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The purpose of this study was to analyze the molecular pathways involved in the development of oral mucositis and to evaluate whether melatonin can prevent this pathology. The tongue of male Wistar rats was subjected to irradiation (<jats:styled-content style=\"fixed-case\">X<\/jats:styled-content>\u2010ray <jats:styled-content style=\"fixed-case\">YXLON<\/jats:styled-content> Y.Tu 320\u2010D03 irradiator; the animals received a dose of 7.5\u00a0Gy\/day for 5\u00a0days). Rats were treated with 45\u00a0mg\/day melatonin or vehicle for 21\u00a0days postirradiation, either by local application into their mouths (melatonin gel) or by subcutaneous injection. A connection between reactive oxygen species, generating mitochondria and the <jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3 (<jats:styled-content style=\"fixed-case\">NLR<\/jats:styled-content>\u2010related protein 3 nucleotide\u2010binding domain leucine\u2010rich repeat containing receptor\u2010related protein 3) inflammasome, has been reported in mucositis. Here, we show that mitochondrial oxidative stress, bioenergetic impairment and subsequent <jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3 inflammasome activation are involved in the development of oral mucositis after irradiation and that melatonin synthesized in the rat tongue is depleted after irradiation. The application of melatonin gel restores physiological melatonin levels in the tongue and prevents mucosal disruption and ulcer formation. Melatonin gel protects the mitochondria from radiation damage and blunts the <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010<jats:italic>\u03ba<\/jats:italic>B\/<jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3 inflammasome signaling activation in the tongue. Our results suggest new molecular pathways involved in radiotherapy\u2010induced mucositis that are inhibited by topical melatonin application, suggesting a potential preventive therapy for mucositis in patients with cancer.<\/jats:p>","DOI":"10.1111\/jpi.12191","type":"journal-article","created":{"date-parts":[[2014,11,11]],"date-time":"2014-11-11T09:06:37Z","timestamp":1415696797000},"page":"34-49","source":"Crossref","is-referenced-by-count":138,"title":["Melatonin blunts the mitochondrial\/<scp>NLRP<\/scp>3 connection and protects against radiation\u2010induced oral mucositis"],"prefix":"10.1111","volume":"58","author":[{"given":"Francisco","family":"Ortiz","sequence":"first","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica Parque Tecnol\u00f3gico de Ciencias de la Salud Universidad de Granada, and RETICEF Granada 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