{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:14:23Z","timestamp":1784556863746,"version":"3.55.0"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R44DE024024"],"award-info":[{"award-number":["R44DE024024"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R44AI126987"],"award-info":[{"award-number":["R44AI126987"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Purpose<\/jats:title>\n<jats:p>Oral mucositis (OM) is a common, painful side effect of radiation therapy used for the treatment of head and neck cancer (HNC). Activation of the innate immune system upon irradiation has been identified as a key precipitating event of OM. To better understand OM\u2019s pathogenesis, we studied pattern recognition receptors (PRRs) and their downstream pro-inflammatory cytokines in a mouse model of radiation-induced OM. We also tested therapeutic efficacy of GM-1111 that targets innate immune system to reduce radiation-induced OM.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and materials<\/jats:title>\n<jats:p>The pathogenesis of OM was studied in a single X-ray induced mouse model. The severity of OM was measured by visual and microscopical examinations. The irradiation-induced changes of PRRs and their downstream effector cytokine gene expression levels were determined. The efficacy of GM-1111 to reduce OM was tested in single and fractionated irradiation mouse models. The impact of the drug on tumor response to radiation therapy was also tested in a mouse model of human HNC.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Radiation-induced tissue ulcerations were radiation-dosage and -time dependent. The lesions showed selective increases in PRR and pro-inflammatory cytokine gene expression levels. Once daily administration of GM-1111 (\u226530 mg\/kg, <jats:italic>s<\/jats:italic>.<jats:italic>c<\/jats:italic>.) significantly reduced the severity and the incidence of OM. The drug had little effect on PRRs but significantly inhibited downstream pro-inflammatory cytokine genes. GM-1111 did not interfere radiation therapy to induce HNC SCC-25 tumor regression. Instead, we observed significant drug-induced tumor regression.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Radiation induces tissue damages. The increased expression levels of PRRs and their downstream pro-inflammatory cytokine genes in the damaged tissues suggest their important contribution to the pathogenesis of OM. Drug GM-1111 that targets these innate immune molecules may be a potential drug candidate as an intervention for OM.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0249343","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T17:30:54Z","timestamp":1616779854000},"page":"e0249343","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["GM-1111 reduces radiation-induced oral mucositis in mice by targeting pattern recognition receptor-mediated inflammatory signaling"],"prefix":"10.1371","volume":"16","author":[{"given":"Abigail","family":"Pulsipher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin R.","family":"Savage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas 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and pharyngitis: results from a Northwestern University Costs of Cancer Program pilot study with head and neck and nonsmall cell lung cancer patients who received care at a county hospital, a Veterans Administration hospital, or a comprehensive cancer care center","volume":"113","author":"NJ Nonzee","year":"2008","journal-title":"Cancer"},{"key":"pone.0249343.ref002","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.oraloncology.2009.08.006","article-title":"Mucositis: The impact, biology and therapeutic opportunities of oral mucositis","volume":"45","author":"ST Sonis","year":"2009","journal-title":"Oral Oncol"},{"key":"pone.0249343.ref003","first-page":"357","article-title":"Systematic review of amifostine for the management of oral mucositis in cancer patients","volume":"21","author":"O Nicolatou-Galitis","year":"2013","journal-title":"Support Care Cancer Off J Multinatl Assoc Support Care 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Damage-associated Molecular Patterns","volume":"289","author":"L Schaefer","year":"2014","journal-title":"J Biol Chem"},{"key":"pone.0249343.ref007","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.canlet.2015.03.031","article-title":"Radiation takes its Toll","volume":"368","author":"JA Ratikan","year":"2015","journal-title":"Cancer Lett"},{"key":"pone.0249343.ref008","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1111\/j.1601-0825.2010.01681.x","article-title":"New thoughts on the initiation of mucositis","volume":"16","author":"ST Sonis","year":"2010","journal-title":"Oral Dis"},{"key":"pone.0249343.ref009","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s00066-017-1119-8","article-title":"Early inflammatory changes in radiation-induced oral mucositis","volume":"193","author":"S Gruber","year":"2017","journal-title":"Strahlenther Onkol"},{"key":"pone.0249343.ref010","doi-asserted-by":"crossref","DOI":"10.3390\/cancers11060857","article-title":"Mucosal Injury during Anti-Cancer Treatment: From Pathobiology to Bedside","volume":"11","author":"D Basile","year":"2019","journal-title":"Cancers"},{"key":"pone.0249343.ref011","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1093\/jrr\/rru040","article-title":"Ionizing radiation affects the expression of Toll-like receptors 2 and 4 in human monocytic cells through c-Jun N-terminal kinase activation","volume":"55","author":"H Yoshino","year":"2014","journal-title":"J Radiat Res (Tokyo)"},{"key":"pone.0249343.ref012","doi-asserted-by":"crossref","first-page":"e0215250","DOI":"10.1371\/journal.pone.0215250","article-title":"Radiation induces changes in toll-like receptors of the uterine cervix of the rat","volume":"14","author":"MF Mukanyangezi","year":"2019","journal-title":"PLOS 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Alkylated semi-synthetic glycosaminoglycosan ethers, and methods for making and using thereof. WO2009124266 A3, 2009. http:\/\/www.google.com.ar\/patents\/WO2009124266A3."},{"key":"pone.0249343.ref016","doi-asserted-by":"crossref","first-page":"e0204709","DOI":"10.1371\/journal.pone.0204709","article-title":"A synthetic glycosaminoglycan reduces sinonasal inflammation in a murine model of chronic rhinosinusitis","volume":"13","author":"JA Alt","year":"2018","journal-title":"PLOS ONE"},{"key":"pone.0249343.ref017","doi-asserted-by":"crossref","first-page":"5121","DOI":"10.1158\/1078-0432.CCR-05-0403","article-title":"Evaluation of Radiation-Induced Oral Mucositis by Optical Coherence Tomography","volume":"11","author":"TM Muanza","year":"2005","journal-title":"Clin Cancer Res"},{"key":"pone.0249343.ref018","doi-asserted-by":"crossref","first-page":"2574","DOI":"10.1016\/j.jspi.2007.10.015","article-title":"Nonparametric multiple comparison procedures for unbalanced one-way factorial designs","volume":"138","author":"X Gao","year":"2008","journal-title":"J Stat Plan 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canonical Wnt\/\u03b2-catenin pathway","volume":"106","author":"J Zhao","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0249343.ref022","first-page":"223","volume-title":"Digestive System","author":"CH Frith","year":"1997"},{"key":"pone.0249343.ref023","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.canlet.2015.03.031","article-title":"Radiation takes its Toll","volume":"368","author":"JA Ratikan","year":"2015","journal-title":"Cancer Lett"},{"key":"pone.0249343.ref024","first-page":"5767","article-title":"Gene expressions of Toll-like receptor 2, but not Toll-like receptor 4, is induced by LPS and inflammatory cytokines in mouse macrophages","volume":"165","author":"T Matsuguchi","year":"2000","journal-title":"J Immunol Baltim Md 1950"},{"key":"pone.0249343.ref025","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1089\/10799900050163299","article-title":"Endotoxin and Cytokine Regulation of Toll-like Receptor (TLR) 2 and TLR4 Gene Expression in Murine Liver and Hepatocytes","volume":"20","author":"T Matsumura","year":"2000","journal-title":"J Interferon Cytokine Res"},{"key":"pone.0249343.ref026","doi-asserted-by":"crossref","first-page":"3948","DOI":"10.1158\/0008-5472.CAN-11-4134","article-title":"The Human TLR Innate Immune Gene Family Is Differentially Influenced by DNA Stress and p53 Status in Cancer Cells","volume":"72","author":"M Shatz","year":"2012","journal-title":"Cancer Res"},{"key":"pone.0249343.ref027","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1113\/expphysiol.2012.068338","article-title":"The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through interleukin-1\u03b2","volume":"98","author":"NA Bracey","year":"2013","journal-title":"Exp Physiol"},{"key":"pone.0249343.ref028","doi-asserted-by":"crossref","DOI":"10.1155\/2014\/847827","article-title":"Activation of Toll-Like Receptors and Inflammasome Complexes in the Diabetic Cardiomyopathy-Associated 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Res (Tokyo)"},{"key":"pone.0249343.ref032","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ijrobp.2018.01.035","article-title":"Protective Effects of Flagellin A N\/C Against Radiation-Induced NLR Pyrin Domain Containing 3 Inflammasome-Dependent Pyroptosis in Intestinal Cells","volume":"101","author":"D Wu","year":"2018","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"pone.0249343.ref033","doi-asserted-by":"crossref","first-page":"e0174474","DOI":"10.1371\/journal.pone.0174474","article-title":"Melatonin protects rats from radiotherapy-induced small intestine toxicity","volume":"12","author":"B Fern\u00e1ndez-Gil","year":"2017","journal-title":"PLOS ONE"},{"key":"pone.0249343.ref034","doi-asserted-by":"crossref","first-page":"E613","DOI":"10.1016\/j.ijrobp.2017.06.2078","article-title":"Radiation Induces IL-1b Production and Promotes Activation of NLRP3 Inflammasome","volume":"99","author":"MS Perrone","year":"2017","journal-title":"Int J Radiat Oncol \u2022 Biol \u2022 Phys"},{"key":"pone.0249343.ref035","doi-asserted-by":"crossref","first-page":"e2579","DOI":"10.1038\/cddis.2016.460","article-title":"NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages","volume":"8","author":"Y Liu","year":"2017","journal-title":"Cell Death Dis"},{"key":"pone.0249343.ref036","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/imr.12534","article-title":"Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases","volume":"277","author":"SM Man","year":"2017","journal-title":"Immunol Rev"},{"key":"pone.0249343.ref037","first-page":"20","article-title":"LGM2605 Reduces Space Radiation-Induced NLRP3 Inflammasome Activation and Damage in In Vitro Lung Vascular Networks","author":"S Chatterjee","year":"2019","journal-title":"Int J Mol Sci"},{"key":"pone.0249343.ref038","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1158\/1541-7786.MCR-07-2131","article-title":"Effects of Palifermin on Antitumor Activity of Chemotherapeutic and Biological Agents in Human Head and Neck and Colorectal Carcinoma Xenograft Models","volume":"6","author":"R Brake","year":"2008","journal-title":"Mol Cancer Res"},{"key":"pone.0249343.ref039","article-title":"A Novel Peptide for Simultaneously Enhanced Treatment of Head and Neck Cancer and Mitigation of Oral Mucositis","volume":"11","author":"P Chen","year":"2016","journal-title":"PLoS ONE"},{"key":"pone.0249343.ref040","doi-asserted-by":"crossref","DOI":"10.3390\/ijms20081963","article-title":"Glycosaminoglycans and Glycosaminoglycan Mimetics in Cancer and Inflammation","volume":"20","author":"S Morla","year":"2019","journal-title":"Int J Mol 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