{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T23:31:41Z","timestamp":1790897501604,"version":"4.1.0"},"reference-count":71,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,29]],"date-time":"2022-10-29T00:00:00Z","timestamp":1667001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biomedical Advanced Research and Development Authority (BARDA)","award":["HHSO100201100029C"],"award-info":[{"award-number":["HHSO100201100029C"]}]},{"name":"Biomedical Advanced Research and Development Authority (BARDA)","award":["261201400016C-0-0-1"],"award-info":[{"award-number":["261201400016C-0-0-1"]}]},{"DOI":"10.13039\/100012399","name":"US Department of Defense","doi-asserted-by":"publisher","award":["HHSO100201100029C"],"award-info":[{"award-number":["HHSO100201100029C"]}],"id":[{"id":"10.13039\/100012399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012399","name":"US Department of Defense","doi-asserted-by":"publisher","award":["261201400016C-0-0-1"],"award-info":[{"award-number":["261201400016C-0-0-1"]}],"id":[{"id":"10.13039\/100012399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["HHSO100201100029C"],"award-info":[{"award-number":["HHSO100201100029C"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["261201400016C-0-0-1"],"award-info":[{"award-number":["261201400016C-0-0-1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Exposure to ionizing radiation (IR) is a lingering threat from accidental or terroristic nuclear events, but is also widely used in cancer therapy. In both cases, host inflammatory responses to IR damage normal tissue causing morbidity and possibly mortality to the victim\/patient. Opaganib, a first-in-class inhibitor of sphingolipid metabolism, has broad anti-inflammatory and anticancer activity. Opaganib elevates ceramide and reduces sphingosine 1-phosphate (S1P) in cells, conditions that increase the antitumor efficacy of radiation while concomitantly suppressing inflammatory damage to normal tissue. Therefore, opaganib may suppress toxicity from unintended IR exposure and improve patient response to chemoradiation. To test these hypotheses, we first examined the effects of opaganib on the toxicity and antitumor activity of radiation in mice exposed to total body irradiation (TBI) or IR with partial bone marrow shielding. Oral treatment with opaganib 2 h before TBI shifted the LD75 from 9.5 Gy to 11.5 Gy, and provided substantial protection against gastrointestinal damage associated with suppression of radiation-induced elevations of S1P and TNF\u03b1 in the small intestines. In the partially shielded model, opaganib provided dose-dependent survival advantages when administered 4 h before or 24 h after radiation exposure, and was particularly effective when given both prior to and following radiation. Relevant to cancer radiotherapy, opaganib decreased the sensitivity of IEC6 (non-transformed mouse intestinal epithelial) cells to radiation, while sensitizing PAN02 cells to in vitro radiation. Next, the in vivo effects of opaganib in combination with radiation were examined in a syngeneic tumor model consisting of C57BL\/6 mice bearing xenografts of PAN02 pancreatic cancer cells and a cross-species xenograft model consisting of nude mice bearing xenografts of human FaDu cells. Mice were treated with opaganib and\/or IR (plus cisplatin in the case of FaDu tumors). In both tumor models, the optimal suppression of tumor growth was attained by the combination of opaganib with IR (\u00b1 cisplatin). Overall, opaganib substantially protects normal tissue from radiation damage that may occur through unintended exposure or cancer radiotherapy.<\/jats:p>","DOI":"10.3390\/ijms232113191","type":"journal-article","created":{"date-parts":[[2022,10,30]],"date-time":"2022-10-30T07:26:50Z","timestamp":1667114810000},"page":"13191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Opaganib Protects against Radiation Toxicity: Implications for Homeland Security and Antitumor Radiotherapy"],"prefix":"10.3390","volume":"23","author":[{"given":"Lynn W.","family":"Maines","sequence":"first","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy S.","family":"Schrecengost","sequence":"additional","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Staci N.","family":"Keller","sequence":"additional","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecelia L.","family":"Green","sequence":"additional","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles D.","family":"Smith","sequence":"additional","affiliation":[{"name":"Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA 17036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.canlet.2015.04.016","article-title":"Radiation triggering immune response and inflammation","volume":"368","author":"Hekim","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/path.4299","article-title":"Responses to ionizing radiation mediated by inflammatory mechanisms","volume":"232","author":"Mukherjee","year":"2014","journal-title":"J. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1080\/09553002.2018.1440092","article-title":"Mechanisms of inflammatory responses to radiation and normal tissues toxicity: Clinical implications","volume":"94","author":"Najafi","year":"2018","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12950-015-0058-3","article-title":"Portrait of inflammatory response to ionizing radiation treatment","volume":"12","author":"Minafra","year":"2015","journal-title":"J. Inflamm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.15190\/d.2015.27","article-title":"NF-kB as a key player in regulation of cellular radiation responses and identification of radiation countermeasures","volume":"3","author":"Singh","year":"2015","journal-title":"Discoveries"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"203","DOI":"10.2174\/1874467210666171108165641","article-title":"Targeting of Inflammation for Radiation Protection and Mitigation","volume":"11","author":"Yahyapour","year":"2018","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_7","first-page":"9","article-title":"Radiation-induced inflammation and autoimmune diseases","volume":"5","author":"Yahyapour","year":"2018","journal-title":"Mil. Med. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"757973","DOI":"10.3389\/fonc.2021.757973","article-title":"Radiotherapy-Induced Digestive Injury: Diagnosis, Treatment and Mechanisms","volume":"11","author":"Chen","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4105","DOI":"10.2217\/fon-2019-0416","article-title":"Radiation-induced intestinal damage: Latest molecular and clinical developments","volume":"15","author":"Lu","year":"2019","journal-title":"Futur. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.21037\/jgo-21-361","article-title":"Pathobiology, irradiation dosimetric parameters and therapy of radiation-induced gastric damage: A narrative review","volume":"12","author":"McKay","year":"2021","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.radonc.2020.06.041","article-title":"Augmenting the therapeutic window of radiotherapy: A perspective on molecularly targeted therapies and nanomaterials","volume":"150","author":"Reda","year":"2020","journal-title":"Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"62742","DOI":"10.18632\/oncotarget.18409","article-title":"Improving radiotherapy in cancer treatment: Promises and challenges","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s41416-018-0201-z","article-title":"Practice-changing radiation therapy trials for the treatment of cancer: Where are we 150 years after the birth of Marie Curie?","volume":"119","author":"Thompson","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s11894-002-0005-3","article-title":"Radiation enteritis","volume":"4","author":"Bismar","year":"2002","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_15","first-page":"215","article-title":"Radiation enteropathy","volume":"99","author":"Toomey","year":"2006","journal-title":"Ir. Med. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/978-3-030-21735-8_15","article-title":"Roles of Ceramides and Other Sphingolipids in Immune Cell Function and Inflammation","volume":"1161","author":"Albeituni","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/bs.acr.2018.04.015","article-title":"Targeting Sphingosine Kinases for the Treatment of Cancer","volume":"140","author":"Lewis","year":"2018","journal-title":"Adv. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Quinville, B.M., Deschenes, N.M., Ryckman, A.E., and Walia, J.S. (2021). A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115793"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrc.2017.96","article-title":"Sphingolipid metabolism in cancer signalling and therapy","volume":"18","author":"Ogretmen","year":"2017","journal-title":"Nat. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"807636","DOI":"10.3389\/fonc.2021.807636","article-title":"The Role of Sphingolipids Metabolism in Cancer Drug Resistance","volume":"11","author":"Bataller","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8162","DOI":"10.1002\/jcp.27612","article-title":"New insights into the roles and regulation of SphK2 as a therapeutic target in cancer chemoresistance","volume":"234","author":"Hasanifard","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/bs.acr.2018.04.013","article-title":"The Onus of Sphingolipid Enzymes in Cancer Drug Resistance","volume":"140","author":"Morad","year":"2018","journal-title":"Adv. Cancer Res."},{"key":"ref_23","first-page":"4468","article-title":"Sphingosine enhances apoptosis of radiation-resistant prostate cancer cells","volume":"60","author":"Nava","year":"2000","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/B978-0-12-394274-6.00001-7","article-title":"Interdiction of Sphingolipid Metabolism to Improve Standard Cancer Therapies","volume":"117","author":"Beckham","year":"2013","journal-title":"Adv. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/978-3-7091-1511-4_6","article-title":"Sphingolipids\u2019 Role in Radiotherapy for Prostate Cancer","volume":"216","author":"Hajj","year":"2013","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sharma, D., and Czarnota, G.J. (2022). Involvement of Ceramide Signalling in Radiation-Induced Tumour Vascular Effects and Vascular-Targeted Therapy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126671"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1124\/jpet.109.163444","article-title":"Pharmacology and Antitumor Activity of ABC294640, a Selective Inhibitor of Sphingosine Kinase-2","volume":"333","author":"French","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gao, P., Peterson, Y.K., Smith, R.A., and Smith, C.D. (2012). Characterization of Isoenzyme-Selective Inhibitors of Human Sphingosine Kinases. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044543"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1124\/jpet.109.163337","article-title":"A Novel Sphingosine Kinase Inhibitor Induces Autophagy in Tumor Cells","volume":"333","author":"Beljanski","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"678","DOI":"10.4161\/cbt.11.7.14903","article-title":"Targeting NF\u0138B mediated breast cancer chemoresistance through selective inhibition of sphingosine kinase-2","volume":"11","author":"Antoon","year":"2011","journal-title":"Cancer Biol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1158\/1541-7786.MCR-14-0626","article-title":"Downregulation of Critical Oncogenes by the Selective SK2 Inhibitor ABC294640 Hinders Prostate Cancer Progression","volume":"13","author":"Schrecengost","year":"2015","journal-title":"Mol. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2744","DOI":"10.1158\/1535-7163.MCT-15-0279","article-title":"The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo","volume":"14","author":"Venant","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1182\/blood-2014-03-559385","article-title":"Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma","volume":"124","author":"Venkata","year":"2014","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"60181","DOI":"10.18632\/oncotarget.11112","article-title":"Suppression of c-Myc and RRM2 expression in pancreatic cancer cells by the sphingosine kinase-2 inhibitor ABC294640","volume":"7","author":"Lewis","year":"2016","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5124","DOI":"10.1210\/en.2010-0420","article-title":"Antiestrogenic Effects of the Novel Sphingosine Kinase-2 Inhibitor ABC294640","volume":"151","author":"Antoon","year":"2010","journal-title":"Endocrinology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1007\/s10637-010-9452-0","article-title":"Combined anticancer effects of sphingosine kinase inhibitors and sorafenib","volume":"29","author":"Beljanski","year":"2010","journal-title":"Investig. New Drugs"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"524","DOI":"10.4161\/cbt.11.5.14677","article-title":"Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts","volume":"11","author":"Beljanski","year":"2011","journal-title":"Cancer Biol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1158\/1535-7163.MCT-13-0466","article-title":"Targeting Sphingosine Kinase Induces Apoptosis and Tumor Regression for KSHV-Associated Primary Effusion Lymphoma","volume":"13","author":"Qin","year":"2014","journal-title":"Mol. Cancer Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s13046-015-0205-y","article-title":"Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo","volume":"34","author":"Xun","year":"2015","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1159\/000323911","article-title":"Experimental Osteoarthritis in Rats Is Attenuated by ABC294640, a Selective Inhibitor of Sphingosine Kinase-2","volume":"87","author":"Fitzpatrick","year":"2011","journal-title":"Pharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s10787-010-0060-6","article-title":"Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine kinase","volume":"19","author":"Fitzpatrick","year":"2010","journal-title":"Inflammopharmacology"},{"key":"ref_42","first-page":"997","article-title":"Suppression of Ulcerative Colitis in Mice by Orally Available Inhibitors of Sphingosine Kinase","volume":"53","author":"Maines","year":"2007","journal-title":"Am. J. Dig. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s10787-010-0032-x","article-title":"Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn\u2019s disease","volume":"18","author":"MainesLeo","year":"2010","journal-title":"Inflammopharmacology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5022","DOI":"10.1167\/iovs.05-1236","article-title":"Pharmacologic Manipulation of Sphingosine Kinase in Retinal Endothelial Cells: Implications for Angiogenic Ocular Diseases","volume":"47","author":"Maines","year":"2006","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1158\/1078-0432.CCR-16-2363","article-title":"A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors","volume":"23","author":"Britten","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.2147\/DDDT.S367612","article-title":"Recent Progress in the Development of Opaganib for the Treatment of COVID-19","volume":"16","author":"Smith","year":"2022","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"ofac232","DOI":"10.1093\/ofid\/ofac232","article-title":"Opaganib in COVID-19 pneumonia: Results of a randomized, placebo-controlled Phase 2a trial","volume":"9","author":"Winthrop","year":"2022","journal-title":"Open Forum. Infect. Dis."},{"key":"ref_48","first-page":"421","article-title":"Radiation biology and protection","volume":"80","author":"Colangelo","year":"2009","journal-title":"Radiol. Technol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"651","DOI":"10.3357\/ASEM.2113.2008","article-title":"Pharmacological Agents for the Prevention and Treatment of Toxic Radiation Exposure in Spaceflight","volume":"79","author":"Langell","year":"2008","journal-title":"Aviat. Space Environ. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1517\/17425255.4.10.1341","article-title":"Pharmacologic normal tissue protection in clinical radiation oncology: Focus on amifostine","volume":"4","author":"Mell","year":"2008","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.drudis.2007.07.017","article-title":"Trends in the development of radioprotective agents","volume":"12","author":"Hosseinimehr","year":"2007","journal-title":"Drug Discov. Today"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.semradonc.2006.11.010","article-title":"Future Strategies for Mitigation and Treatment of Chronic Radiation-Induced Normal Tissue Injury","volume":"17","author":"Moulder","year":"2007","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1053\/srao.2003.50006","article-title":"Chemical radioprotection: A critical review of amifostine as a cytoprotector in radiotherapy","volume":"13","author":"Andreassen","year":"2003","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1159\/000067146","article-title":"Radioprotectants: Current Status and New Directions","volume":"63","author":"Grdina","year":"2002","journal-title":"Oncology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1517\/14656566.2.3.479","article-title":"Amifostine: Chemotherapeutic and radiotherapeutic protective effects","volume":"2","author":"Santini","year":"2001","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1634\/theoncologist.12-6-738","article-title":"Amifostine: The First Selective-Target and Broad-Spectrum Radioprotector","volume":"12","author":"Kouvaris","year":"2007","journal-title":"Oncologist"},{"key":"ref_57","first-page":"108","article-title":"Dosing considerations with amifostine: A review of the literature and clinical experience","volume":"26","author":"Dorr","year":"1999","journal-title":"Semin. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"14196","DOI":"10.1073\/pnas.95.24.14196","article-title":"Tumor necrosis factor- induces adhesion molecule expression through the sphingosine kinase pathway","volume":"95","author":"Xia","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"34499","DOI":"10.1074\/jbc.274.48.34499","article-title":"Activation of Sphingosine Kinase by Tumor Necrosis Factor-\u03b1 Inhibits Apoptosis in Human Endothelial Cells","volume":"274","author":"Xia","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6433","DOI":"10.4049\/jimmunol.177.9.6433","article-title":"Involvement of TNF-Like Weak Inducer of Apoptosis in the Pathogenesis of Collagen-Induced Arthritis","volume":"177","author":"Kamata","year":"2006","journal-title":"J. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S0024-3205(99)00587-1","article-title":"Tumor necrosis factor-alpha-mediated signal transduction in human neutrophils: Involvement of sphingomyelin metabolites in the priming effect of TNF-alpha on the fMLP-stimulated superoxide production","volume":"66","author":"Niwa","year":"2000","journal-title":"Life Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/S0898-6568(02)00117-1","article-title":"Activation of human monocytic cells by lysophosphatidic acid and sphingosine-1-phosphate","volume":"15","author":"Fueller","year":"2003","journal-title":"Cell. Signal."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1096\/fj.02-1038com","article-title":"The sphingosine kinase 1\/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-alpha","volume":"17","author":"Pettus","year":"2003","journal-title":"FASEB J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"6394","DOI":"10.4049\/jimmunol.169.11.6394","article-title":"Sphingosine Kinase: A Point of Convergence in the Action of Diverse Neutrophil Priming Agents","volume":"169","author":"MacKinnon","year":"2002","journal-title":"J. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"27540","DOI":"10.1074\/jbc.M301763200","article-title":"Sphingosine 1-Phosphate, a Diffusible Calcium Influx Factor Mediating Store-operated Calcium Entry","volume":"278","author":"Itagaki","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.suc.2021.12.004","article-title":"Head and Neck Radiation Therapy: From Consultation to Survivorship and Future Directions","volume":"102","author":"Guss","year":"2022","journal-title":"Surg. Clin. N. Am."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"961594","DOI":"10.3389\/froh.2022.961594","article-title":"Over 300 Radiation Caries Papers: Reflections From the Rearview Mirror","volume":"3","author":"Pedroso","year":"2022","journal-title":"Front. Oral Health"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"101707","DOI":"10.1016\/j.bpg.2020.101707","article-title":"Radiation-induced damage in the lower gastrointestinal tract: Clinical presentation, diagnostic tests and treatment options","volume":"48","author":"Araujo","year":"2020","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"888962","DOI":"10.3389\/fonc.2022.888962","article-title":"Research progress on the mechanism of radiation enteritis","volume":"12","author":"Fan","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.jviscsurg.2020.08.012","article-title":"Radiation enteritis: Diagnostic and therapeutic issues","volume":"157","author":"Loge","year":"2020","journal-title":"J. Visc. Surg."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Yura, Y., Masui, A., and Hamada, M. (2020). Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma. Cancers, 12.","DOI":"10.3390\/cancers12082062"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13191\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:05:53Z","timestamp":1760144753000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,29]]},"references-count":71,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232113191"],"URL":"https:\/\/doi.org\/10.3390\/ijms232113191","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,29]]}}}