{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:09:00Z","timestamp":1792130940700,"version":"4.4.0"},"reference-count":101,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2018,7,13]],"date-time":"2018-07-13T00:00:00Z","timestamp":1531440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Melatonin is a tryptophan-derived molecule with pleiotropic activities which is produced in all living organisms. This \u201csleep\u201d hormone is a free radical scavenger, which activates several anti-oxidative enzymes and mechanisms. Melatonin, a highly lipophilic hormone, can reach body target cells rapidly, acting as the circadian signal to alter numerous physiological functions in the body. This indoleamine can protect the organs against a variety of damaging agents via multiple signaling. This review focused on the role played by melatonin in the mechanism of esophagoprotection, starting with its short-term protection against acute reflux esophagitis and then investigating the long-term prevention of chronic inflammation that leads to gastroesophageal reflux disease (GERD) and Barrett\u2019s esophagus. Since both of these condition are also identified as major risk factors for esophageal carcinoma, we provide some experimental and clinical evidence that supplementation therapy with melatonin could be useful in esophageal injury by protecting various animal models and patients with GERD from erosions, Barrett\u2019s esophagus and neoplasia. The physiological aspects of the synthesis and release of this indoleamine in the gut, including its release into portal circulation and liver uptake is examined. The beneficial influence of melatonin in preventing esophageal injury from acid-pepsin and acid-pepsin-bile exposure in animals as well as the usefulness of melatonin and its precursor, L-tryptophan in prophylactic and supplementary therapy against esophageal disorders in humans, are also discussed.<\/jats:p>","DOI":"10.3390\/ijms19072033","type":"journal-article","created":{"date-parts":[[2018,7,16]],"date-time":"2018-07-16T04:05:33Z","timestamp":1531713933000},"page":"2033","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Melatonin in Prevention of the Sequence from Reflux Esophagitis to Barrett\u2019s Esophagus and Esophageal Adenocarcinoma: Experimental and Clinical Perspectives"],"prefix":"10.3390","volume":"19","author":[{"given":"Jolanta","family":"Majka","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateusz","family":"Wierdak","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwona","family":"Brzozowska","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Jagiellonian University Medical College, 33-332 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0175-5600","authenticated-orcid":false,"given":"Marcin","family":"Magierowski","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Szlachcic","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmara","family":"Wojcik","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Slawomir","family":"Kwiecien","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Magierowska","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek","family":"Zagajewski","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, 31-034 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5805-0065","authenticated-orcid":false,"given":"Tomasz","family":"Brzozowski","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1136\/gut.2004.051821","article-title":"Epidemiology of gastroesophageal reflux disease: A systemic review","volume":"54","author":"Dent","year":"2005","journal-title":"Gut"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.cgh.2006.09.016","article-title":"Time trends of gastroesophageal reflux disease: A systemic review","volume":"5","year":"2007","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.bpg.2010.09.009","article-title":"Disease definition, clinical manifestations, epidemiology and natural history of GERD","volume":"24","author":"Vakil","year":"2010","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/j.1365-2036.2007.03372.x","article-title":"Review article: The pathophysiology of gastro-esophageal reflux disease","volume":"26","author":"Boeckxstaens","year":"2007","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1111\/nmo.12201","article-title":"Pathophysiology of gastro-esophageal reflux disease: A role for mucosa integrity?","volume":"25","author":"Farre","year":"2013","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.bpg.2010.08.008","article-title":"The integrity of the esophageal mucosa. Balance between offensive and defensive mechanisms","volume":"24","author":"Orlando","year":"2010","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s10620-006-3129-8","article-title":"Essential role of pepsin in pathogenesis of acid reflux esophagitis in rats","volume":"51","author":"Nagahama","year":"2006","journal-title":"Dig. Dis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"532594","DOI":"10.1155\/2014\/532594","article-title":"Animal model of acid-reflux esophagitis: Pathogenic roles of acid\/pepsin, prostaglandins, and amino acids","volume":"2014","author":"Takeuchi","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_9","first-page":"295","article-title":"New insight into oseophageal injury and protection in physiologically relevant animal models","volume":"65","author":"Zayachkivska","year":"2014","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1007\/s00535-005-1742-5","article-title":"Role of pancreatic trypsin in chronic esophagitis induced by gastroduodenal reflux in rats","volume":"41","author":"Naito","year":"2006","journal-title":"J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1007\/BF01315148","article-title":"Pill-induced esophageal injury: Case reports and review of medical literature","volume":"28","author":"Kikendall","year":"1983","journal-title":"Dig. Dis. Sci."},{"key":"ref_12","first-page":"431","article-title":"The effect of cigarette smoking on salivation and esophageal acid clearance in clinical esophagitis","volume":"114","author":"Kahrilas","year":"1989","journal-title":"J. Lab. Clin. Med."},{"key":"ref_13","first-page":"335","article-title":"Effect of aspirin, alcohol, and pepsin on mucosal permeability of esophageal mucosa","volume":"25","author":"Zike","year":"1974","journal-title":"Surg. Forum"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1136\/bmj.285.6336.167","article-title":"Non-steroidal anti-inflammatory drugs and benign oesophageal stricture","volume":"285","author":"Heller","year":"1982","journal-title":"Br. Med. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1097\/00004836-199112000-00005","article-title":"Significant role of aspirin use in patients with esophagitis","volume":"13","author":"Lanas","year":"1991","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_16","first-page":"75","article-title":"Nitric oxide (NO)-releasing aspirin exhibits a potent esophagoprotection in experimental model of acute reflux esophagitis. Role of nitric oxide and proinflammatory cytokines","volume":"62","author":"Pawlik","year":"2011","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1046\/j.1572-0241.2003.04018.x","article-title":"Dilated intercellular spaces and shunt permeability in non-erosive acid-damaged esophageal epithelium","volume":"9","author":"Tobey","year":"2004","journal-title":"Am. J. Gastroenterol."},{"key":"ref_18","first-page":"G736","article-title":"HCO3\u2212 secretion in the esophageal submucosal glands","volume":"288","author":"Nakhoul","year":"2006","journal-title":"Am. J. Physiol."},{"key":"ref_19","first-page":"G665","article-title":"Roles of epidermal growth factor and Na+\/H+ exchanger-1 in esophageal epithelial defense against acid-induced injury","volume":"290","author":"Fujiwara","year":"2006","journal-title":"Am. J. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/4-431-27174-0_10","article-title":"Gastroduodenal microcirculatory response to luminal acid","volume":"Volume 13","author":"Ishii","year":"2005","journal-title":"Organ Microcirculation. A Gateway to Diagnostic and Therapeutic Interventions. Series: Keio University International Symposia for Life Sciences and Medicine"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/4-431-27174-0_7","article-title":"Esophageal and gastrointestinal microcirculation: Essential for mucosal protection, a target for injury, and critical component of injury and ulcer healing","volume":"Volume 13","author":"Ishii","year":"2005","journal-title":"Organ Microcirculation. A Gateway to Diagnostic and Therapeutic Interventions. Series: Keito University International Symposia for Life Sciences and Medicine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/0016-5085(86)91116-9","article-title":"Esophageal blood flow in the cat. Normal distribution and effects of acid perfusion","volume":"90","author":"Hollwarth","year":"1986","journal-title":"Gastroenterology"},{"key":"ref_23","first-page":"404","article-title":"H+ back diffusion interferes with intrinsic reactive regulation of esophageal mucosal blood flow","volume":"96","author":"Bass","year":"1984","journal-title":"Surgery"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1080\/00365520310005181","article-title":"Microcirculatory changes in the canine oesophageal mucosa during experimental reflux oesophagitis: Comparison of the effects of acid and bile","volume":"38","author":"Szentpali","year":"2003","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/j.1440-1746.2007.05113.x","article-title":"Increased esophageal mucosal\/submucosal blood flow in patients with gastroesophageal reflux disease: Normalization by treatmentwith proton pump inhibitor","volume":"23","author":"Mine","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_26","first-page":"409","article-title":"Esophageal blood flow: A central role for calcitonin gene related peptide","volume":"116","author":"McKie","year":"1994","journal-title":"Surgery"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.coph.2007.09.004","article-title":"Role of visceral afferent neurons in mucosal inflammation","volume":"7","author":"Holzer","year":"2007","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_28","first-page":"419","article-title":"Capsaicin sensitive nerves mediate esophageal mucosal protection","volume":"110","author":"Bass","year":"1991","journal-title":"Surgery"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1111\/jpi.12048","article-title":"Esophagoprotection mediated by exogenous and endogenous melatonin in an experimental model of reflux esophagitis","volume":"55","author":"Konturek","year":"2013","journal-title":"J. Pineal Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3109\/00365528909091112","article-title":"Healing process of experimental esophageal ulcers induced by acetic acid in rats","volume":"24","author":"Tsuji","year":"1989","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.1111\/j.1440-1746.1994.tb01304.x","article-title":"Validity of kissing gastric ulcers induced in rats for screening of antiulcer drugs","volume":"9","author":"Tsukimi","year":"1994","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_32","first-page":"948","article-title":"Establishment of surgically induced chronic acid reflux esophagitis in rats","volume":"10","author":"Omura","year":"1999","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/01.sla.0000130850.31178.8c","article-title":"Impact of the biliary diversion procedure on carcinogenesis in Barrett\u2019s esophagus surgically induced by duodenoesophageal reflux in rats","volume":"240","author":"Nishijima","year":"2004","journal-title":"Ann. Surg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3346\/jkms.2005.20.1.56","article-title":"Expression of inducible nitric oxide synthase is increased in rat Barrett\u2019s esophagus induced by duodenal contents reflux","volume":"20","author":"Bae","year":"2005","journal-title":"J. Korean Med. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jss.2005.04.018","article-title":"Esophageal injury with external esophageal perfusion","volume":"129","author":"Li","year":"2005","journal-title":"J. Surg. Res."},{"key":"ref_36","first-page":"2","article-title":"The changing epidemiology of esophageal cancer","volume":"26","author":"Blot","year":"1999","journal-title":"Semin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1056\/NEJM197608262950904","article-title":"The histologic spectrum of Barrett\u2019s esophagus","volume":"295","author":"Paull","year":"1976","journal-title":"N. Engl. J. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1001\/jama.287.15.1972","article-title":"Gastroesophageal reflux, Barrett esophagus and esophageal cancer: Scientific review","volume":"287","author":"Shaheen","year":"2002","journal-title":"JAMA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/ajcp\/87.3.301","article-title":"The relationship between columnar epithelial dysplasia and invasive adenocarcinoma arising in Barrett\u2019s esophagus","volume":"87","author":"Hamilton","year":"1987","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/ajcp\/70.1.1","article-title":"Adenocarcinoma complicating columnar epithelium-lined (Barrett\u2019s) esophagus","volume":"70","author":"Haggitt","year":"1978","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1056\/NEJM199903183401101","article-title":"Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma","volume":"340","author":"Lagergren","year":"1999","journal-title":"N. Engl. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/j.1749-6632.2011.06064.x","article-title":"Esophageal disease: Updated information on inflammation","volume":"1232","author":"Orlando","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6523","DOI":"10.3748\/wjg.v19.i39.6523","article-title":"Gastroesophageal reflux disease: Update on inflammation and symptom perception","volume":"19","author":"Altomare","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1053\/gast.2002.30993","article-title":"Acid exposure activates the mitogen-activated protein kinase pathways in Barrett\u2019s esophagus","volume":"122","author":"Souza","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s11605-006-0006-x","article-title":"Duodenogastric reflux potentiate the injurious effects of gastroesophageal reflux","volume":"1","author":"Fein","year":"1997","journal-title":"J. Gastrointest. Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1006\/abbi.1993.1496","article-title":"Prostaglandin G\/H synthase isoenzyme 2 expression in fibroblasts: Regulation by dexamethasone, mitogens and oncogenes","volume":"306","author":"Evett","year":"1993","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"G327","DOI":"10.1152\/ajpgi.00543.2001","article-title":"Acid-and bile-induced PGE2 release and hyperproliferation in Barrett\u2019s esophagus are COX-2 and PKC-epsilon dependent","volume":"283","author":"Kaur","year":"2002","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1053\/j.seminoncol.2004.03.040","article-title":"Multiple roles of COX-2 in tumor angiogenesis: A target for antiangiogenetic therapy","volume":"31","author":"Gately","year":"2004","journal-title":"Semin. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.gassur.2004.09.025","article-title":"Quantitative, tissue-specific analysis of cyclooxygenase gene expression in the pathogenesis of Barrett\u2019s adenocarcinoma","volume":"8","author":"Kuramochi","year":"2004","journal-title":"J. Gastrointest. Surg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/0092-8674(95)90127-2","article-title":"Alternations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin end peroxide synthase 2","volume":"83","author":"Tsujii","year":"1995","journal-title":"Cell"},{"key":"ref_51","first-page":"198","article-title":"Cyclooxygenase-2 expression in human esophageal carcinoma","volume":"59","author":"Zimmermann","year":"1999","journal-title":"Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0306-9877(97)90285-1","article-title":"Deleterious effects of prostaglandin E2 in esophageal carcinogenesis","volume":"48","author":"Morgan","year":"1997","journal-title":"Med. Hypotheses"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1002\/1097-0142(19951001)76:7<1116::AID-CNCR2820760703>3.0.CO;2-I","article-title":"Aspirin and reduced risk of esophageal carcinoma","volume":"76","author":"Funkhouser","year":"1995","journal-title":"Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1111\/j.1572-0241.1998.00324.x","article-title":"Short segment Barrett\u2019s esophagus\u2014The need for standardization of the definition and of endoscopic criteria","volume":"93","author":"Sharma","year":"1998","journal-title":"Am. J. Gastroenterol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1097\/00042737-200311000-00011","article-title":"Characteristics and regional variations of patients with Barrett\u2019s oesophagus in the UK","volume":"15","author":"Caygill","year":"2003","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1016\/0016-5085(95)90642-8","article-title":"Adenocarcinoma of the esophagogastric junction and Barrett\u2019s esophagus","volume":"109","author":"Cameron","year":"1995","journal-title":"Gastroenterology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S1052-5157(03)00006-0","article-title":"Biomarkers in Barrett\u2019s esophagus","volume":"13","author":"Reid","year":"2003","journal-title":"Gastrointest. Endosc. Clin. N. Am."},{"key":"ref_58","first-page":"119","article-title":"Quality of life of patients with gastroesophageal reflux disease after laparoscopic Nissen fundoplication","volume":"3","author":"Migaczewski","year":"2008","journal-title":"Videosurg. Miniinvasive Tech."},{"key":"ref_59","first-page":"102","article-title":"Argon plasma coagulation (APC) for treatment of Barrett\u2019s oesophagus","volume":"4","author":"Migaczewski","year":"2009","journal-title":"Videosurg. Miniinvasive Tech."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1146\/annurev.med.48.1.253","article-title":"Circadian rhythms: Basic neurobiology and clinical applications","volume":"48","author":"Moore","year":"1997","journal-title":"Annu. Rev. Med."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"De Masi, L., Castaldo, D., Pignone, D., and Servillo, L. (2017). Facchiano A. Experimental evidence and in silico identification of tryptophan decarboxylase in citrus genus. Molecules, 22.","DOI":"10.3390\/molecules22020272"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Zhao, D., Wang, R., Liu, D., Wu, Y., Sun, J., and Tao, J. (2018). Melatonin and expression of tryptophan decarboxylase Gene (TDC) in Herbaceous Peony (Paeonia lactiflora Pall.) Flowers. Molecules, 23.","DOI":"10.3390\/molecules23051164"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1007\/BF01953049","article-title":"Melatonin biosynthesis in the mammalian pineal gland","volume":"45","author":"Sudgen","year":"1989","journal-title":"Experientia"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0065-1281(76)80092-X","article-title":"Melatonin and enterochromaffine cells","volume":"55","author":"Raikhlin","year":"1976","journal-title":"Acta Histochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1159\/000109491","article-title":"Melatonin and its receptors in the gastrointestinal tract","volume":"2","author":"Lee","year":"1993","journal-title":"Biol. Signals"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/j.1600-079X.1996.tb00294.x","article-title":"Melatonin concentrations in serum and tissues of porcine gastrointestinal tract and their relationship to the intake and passage of food","volume":"21","author":"Bubenik","year":"1996","journal-title":"J. Pineal Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1034\/j.1600-079x.2000.280102.x","article-title":"Circadian variation of portent arterial and venous blood levels of melatonin in pigs and its relationship to food intake and sleep","volume":"28","author":"Bubenik","year":"2000","journal-title":"J. Pineal Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/0024-3205(92)90402-B","article-title":"Effect of tryptophan administration on circulating melatonin levels in chicks and rats: Evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract","volume":"51","author":"Huether","year":"1992","journal-title":"Life Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/BF02433372","article-title":"Extrapineal melatonin and its role in neuroendocrine regulation of homeostasis","volume":"127","author":"Kvetnoy","year":"1999","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1267\/ahc.11.75","article-title":"Immunomorphological studies on synthesis of melatonin in enterochromaffine cells","volume":"11","author":"Raikhlin","year":"1978","journal-title":"Acta Histochem. Cytochem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/S0024-3205(01)01143-2","article-title":"Presence of melatonin in the human hepatobiliary-gastrointestinal tract","volume":"69","author":"Messner","year":"2001","journal-title":"Life Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1124\/dmd.104.002410","article-title":"Metabolism of melatonin by human cytochromes p450","volume":"33","author":"Ma","year":"2005","journal-title":"Drug Metab. Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1111\/j.1742-4658.2006.05322.x","article-title":"Melatonin nature\u2019s most versatile biological signal?","volume":"273","author":"Srinivasan","year":"2006","journal-title":"FEBS J."},{"key":"ref_74","unstructured":"Pandi-Perumal, S.R., and Cardinali, D.P. (2006). Therapeutic perspectives of gastrointestinal melatonin. The Melatonin: From Molecules to Therapy, Nova Science Publishers Inc."},{"key":"ref_75","first-page":"381","article-title":"Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT)","volume":"58","author":"Konturek","year":"2007","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1600-079X.1997.tb00328.x","article-title":"Autoradiographic localization of 2[125I]iodomelatonin binding sites in the gastrointestinal tract of mammals including humans and birds","volume":"23","author":"Poon","year":"1997","journal-title":"J. Pineal Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/j.1600-079X.1999.tb00567.x","article-title":"Melatonin concentrations in the luminal fluid, mucosa and muscularis of the bovine and porcine gastrointestinal tract","volume":"29","author":"Bubenik","year":"1999","journal-title":"J. Pineal Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"4807","DOI":"10.2174\/1381612819666131119110258","article-title":"Mechanisms of esophageal protection, gastroprotection and ulcer healing by melatonin. Implications for the therapeutic use of melatonin in gastroesophageal reflux disease (GERD) and peptic ulcer disease","volume":"20","author":"Brzozowska","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1600-079X.2006.00359.x","article-title":"Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and amino acids: Comparison with omeprazole","volume":"41","year":"2006","journal-title":"J. Pineal Res."},{"key":"ref_80","first-page":"116","article-title":"Gastroesophageal reflux disease (GERD): A review of conventional and alternative treatments","volume":"16","author":"Patrick","year":"2011","journal-title":"Altern. Med. Rev."},{"key":"ref_81","first-page":"371","article-title":"Protective influence of melatonin against acute esophageal lesions involves prostaglandins, nitric oxide and sensory nerves","volume":"58","author":"Konturek","year":"2007","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1159\/000075698","article-title":"Increased expression of cytokines and adhesion molecules in rat chronic esophagitis","volume":"68","author":"Hamaguchi","year":"2003","journal-title":"Digestion"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S0016-5085(00)70135-1","article-title":"Long-term omeprazole treatment in resistant gastroesophageal reflux disease. Efficacy, safety, and influence on gastric mucosa","volume":"118","author":"Nelis","year":"2000","journal-title":"Gastroenterology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"4784","DOI":"10.1158\/1078-0432.CCR-04-0015","article-title":"Gastrin induced cyclooxygenase-2 expression in Barrett\u2019s carcinogenesis","volume":"10","author":"Abdalla","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.bpg.2010.08.011","article-title":"Alterations confined to the gastro-oesophageal junction: The relationship between low LOSP, TLOSRs, hiatus hernia and acid pocket","volume":"24","author":"Boeckxstaens","year":"2010","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1159\/000369656","article-title":"Melatonin protects the esophageal epithelial barrier by suppressing the transcription, expression and activity of myosin light chain kinase through ERK1\/2 signal transduction","volume":"34","author":"Tan","year":"2014","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_87","first-page":"13","article-title":"Melatonin and aging: Prospects for human treatment","volume":"62","author":"Bubenik","year":"2011","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"50","DOI":"10.4292\/wjgpt.v2.i6.50","article-title":"Does a melatonin supplement alter the course of gastro-esophageal reflux disease?","volume":"2","author":"Madalinski","year":"2011","journal-title":"World J. Gastrointest. Pharmacol. Ther."},{"key":"ref_89","first-page":"41","article-title":"Nocturnal secretion of melatonin in patients with upper digestive tract disorders","volume":"57","author":"Klupinska","year":"2006","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/0-306-46814-X_51","article-title":"Melatonin as a marker and phase-resetter of circadian rhythms in humans","volume":"460","author":"Lewy","year":"1999","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_91","first-page":"1","article-title":"Melatonin for treatment of sleep disorders","volume":"108","author":"Buscemi","year":"2004","journal-title":"Evid. Rep. Technol. Assess. (Summ.)"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/S0140-6736(05)64715-0","article-title":"Melatonin and fragmented sleep patterns","volume":"348","author":"Middleton","year":"1996","journal-title":"Lancet"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/j.1600-079X.1998.tb00385.x","article-title":"Effect of day time oral melatonin administration on neurobehavioral performance in humans","volume":"25","author":"Rogers","year":"1998","journal-title":"J. Pineal Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1034\/k.1600-079X.2002.01881.x","article-title":"Melatonin triggers Crohn\u2019s disease symptoms","volume":"32","author":"Calvo","year":"2002","journal-title":"J. Pineal Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1007\/s00018-014-1579-2","article-title":"Extrapineal melatonin: Sources, regulation, and potential functions","volume":"71","author":"Escames","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1136\/gut.46.2.144","article-title":"Proton pomp inhibitors for Barrett\u2019s oesophagus","volume":"46","author":"Triadafilopoulos","year":"2000","journal-title":"Gut"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1053\/gast.2003.50091","article-title":"Gastrin induces proliferation in Barrett\u2019s metaplasia through activation of the CCK2 receptor","volume":"124","author":"Haigh","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/S0016-5085(99)70231-3","article-title":"Gastrin induces heparin-binding epidermal growth factor-like growth factor in rat gastric epithelial cells transfected with gastrin receptor","volume":"116","author":"Miyazaki","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"S105","DOI":"10.1097\/00004836-199700001-00018","article-title":"Expression of the cyclooxygenase-2 gene in gastric epithelium","volume":"25","author":"Sawaoka","year":"1997","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1054\/plef.1999.0106","article-title":"Involvement of cyclooxygenase-2 in proliferation and morphogenesis induced by transforming growth factor alpha in gastric epithelial cells","volume":"61","author":"Sawaoka","year":"1999","journal-title":"Prostaglandins Leukot. Essent. Fatty Acids"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Rybak, A., Pesce, M., Thapar, N., and Borrelli, O. (2017). Gastro-esophageal reflux in children. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081671"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/7\/2033\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:11:55Z","timestamp":1760195515000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/7\/2033"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,13]]},"references-count":101,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2018,7]]}},"alternative-id":["ijms19072033"],"URL":"https:\/\/doi.org\/10.3390\/ijms19072033","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,13]]}}}