-title":"A decreased incidence of necrotizing enterocolitis after prenatal glucocorticoid therapy","volume":"73","author":"CR Bauer","year":"1984","journal-title":"Pediatrics"},{"issue":"1","key":"pone.0246412.ref023","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1471-0528.1990.tb01711.x","article-title":"The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials","volume":"97","author":"P Crowley","year":"1990","journal-title":"Br J Obstet Gynaecol"},{"issue":"1 Pt 1","key":"pone.0246412.ref024","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/S0022-3476(05)72461-6","article-title":"Prenatal and postnatal corticosteroid therapy to prevent neonatal necrotizing enterocolitis: a controlled trial","volume":"117","author":"E Halac","year":"1990","journal-title":"J Pediatr"},{"issue":"4","key":"pone.0246412.ref025","doi-asserted-by":"crossref","DOI":"10.3390\/cells9040839","article-title":"Corticotropin-Releasing Factor Family: A Stress Hormone-Receptor System\u2019s Emerging Role in Mediating Sex-Specific Signaling","volume":"9","author":"L Vuppaladhadiam","year":"2020","journal-title":"Cells"},{"issue":"2","key":"pone.0246412.ref026","doi-asserted-by":"crossref","DOI":"10.3390\/cells8020101","article-title":"Plasma Corticotropin-Releasing Factor Receptors and B7-2(+) Extracellular Vesicles in Blood Correlate with Irritable Bowel Syndrome Disease Severity","volume":"8","author":"SI Hagiwara","year":"2019","journal-title":"Cells"},{"key":"pone.0246412.ref027","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1146\/annurev.pharmtox.44.101802.121410","article-title":"CRF and CRF receptors: role in stress responsivity and other behaviors","volume":"44","author":"TL Bale","year":"2004","journal-title":"Annu Rev Pharmacol Toxicol"},{"issue":"44","key":"pone.0246412.ref028","doi-asserted-by":"crossref","first-page":"19020","DOI":"10.1073\/pnas.1013761107","article-title":"A triple urocortin knockout mouse model reveals an essential role for urocortins in stress recovery","volume":"107","author":"A Neufeld-Cohen","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"pone.0246412.ref029","doi-asserted-by":"crossref","first-page":"R1244","DOI":"10.1152\/ajpregu.00445.2015","article-title":"Sex- and corticotropin-releasing factor receptor 2- dependent actions of urocortin 1 during inflammation","volume":"310","author":"B Hasdemir","year":"2016","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"5","key":"pone.0246412.ref030","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1016\/j.jaci.2018.08.053","article-title":"Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability","volume":"143","author":"S D\u2019Costa","year":"2019","journal-title":"J Allergy Clin Immunol"},{"issue":"7","key":"pone.0246412.ref031","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/j.peptides.2007.05.008","article-title":"Urocortin 2 expression in the rat gastrointestinal tract under basal conditions and in chemical colitis","volume":"28","author":"J Chang","year":"2007","journal-title":"Peptides"},{"issue":"12","key":"pone.0246412.ref032","doi-asserted-by":"crossref","first-page":"5428","DOI":"10.1210\/en.2009-0489","article-title":"Local secretion of urocortin 1 promotes microvascular permeability during lipopolysaccharide-induced inflammation","volume":"150","author":"EL Cureton","year":"2009","journal-title":"Endocrinology"},{"issue":"9","key":"pone.0246412.ref033","doi-asserted-by":"crossref","first-page":"e0203704","DOI":"10.1371\/journal.pone.0203704","article-title":"Gastric corticotropin-releasing factor influences mast cell infiltration in a rat model of functional dyspepsia","volume":"13","author":"SI Hagiwara","year":"2018","journal-title":"PLoS One"},{"issue":"21","key":"pone.0246412.ref034","doi-asserted-by":"crossref","first-page":"7647","DOI":"10.1073\/pnas.0408531102","article-title":"Role of peripheral corticotropin-releasing factor and urocortin II in intestinal inflammation and motility in terminal ileum","volume":"102","author":"SE la Fleur","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"pone.0246412.ref035","doi-asserted-by":"crossref","first-page":"274","DOI":"10.2174\/156652408784533760","article-title":"Pathophysiological mechanisms of stress-induced intestinal damage","volume":"8","author":"MG Gareau","year":"2008","journal-title":"Curr Mol Med"},{"issue":"5","key":"pone.0246412.ref036","doi-asserted-by":"crossref","first-page":"G884","DOI":"10.1152\/ajpgi.00319.2010","article-title":"Urocortin 1 modulates immunosignaling in a rat model of colitis via corticotropin-releasing factor receptor 2","volume":"300","author":"J Chang","year":"2011","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"10","key":"pone.0246412.ref037","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1258\/ebm.2010.009347","article-title":"Corticotropin-releasing factor signaling and visceral response to stress","volume":"235","author":"A Stengel","year":"2010","journal-title":"Exp Biol Med (Maywood)"},{"issue":"4","key":"pone.0246412.ref038","doi-asserted-by":"crossref","first-page":"299","DOI":"10.2174\/156652408784533751","article-title":"The effects of physical and psychological stress on the gastro-intestinal tract: lessons from animal models","volume":"8","author":"JR Caso","year":"2008","journal-title":"Curr Mol Med"},{"issue":"4","key":"pone.0246412.ref039","doi-asserted-by":"crossref","first-page":"282","DOI":"10.2174\/156652408784533779","article-title":"The role of microbiota and probiotics in stress-induced gastro-intestinal damage","volume":"8","author":"F Lutgendorff","year":"2008","journal-title":"Curr Mol Med"},{"issue":"1 Pt 1","key":"pone.0246412.ref040","first-page":"G214","article-title":"Pathways mediating CRF-induced inhibition of gastric acid secretion in rats","volume":"256","author":"G Druge","year":"1989","journal-title":"Am J Physiol"},{"issue":"1","key":"pone.0246412.ref041","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/s13311-017-0585-0","article-title":"Anxiety, Depression, and the Microbiome: A Role for Gut Peptides","volume":"15","author":"G Lach","year":"2018","journal-title":"Neurotherapeutics"},{"issue":"7","key":"pone.0246412.ref042","first-page":"147887 e1-8","article-title":"Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice","volume":"144","author":"Y Sun","year":"2013","journal-title":"Gastroenterology"},{"issue":"1","key":"pone.0246412.ref043","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000452364","article-title":"Changes in Intestinal Motility and Gut Microbiota Composition in a Rat Stress Model","volume":"95","author":"T Murakami","year":"2017","journal-title":"Digestion"},{"issue":"3","key":"pone.0246412.ref044","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1053\/j.sempedsurg.2005.05.001","article-title":"Intestinal innate immunity: how does it relate to the pathogenesis of necrotizing enterocolitis","volume":"14","author":"J Neu","year":"2005","journal-title":"Semin Pediatr Surg"},{"issue":"3","key":"pone.0246412.ref045","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1097\/MOP.0b013e3283600e91","article-title":"The intestinal microbiome and necrotizing enterocolitis","volume":"25","author":"EM Carlisle","year":"2013","journal-title":"Curr Opin Pediatr"},{"issue":"6","key":"pone.0246412.ref046","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1053\/j.gastro.2010.08.024","article-title":"Corticotropin-releasing factor regulates TLR4 expression in the colon and protects mice from colitis","volume":"139","author":"Z Chaniotou","year":"2010","journal-title":"Gastroenterology"},{"issue":"3","key":"pone.0246412.ref047","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.4049\/jimmunol.176.3.1869","article-title":"Corticotropin-releasing factor and the urocortins induce the expression of TLR4 in macrophages via activation of the transcription factors PU.1 and AP-1","volume":"176","author":"C Tsatsanis","year":"2006","journal-title":"J Immunol"},{"issue":"23","key":"pone.0246412.ref048","doi-asserted-by":"crossref","first-page":"24592","DOI":"10.1074\/jbc.M313620200","article-title":"Endotoxin inhibits intestinal epithelial restitution through activation of Rho-GTPase and increased focal adhesions","volume":"279","author":"S Cetin","year":"2004","journal-title":"J Biol Chem"},{"issue":"7","key":"pone.0246412.ref049","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1111\/j.1365-2982.2010.01471.x","article-title":"Stress-induced barrier disruption of rat follicle-associated epithelium involves corticotropin-releasing hormone, acetylcholine, substance P, and mast cells","volume":"22","author":"AV Keita","year":"2010","journal-title":"Neurogastroenterol Motil"},{"issue":"7","key":"pone.0246412.ref050","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1111\/j.1365-2982.2010.01498.x","article-title":"The intestinal barrier and its regulation by neuroimmune factors","volume":"22","author":"AV Keita","year":"2010","journal-title":"Neurogastroenterol Motil"},{"key":"pone.0246412.ref051","doi-asserted-by":"crossref","first-page":"54","DOI":"10.3389\/fnins.2011.00054","article-title":"Corticotrophin-releasing factor, related peptides, and receptors in the normal and inflamed gastrointestinal tract","volume":"5","author":"R Buckinx","year":"2011","journal-title":"Front Neurosci"},{"issue":"Suppl 7","key":"pone.0246412.ref052","first-page":"33","article-title":"Corticotropin releasing factor signaling in colon and ileum: regulation by stress and pathophysiological implications","volume":"60","author":"M Larauche","year":"2009","journal-title":"J Physiol Pharmacol"},{"issue":"11","key":"pone.0246412.ref053","doi-asserted-by":"crossref","first-page":"6068","DOI":"10.1128\/IAI.70.11.6068-6074.2002","article-title":"Corticotropin-releasing hormone augments proinflammatory cytokine production from macrophages in vitro and in lipopolysaccharide-induced endotoxin shock in mice","volume":"70","author":"S Agelaki","year":"2002","journal-title":"Infect Immun"},{"issue":"7","key":"pone.0246412.ref054","doi-asserted-by":"crossref","first-page":"803","DOI":"10.3109\/10715762.2010.485988","article-title":"Effect of CRH on NO bioavailability, ROS production and antioxidant defense systems in endothelial EAhy926 cells","volume":"44","author":"S Gougoura","year":"2010","journal-title":"Free Radic Res"},{"issue":"1","key":"pone.0246412.ref055","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1097\/01.fjc.0000196240.58641.d3","article-title":"Effects of corticotropin-releasing hormone (CRH) on monocyte function, mediated by CRH-receptor subtype R1 and R2: a potential link between mood disorders and endothelial dysfunction?","volume":"47","author":"U Wilbert-Lampen","year":"2006","journal-title":"J Cardiovasc Pharmacol"},{"issue":"2","key":"pone.0246412.ref056","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1159\/000081898","article-title":"The \u2019myth\u2019 of asphyxia and hypoxia-ischemia as primary causes of necrotizing enterocolitis","volume":"87","author":"J Neu","year":"2005","journal-title":"Biol Neonate"},{"issue":"2","key":"pone.0246412.ref057","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1046\/j.0300-0664.2001.01467.x","article-title":"The corticotrophin-releasing hormone test in preterm infants","volume":"56","author":"RJ Bolt","year":"2002","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"6","key":"pone.0246412.ref058","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1136\/gut.2009.190728","article-title":"Maternal deprivation alters epithelial secretory cell lineages in rat duodenum: role of CRF-related peptides","volume":"59","author":"M Estienne","year":"2010","journal-title":"Gut"},{"issue":"6","key":"pone.0246412.ref059","doi-asserted-by":"crossref","first-page":"G1257","DOI":"10.1152\/ajpgi.00314.2002","article-title":"Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress","volume":"283","author":"JD S\u00f6derholm","year":"2002","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"8","key":"pone.0246412.ref060","doi-asserted-by":"crossref","first-page":"e241","DOI":"10.1111\/j.1365-2982.2010.01507.x","article-title":"Functional changes induced by psychological stress are not enough to cause intestinal inflammation in Sprague-Dawley rats","volume":"22","author":"E Jorge","year":"2010","journal-title":"Neurogastroenterol Motil"},{"issue":"3","key":"pone.0246412.ref061","doi-asserted-by":"crossref","first-page":"G442","DOI":"10.1152\/ajpgi.00182.2009","article-title":"Changes in intestinal Toll-like receptors and cytokines precede histological injury in a rat model of necrotizing enterocolitis","volume":"297","author":"Y Liu","year":"2009","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"1","key":"pone.0246412.ref062","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1006\/jsre.2000.5877","article-title":"Expression of inducible nitric oxide synthase and interleukin-12 in experimental necrotizing enterocolitis","volume":"92","author":"EP Nadler","year":"2000","journal-title":"J Surg Res"},{"key":"pone.0246412.ref063","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1477-7827-7-43","article-title":"Reduced expression of CRH receptor type 1 in upper segment human myometrium during labour","volume":"7","author":"B Cong","year":"2009","journal-title":"Reprod Biol Endocrinol"},{"key":"pone.0246412.ref064","doi-asserted-by":"crossref","first-page":"7397659","DOI":"10.1155\/2018\/7397659","article-title":"Oxidative Stress and Necrotizing Enterocolitis: Pathogenetic Mechanisms, Opportunities for Intervention, and Role of Human Milk","volume":"2018","author":"A Aceti","year":"2018","journal-title":"Oxid Med Cell Longev"},{"issue":"1","key":"pone.0246412.ref065","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/MPG.0b013e318198cd36","article-title":"Enteral glutamine and\/or arginine supplementation have favorable effects on oxidative stress parameters in neonatal rat intestine","volume":"49","author":"M Kul","year":"2009","journal-title":"J Pediatr Gastroenterol Nutr"},{"issue":"1","key":"pone.0246412.ref066","article-title":"The effects of prolonged oral administration of the disinfectant calcium hypochlorite in Nigerian commercial cockerels","volume":"84","author":"TO Iji","year":"2013","journal-title":"J S Afr Vet Assoc"},{"key":"pone.0246412.ref067","doi-asserted-by":"crossref","first-page":"46616","DOI":"10.1038\/srep46616","article-title":"Inhibition of corticotropin-releasing hormone receptor 1 and activation of receptor 2 protect against colonic injury and promote epithelium repair","volume":"7","author":"B Li","year":"2017","journal-title":"Sci Rep"},{"issue":"2","key":"pone.0246412.ref068","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/nmo.12725","article-title":"Endogenous CRF in rat large intestine mediates motor and secretory responses to stress","volume":"28","author":"S Liu","year":"2016","journal-title":"Neurogastroenterol Motil"},{"key":"pone.0246412.ref069","first-page":"e14021","article-title":"Effects of stress-related peptides on chloride secretion in the mouse proximal colon","author":"S Liu","year":"2020","journal-title":"Neurogastroenterol Motil"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0246412","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T12:41:33Z","timestamp":1672404093000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0246412"}},"subtitle":[],"editor":[{"given":"Arda","family":"Yildirim","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,6,10]]},"references-count":69,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0246412","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.01.20.427423","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,10]]}}}