{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:34:26Z","timestamp":1788845666431,"version":"build-2803163510"},"reference-count":35,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,9]],"date-time":"2020-10-09T00:00:00Z","timestamp":1602201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["GR-2011-02346974"],"award-info":[{"award-number":["GR-2011-02346974"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Mesenteric ischemia\/reperfusion (I\/R), following the transient deprivation of blood flow to the gut, triggers an acute flogistic process involving the disruption of endothelial and epithelial barriers integrity, the activation of immune cells, and the abundant release of inflammatory mediators. Among them, the lipid mediator sphingosine-1-phosphate (S1P) is involved in maintaining epithelial and endothelial barrier integrity and in governing the migration of immune cells through the interaction with S1P1\u20135 receptors. Therefore, the present work aims to investigate the involvement of S1P signaling in intestinal I\/R-induced injury by studying the effects of FTY720, the non-selective S1P1,3\u20135 agonist, and comparing them with the responses to ozanimod, selective S1P1,5 agonist, in a murine model of gut I\/R. Intestinal edema, gut and lung neutrophil infiltration, and oxidative stress were evaluated through biochemical and morphological assays. The collected results highlight the protective action of FTY720 against the inflammatory cascade elicited by mesenteric I\/R injury, mainly through the control of vascular barrier integrity. While these beneficial effects were mimicked by ozanimod and can be therefore attributed largely to the effects exerted by FTY720 on S1P1, the recruitment of myeloid cells to the injured areas, limited by FTY720 but not by ozanimod, rather suggests the involvement of other receptor subtypes.<\/jats:p>","DOI":"10.3390\/ph13100298","type":"journal-article","created":{"date-parts":[[2020,10,9]],"date-time":"2020-10-09T10:19:23Z","timestamp":1602238763000},"page":"298","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Impact of S1P Mimetics on Mesenteric Ischemia\/Reperfusion Injury"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1708-0719","authenticated-orcid":false,"given":"Francesco","family":"Pot\u00ec","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, via Gramsci 14, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"Giorgio","sequence":"additional","affiliation":[{"name":"Food and Drug Department, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Zini","sequence":"additional","affiliation":[{"name":"Food and Drug Department, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerzy-Roch","family":"Nofer","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Vivo","sequence":"additional","affiliation":[{"name":"Food and Drug Department, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Palese","sequence":"additional","affiliation":[{"name":"Food and Drug Department, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vigilio","family":"Ballabeni","sequence":"additional","affiliation":[{"name":"Food and Drug Department, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8152-3166","authenticated-orcid":false,"given":"Elisabetta","family":"Barocelli","sequence":"additional","affiliation":[{"name":"Food and Drug Department, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2854-1306","authenticated-orcid":false,"given":"Simona","family":"Bertoni","sequence":"additional","affiliation":[{"name":"Food and Drug Department, University of Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.tcb.2011.09.003","article-title":"Sphingosine-1-phosphate signaling and its role in disease","volume":"22","author":"Maceyka","year":"2012","journal-title":"Trends Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"107464","DOI":"10.1016\/j.pharmthera.2019.107464","article-title":"Sphingosine kinase and sphingosine-1-phosphate receptor signaling pathway in inflammatory gastrointestinal disease and cancers: A novel therapeutic target","volume":"207","author":"Sukocheva","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104170","DOI":"10.1016\/j.phrs.2019.02.009","article-title":"Targeting the S1P receptor signaling pathways as a promising approach for treatment of autoimmune and inflammatory diseases","volume":"154","author":"Stepanovska","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.pharmthera.2017.11.001","article-title":"The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives","volume":"185","author":"Huwiler","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1016\/j.drudis.2018.05.034","article-title":"Mesenteric ischemia-reperfusion: An overview of preclinical drug strategies","volume":"23","author":"Bertoni","year":"2018","journal-title":"Drug Discov. Today"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S0041-1345(00)02349-6","article-title":"FTY 720 prevents ischemic reperfusion damage in rat kidneys","volume":"33","author":"Troncoso","year":"2001","journal-title":"Transplant. Proc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"F1516","DOI":"10.1152\/ajprenal.00311.2005","article-title":"Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney","volume":"290","author":"Awad","year":"2006","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_8","first-page":"40","article-title":"FTY720 Attenuates Hepatic Ischemia-Reperfusion Injury in Normal and Cirrhotic Livers","volume":"5","author":"Man","year":"2005","journal-title":"Arab. Archaeol. Epigr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"L1245","DOI":"10.1152\/ajplung.00302.2014","article-title":"Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury","volume":"308","author":"Stone","year":"2015","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1097\/SHK.0000000000000227","article-title":"A Sphingosine-1 Phosphate Agonist (FTY720) Limits Trauma\/Hemorrhagic Shock\u2013Induced Multiple Organ Dysfunction Syndrome","volume":"42","author":"Bonitz","year":"2014","journal-title":"Shock"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1007\/s40265-020-01319-7","article-title":"Ozanimod: First Approval","volume":"80","author":"Lamb","year":"2020","journal-title":"Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.neuropharm.2016.11.006","article-title":"Sphingosine-1-phosphate receptor therapies: Advances in clinical trials for CNS-related diseases","volume":"113","author":"Dev","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_13","first-page":"11","article-title":"Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus","volume":"3","author":"Chiba","year":"2006","journal-title":"Cell. Mol. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"106436","DOI":"10.1016\/j.prostaglandins.2020.106436","article-title":"Sphingosine 1-phosphate signaling in ischemia and reperfusion injury","volume":"149","author":"Raza","year":"2020","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1093\/cvr\/cvn309","article-title":"Sphingosine kinase regulation and cardioprotection","volume":"82","author":"Karliner","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s11883-016-0586-1","article-title":"Sphingosine-1-Phosphate Signaling in Endothelial Disorders","volume":"18","author":"Sanchez","year":"2016","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1007\/s10753-011-9301-0","article-title":"Sphingosine-1-Phosphate Attenuates Lung Injury Induced by Intestinal Ischemia\/Reperfusion in Mice: Role of Inducible Nitric-Oxide Synthase","volume":"35","author":"Ding","year":"2011","journal-title":"Inflammation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1038\/ki.2011.281","article-title":"Sphingosine kinase 1 protects against renal ischemia\u2013reperfusion injury in mice by sphingosine-1-phosphate1 receptor activation","volume":"80","author":"Park","year":"2011","journal-title":"Kidney Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13048-016-0216-0","article-title":"Supplementation of transport and freezing media with anti-apoptotic drugs improves ovarian cortex survival","volume":"9","author":"Henry","year":"2016","journal-title":"J. Ovarian Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1681\/ASN.2015010095","article-title":"Sphingosine 1-Phosphate Receptor 3\u2013Deficient Dendritic Cells Modulate Splenic Responses to Ischemia-Reperfusion Injury","volume":"27","author":"Bajwa","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.hbpd.2019.04.001","article-title":"Sphingosine kinase 1 knockout alleviates hepatic ischemia\/reperfusion injury by attenuating inflammation and oxidative stress in mice","volume":"18","author":"Qiang","year":"2019","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1111\/bph.13476","article-title":"Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity","volume":"173","author":"Scott","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"47408","DOI":"10.1074\/jbc.M307687200","article-title":"Phosphorylation of the Immunomodulatory Drug FTY720 by Sphingosine Kinases","volume":"278","author":"Billich","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e12860","DOI":"10.1111\/apha.12860","article-title":"Mind the gap: Mechanisms regulating the endothelial barrier","volume":"222","author":"Radeva","year":"2017","journal-title":"Acta Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.pharmthera.2007.04.006","article-title":"Sphingosine 1-phosphate receptors in health and disease: Mechanistic insights from gene deletion studies and reverse pharmacology","volume":"115","author":"Brinkmann","year":"2007","journal-title":"Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/6059203","article-title":"Beyond Immune Cell Migration: The Emerging Role of the Sphingosine-1-phosphate Receptor S1PR4 as a Modulator of Innate Immune Cell Activation","volume":"2017","author":"Olesch","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1096\/fj.201800221R","article-title":"Sphingosine-1-phosphate (S1P) induces potent anti-inflammatory effects in vitro and in vivo by S1P receptor 4-mediated suppression of 5-lipoxygenase activity","volume":"33","author":"Fettel","year":"2018","journal-title":"FASEB J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1007\/s00210-015-1159-5","article-title":"FTY720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of S1P3 and phosphoinositide 3-kinase","volume":"388","author":"Imeri","year":"2015","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1080\/mic.9.2.99.109","article-title":"T-lymphocytes modulate the microvascular and inflammatory responses to intestinal ischemia-reperfusion","volume":"9","author":"Shigematsu","year":"2002","journal-title":"Microcirculation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.phrs.2014.02.002","article-title":"Suppression of inflammatory events associated to intestinal ischemia\u2013reperfusion by 5-HT1A blockade in mice","volume":"81","author":"Ebertoni","year":"2014","journal-title":"Pharmacol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.4049\/jimmunol.178.4.2458","article-title":"FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells","volume":"178","author":"Daniel","year":"2007","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1016\/0016-5085(84)90202-6","article-title":"Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models","volume":"87","author":"Krawisz","year":"1984","journal-title":"Gastroenterology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction","volume":"95","author":"Ohkawa","year":"1979","journal-title":"Anal. Biochem."},{"key":"ref_34","first-page":"258","article-title":"Ischemic preconditioning protects against gut dysfunction and mucosal injury after ischemia\/reperfusion injury","volume":"23","author":"Kozar","year":"2005","journal-title":"Shock"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/10\/298\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:17:58Z","timestamp":1760177878000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/10\/298"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,9]]},"references-count":35,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["ph13100298"],"URL":"https:\/\/doi.org\/10.3390\/ph13100298","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,9]]}}}