{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T04:15:04Z","timestamp":1793074504909,"version":"4.5.0"},"reference-count":97,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T00:00:00Z","timestamp":1636502400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"S\u00e3o Paulo Research Foundation (FAPESP)","award":["2019\/03348-4"],"award-info":[{"award-number":["2019\/03348-4"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Melatonin is a highly conserved molecule found in prokaryotes and eukaryotes that acts as the darkness hormone, translating environmental lighting to the whole body, and as a moderator of innate and acquired defense, migration, and cell proliferation processes. This review evaluates the importance of pineal activity in monitoring PAMPs and DAMPs and in mounting an inflammatory response or innate immune response. Activation of the immune\u2013pineal axis, which coordinates the pro-and anti-inflammatory phases of an innate immune response, is described. PAMPs and DAMPs promote the immediate suppression of melatonin production by the pineal gland, which allows leukocyte migration. Monocyte-derived macrophages, important phagocytes of microbes, and cellular debris produce melatonin locally and thereby initiate the anti-inflammatory phase of the acute inflammatory response. The role of locally produced melatonin in organs that directly contact the external environment, such as the skin and the gastrointestinal and respiratory tracts, is also discussed. In this context, as resident macrophages are self-renewing cells, we explore evidence indicating that, besides avoiding overreaction of the immune system, extra-pineal melatonin has a fundamental role in the homeostasis of organs and tissues.<\/jats:p>","DOI":"10.3390\/ijms222212143","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T21:39:07Z","timestamp":1636493947000},"page":"12143","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Possible Role of Pineal and Extra-Pineal Melatonin in Surveillance, Immunity, and First-Line Defense"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4606-6120","authenticated-orcid":false,"given":"Regina P.","family":"Markus","sequence":"first","affiliation":[{"name":"Laboratory Chronopharmacology, Department Physiology, Institute Bioscience, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kassiano S.","family":"Sousa","sequence":"additional","affiliation":[{"name":"Laboratory Chronopharmacology, Department Physiology, Institute Bioscience, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanseray","family":"da Silveira Cruz-Machado","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular, Endocrine and Reproductive Pharmacology, Department of Pharmacology, Escola Paulista de Medicina, UNIFESP, S\u00e3o Paulo 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro A.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Laboratory Chronopharmacology, Department Physiology, Institute Bioscience, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6571-837X","authenticated-orcid":false,"given":"Zulma S.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Laboratory Chronopharmacology, Department Physiology, Institute Bioscience, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-090, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Cannon, W.B. (1915). Bodily Changes in Pain, Hunger, Fear and Rage: An Account of Recent Researches into the Function of Emotional Excitement, D Appleton & Company.","DOI":"10.1037\/10013-000"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/j.1600-079X.1997.tb00338.x","article-title":"Circadian Rhythm in Experimental Granulomatous Inflammation Is Modulated by Melatonin","volume":"23","author":"Lopes","year":"1997","journal-title":"J. Pineal Res."},{"key":"ref_3","unstructured":"Brown, J.W., and Churchill, R.V. (2012). Fourier Series and Boundary Value Problems, McGraw-Hill. [8th ed.]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0014-2999(01)01369-3","article-title":"Melatonin and N-Acetylserotonin Inhibit Leukocyte Rolling and Adhesion to Rat Microcirculation","volume":"430","author":"Lotufo","year":"2001","journal-title":"Eur. J. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.1111\/bph.14083","article-title":"Immune-Pineal Axis\u2014Acute Inflammatory Responses Coordinate Melatonin Synthesis by Pinealocytes and Phagocytes","volume":"175","author":"Markus","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S1054-3589(08)60981-3","article-title":"Antioxidant Actions of Melatonin","volume":"Volume 38","author":"Reiter","year":"1996","journal-title":"Advances in Pharmacology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1159\/000014636","article-title":"Pharmacology and Physiology of Melatonin in the Reduction of Oxidative Stress In Vivo","volume":"9","author":"Reiter","year":"2000","journal-title":"Biol. Signals Recept."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/s10517-006-0177-1","article-title":"Role of the Hypothalamic Suprachiasmatic Nucleus in the Effect of Melatonin on the Thymus, Adrenal Glands, and Spleen in Rats","volume":"141","author":"Pertsov","year":"2006","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s000110050717","article-title":"Interaction between the Adrenal and the Pineal Gland in Chronic Experimental Inflammation Induced by BCG in Mice","volume":"50","author":"Lopes","year":"2001","journal-title":"Inflamm. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8638","DOI":"10.3390\/ijms14048638","article-title":"Melatonin: Buffering the Immune System","volume":"14","author":"Lardone","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3187","DOI":"10.1111\/bph.14371","article-title":"Recent Developments in Research of Melatonin and Its Potential Therapeutic Applications","volume":"175","author":"Stanford","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1111\/j.1600-079X.2006.00373.x","article-title":"Effect of TNF-Alpha on the Melatonin Synthetic Pathway in the Rat Pineal Gland: Basis for a \u201cfeedback\u201d of the Immune Response on Circadian Timing","volume":"41","author":"Fernandes","year":"2006","journal-title":"J. Pineal Res."},{"key":"ref_13","first-page":"183","article-title":"TLR4 and CD14 Receptors Expressed in Rat Pineal Gland Trigger NFKB Pathway","volume":"49","author":"Tamura","year":"2010","journal-title":"J. Pineal Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Da Silveira Cruz-Machado, S., Pinato, L., Tamura, E.K., Carvalho-Sousa, C.E., and Markus, R.P. (2012). Glia-Pinealocyte Network: The Paracrine Modulation of Melatonin Synthesis by Tumor Necrosis Factor (TNF). PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040142"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1159\/000110635","article-title":"The Immune-Pineal Axis: A Shuttle between Endocrine and Paracrine Melatonin Sources","volume":"14","author":"Markus","year":"2007","journal-title":"Neuroimmunomodulation"},{"key":"ref_16","first-page":"10","article-title":"Molecular Basis for Defining the Pineal Gland and Pinealocytes as Targets for Tumor Necrosis Factor","volume":"2","author":"Tamura","year":"2011","journal-title":"Front. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1038\/s41598-017-02286-y","article-title":"Daily Corticosterone Rhythm Modulates Pineal Function through NF\u03baB-Related Gene Transcriptional Program","volume":"7","author":"Tamura","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.1600-079X.2004.00170.x","article-title":"Reactive Changes of Interstitial Glia and Pinealocytes in the Rat Pineal Gland Challenged with Cell Wall Components from Gram-Positive and -Negative Bacteria","volume":"38","author":"Wu","year":"2005","journal-title":"J. Pineal Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s15010-003-4038-9","article-title":"Reduction of Serum Melatonin Levelsin HIV-1-Infected Individuals\u2019 Parallel Disease Progression:Correlation with Serum Interleukin-12 Levels","volume":"31","author":"Nunnari","year":"2003","journal-title":"Infection"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2566","DOI":"10.1096\/fj.14-265678","article-title":"Amyloid \u03b2 Peptide Directly Impairs Pineal Gland Melatonin Synthesis and Melatonin Receptor Signaling through the ERK Pathway","volume":"29","author":"Cecon","year":"2015","journal-title":"FASEB J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1007\/s00429-013-0686-4","article-title":"Selective Protection of the Cerebellum against Intracerebroventricular LPS Is Mediated by Local Melatonin Synthesis","volume":"220","author":"Pinato","year":"2015","journal-title":"Brain Struct. Funct."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e12636","DOI":"10.1111\/jpi.12636","article-title":"Immune-Pineal Axis Protects Rat Lungs Exposed to Polluted Air","volume":"68","author":"Pereira","year":"2020","journal-title":"J. Pineal Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1111\/ppl.13307","article-title":"Mechanistic Insights on Melatonin-mediated Drought Stress Mitigation in Plants","volume":"172","author":"Tiwari","year":"2021","journal-title":"Physiol. Plant."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/jpi.12336","article-title":"On the Significance of an Alternate Pathway of Melatonin Synthesis via 5-Methoxytryptamine: Comparisons across Species","volume":"61","author":"Tan","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10407","DOI":"10.1021\/bi801189d","article-title":"Analysis of Serotonin N -Acetyltransferase Regulation in Vitro and in Live Cells Using Protein Semisynthesis","volume":"47","author":"Szewczuk","year":"2008","journal-title":"Biochemistry"},{"key":"ref_26","unstructured":"(2021, August 18). Mechanisms Regulating Melatonin Synthesis in the Mammalian Pineal Organ\u2014SCHOMERUS\u20142005\u2014Annals of the New York Academy of Sciences\u2014Wiley Online Library. Available online: https:\/\/nyaspubs.onlinelibrary.wiley.com\/doi\/abs\/10.1196\/annals.1356.028."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.pbb.2007.10.010","article-title":"Application of Long-Term Microdialysis in Circadian Rhythm Research","volume":"90","author":"Borjigin","year":"2008","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Bastos, P.R.O., Titon, S.C.M., Titon Junior, B., Gomes, F.R., Markus, R.P., and Ferreira, Z.S. (2021). Daily and LPS-Induced Variation of Endocrine Mediators in Cururu Toads (Rhinella icterica). Chronobiol. Int., 1\u20138.","DOI":"10.1080\/07420528.2021.1974470"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/j.1600-079X.2007.00487.x","article-title":"Pineal Melatonin and the Innate Immune Response: The TNF-Alpha Increase after Cesarean Section Suppresses Nocturnal Melatonin Production","volume":"43","author":"Pontes","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Pires-Lapa, M.A., Carvalho-Sousa, C.E., Cecon, E., Fernandes, P.A., and Markus, R.P. (2018). \u03b2-Adrenoceptors Trigger Melatonin Synthesis in Phagocytes. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082182"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1139\/y03-026","article-title":"Bidirectional Communication between the Pineal Gland and the Immune System","volume":"81","author":"Majewski","year":"2003","journal-title":"Can. J. Physiol Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ygcen.2012.08.013","article-title":"Pineal Arylalkylamine N-Acetyltransferase (Aanat) Gene Expression as a Target of Inflammatory Mediators in the Chicken","volume":"179","author":"Piesiewicz","year":"2012","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2589483","DOI":"10.1155\/2016\/2589483","article-title":"Central Interleukin-1\u03b2 Suppresses the Nocturnal Secretion of Melatonin","volume":"2016","author":"Herman","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"526464","DOI":"10.1155\/2015\/526464","article-title":"Interleukin-1 \u03b2 Modulates Melatonin Secretion in Ovine Pineal Gland: Ex Vivo Study","volume":"2015","author":"Herman","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/j.1600-079X.2006.00345.x","article-title":"Injury Switches Melatonin Production Source from Endocrine (Pineal) to Paracrine (Phagocytes)\u2014Melatonin in Human Colostrum and Colostrum Phagocytes","volume":"41","author":"Pontes","year":"2006","journal-title":"J. Pineal Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Da Silveira Cruz-Machado, S., Guissoni Campos, L.M., Fadini, C.C., Anderson, G., Markus, R.P., and Pinato, L. (2021). Disrupted Nocturnal Melatonin in Autism: Association with Tumor Necrosis Factor and Sleep Disturbances. J. Pineal Res., e12715.","DOI":"10.1111\/jpi.12715"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1111\/jpi.12066","article-title":"Melatonin Synthesis in Human Colostrum Mononuclear Cells Enhances Dectin-1-Mediated Phagocytosis by Mononuclear Cells","volume":"55","author":"Tamura","year":"2013","journal-title":"J. Pineal Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.mce.2009.04.010","article-title":"The Melatonin-Producing System Is Fully Functional in Retinal Pigment Epithelium (ARPE-19)","volume":"307","author":"Zmijewski","year":"2009","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"189","DOI":"10.32794\/mr11250090","article-title":"Melatonin-Index as a Biomarker for Predicting the Distribution of Presymptomatic and Asymptomatic SARS-CoV-2 Carriers","volume":"4","author":"Fernandes","year":"2021","journal-title":"Melatonin Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e12520","DOI":"10.1111\/jpi.12520","article-title":"Melatonin Modulates Autophagy and Inflammation Protecting Human Placental Trophoblast from Hypoxia\/Reoxygenation","volume":"65","author":"Ruano","year":"2018","journal-title":"J. Pineal Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/jpi.12293","article-title":"Melatonergic System-Based Two-Gene Index Is Prognostic in Human Gliomas","volume":"60","author":"Kinker","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e12557","DOI":"10.1111\/jpi.12557","article-title":"Pan-Cancer Genomic Analyses Reveal Prognostic and Immunogenic Features of the Tumor Melatonergic Microenvironment across 14 Solid Cancer Types","volume":"66","author":"Lv","year":"2019","journal-title":"J. Pineal Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1007\/s12020-018-1624-2","article-title":"Evaluation of Melatonin and AFMK Levels in Women with Breast Cancer","volume":"62","year":"2018","journal-title":"Endocrine"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1101\/gad.1228704","article-title":"Signaling to NF-KappaB","volume":"18","author":"Hayden","year":"2004","journal-title":"Genes Dev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"945","DOI":"10.2174\/138955706777934937","article-title":"Naturally Occurring NF-KappaB Inhibitors","volume":"6","author":"Nam","year":"2006","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.bbrc.2013.12.091","article-title":"Distal NF-KB Binding Motif Functions as an Enhancer for Nontypeable H. Influenzae-Induced DEFB4 Regulation in Epithelial Cells","volume":"443","author":"Woo","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e52010","DOI":"10.1371\/journal.pone.0052010","article-title":"NF-\u039aB Drives the Synthesis of Melatonin in RAW 264.7 Macrophages by Inducing the Transcription of the Arylalkylamine-N-Acetyltransferase (AA-NAT) Gene","volume":"7","author":"Muxel","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/BF00294615","article-title":"The Human Pineal Gland in Aging and Alzheimer\u2019s Disease: Patterns of Cytoskeletal Antigen Immunoreactivity","volume":"80","author":"Pardo","year":"1990","journal-title":"Acta Neuropathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1034\/j.1600-079X.2003.00065.x","article-title":"Early Neuropathological Alzheimer\u2019s Changes in Aged Individuals Are Accompanied by Decreased Cerebrospinal Fluid Melatonin Levels: AD Neuropathological Changes and Melatonin","volume":"35","author":"Zhou","year":"2003","journal-title":"J. Pineal Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S0014-2999(00)00416-7","article-title":"Purinergic and Noradrenergic Cotransmission in the Rat Pineal Gland","volume":"401","author":"Ferreira","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0014-2999(01)00823-8","article-title":"Characterisation of P2Y1-like Receptor in Cultured Rat Pineal Glands","volume":"415","author":"Ferreira","year":"2001","journal-title":"Eur. J. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s11302-015-9493-0","article-title":"P2X Ion Channel Receptors and Inflammation","volume":"12","author":"Burnstock","year":"2016","journal-title":"Purinergic Signal."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/jpi.12309","article-title":"Adenosine Triphosphate Inhibits Melatonin Synthesis in the Rat Pineal Gland","volume":"60","author":"Fernandes","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1177\/1073858412446634","article-title":"N -Acetylserotonin: Neuroprotection, Neurogenesis, and the Sleepy Brain","volume":"18","author":"Tosini","year":"2012","journal-title":"Neuroscientist"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.tem.2007.10.007","article-title":"Melatonin in the Skin: Synthesis, Metabolism and Functions","volume":"19","author":"Slominski","year":"2008","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1159\/000046903","article-title":"Localization, Physiological Significance and Possible Clinical Implication of Gastrointestinal Melatonin","volume":"10","author":"Bubenik","year":"2001","journal-title":"Neurosignals"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1096\/fj.12-224691","article-title":"Metabolism of Melatonin and Biological Activity of Intermediates of Melatoninergic Pathway in Human Skin Cells","volume":"27","author":"Kim","year":"2013","journal-title":"FASEB J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1111\/j.1600-079X.2008.00630.x","article-title":"Metabolism of Melatonin by Cytochrome P450s in Rat Liver Mitochondria and Microsomes","volume":"45","author":"Semak","year":"2008","journal-title":"J. Pineal Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1096\/fj.05-5227fje","article-title":"Constitutive and UV-induced Metabolism of Melatonin in Keratinocytes and Cell-free Systems","volume":"20","author":"Fischer","year":"2006","journal-title":"FASEB J."},{"key":"ref_60","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_61","doi-asserted-by":"crossref","first-page":"113693","DOI":"10.1016\/j.ygcen.2020.113693","article-title":"Gut Melatonin: A Potent Candidate in the Diversified Journey of Melatonin Research","volume":"303","author":"Yasmin","year":"2021","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1007\/BF01946561","article-title":"Immunohistological Localization of Melatonin in the Rat Digestive System","volume":"33","author":"Bubenik","year":"1977","journal-title":"Experientia"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1007\/BF02247718","article-title":"The Metabolic Fate of Infusedl-Tryptophan in Men: Possible Clinical Implications of the Accumulation of Circulating Tryptophan and Tryptophan Metabolites","volume":"109","author":"Huether","year":"1992","journal-title":"Psychopharmacology"},{"key":"ref_64","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_65","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/0024-3205(93)90106-D","article-title":"Tryptophan Loading Increases Daytime Serum Melatonin Levels in Intact and Pinealectomized Rats","volume":"52","author":"Yaga","year":"1993","journal-title":"Life Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1034\/j.1600-079X.2003.02937.x","article-title":"Protective Effect of Melatonin and Its Precursor L-Tryptophan on Acute Pancreatitis Induced by Caerulein Overstimulation or Ischemia\/Reperfusion","volume":"34","author":"Jaworek","year":"2003","journal-title":"J. Pineal Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3602","DOI":"10.3748\/wjg.v19.i23.3602","article-title":"Evaluation of Enterochromaffin Cells and Melatonin Secretion Exponents in Ulcerative Colitis","volume":"19","author":"Chojnacki","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/j.1440-1746.2004.03579.x","article-title":"Exposure to Continuous Darkness Ameliorates Gastric and Colonic Inflammation in the Rat: Both Receptor and Non-Receptor-Mediated Processes","volume":"20","author":"Cevik","year":"2005","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_69","first-page":"158","article-title":"Epidemiology of Irritable Bowel Syndrome","volume":"28","author":"Endo","year":"2015","journal-title":"Ann. Gastroenterol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Paulose, J.K., Wright, J.M., Patel, A.G., and Cassone, V.M. (2016). Human Gut Bacteria Are Sensitive to Melatonin and Express Endogenous Circadian Rhythmicity. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0146643"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"292","DOI":"10.14348\/molcells.2021.0058","article-title":"Development and Functions of Alveolar Macrophages","volume":"44","author":"Woo","year":"2021","journal-title":"Mol. Cells"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1164\/rccm.2210007","article-title":"Alveolar Macrophages: Wielding the Double-Edged Sword of Inflammation","volume":"167","author":"Rubins","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.4049\/jimmunol.166.4.2727","article-title":"Surfactant Protein A Enhances Alveolar Macrophage Phagocytosis of Apoptotic Neutrophils","volume":"166","author":"Schagat","year":"2001","journal-title":"J. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1164\/rccm.200207-698OC","article-title":"Alveolar Macrophages Have a Protective Antiinflammatory Role during Murine Pneumococcal Pneumonia","volume":"167","author":"Knapp","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Gibbs, J.L., Dallon, B.W., Lewis, J.B., Walton, C.M., Arroyo, J.A., Reynolds, P.R., and Bikman, B.T. (2019). Diesel Exhaust Particle Exposure Compromises Alveolar Macrophage Mitochondrial Bioenergetics. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225598"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.neuro.2011.12.001","article-title":"Neurological Impacts from Inhalation of Pollutants and the Nose\u2013Brain Connection","volume":"33","author":"Lucchini","year":"2012","journal-title":"NeuroToxicology"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Ramos, E., L\u00f3pez-Mu\u00f1oz, F., Gil-Mart\u00edn, E., Egea, J., \u00c1lvarez-Merz, I., Painuli, S., Semwal, P., Martins, N., Hern\u00e1ndez-Guijo, J.M., and Romero, A. (2021). The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy. Antioxidants, 10.","DOI":"10.3390\/antiox10071152"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Anderson, G., and Reiter, R.J. (2020). Melatonin: Roles in Influenza, Covid-19, and Other Viral Infections. Rev. Med. Virol., 30.","DOI":"10.1002\/rmv.2109"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Anderson, G., Carbone, A., and Mazzoccoli, G. (2020). Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress. Biology, 9.","DOI":"10.3390\/biology9090249"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Anderson, G., Carbone, A., and Mazzoccoli, G. (2021). Tryptophan Metabolites and Aryl Hydrocarbon Receptor in Severe Acute Respiratory Syndrome, Coronavirus-2 (SARS-CoV-2) Pathophysiology. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041597"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e13843","DOI":"10.1111\/nmo.13843","article-title":"Intestinal Resident Macrophages: Multitaskers of the Gut","volume":"32","author":"Viola","year":"2020","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1126\/science.1219179","article-title":"A Lineage of Myeloid Cells Independent of Myb and Hematopoietic Stem Cells","volume":"336","author":"Schulz","year":"2012","journal-title":"Science"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"eaax8756","DOI":"10.1126\/sciimmunol.aax8756","article-title":"Identification of a Nerve-Associated, Lung-Resident Interstitial Macrophage Subset with Distinct Localization and Immunoregulatory Properties","volume":"5","author":"Ural","year":"2020","journal-title":"Sci. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nature12034","article-title":"Macrophage Biology in Development, Homeostasis and Disease","volume":"496","author":"Wynn","year":"2013","journal-title":"Nature"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4799","DOI":"10.1038\/s41598-020-61652-5","article-title":"Rhythmic Expression of the Melatonergic Biosynthetic Pathway and Its Differential Modulation in Vitro by LPS and IL10 in Bone Marrow and Spleen","volume":"10","author":"Quiles","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/ni.2408","article-title":"Monocytes-Macrophages That Express \u03b1-Smooth Muscle Actin Preserve Primitive Hematopoietic Cells in the Bone Marrow","volume":"13","author":"Ludin","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.stem.2018.08.002","article-title":"Daily Onset of Light and Darkness Differentially Controls Hematopoietic Stem Cell Differentiation and Maintenance","volume":"23","author":"Golan","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.exphem.2019.08.008","article-title":"Daily Light and Darkness Onset and Circadian Rhythms Metabolically Synchronize Hematopoietic Stem Cell Differentiation and Maintenance: The Role of Bone Marrow Norepinephrine, Tumor Necrosis Factor, and Melatonin Cycles","volume":"78","author":"Golan","year":"2019","journal-title":"Exp. Hematol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/jez.1400230108","article-title":"Evidences Associating Pineal Gland Function with Alterations in Pigmentation","volume":"23","author":"McCord","year":"1917","journal-title":"J. Exp. Zool."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1038\/1831821a0","article-title":"Melatonin in Peripheral Nerve","volume":"183","author":"Lerner","year":"1959","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1111\/j.1600-079X.2011.00895.x","article-title":"Analgesic Effects of Melatonin: A Review of Current Evidence from Experimental and Clinical Studies","volume":"51","author":"Wilhelmsen","year":"2011","journal-title":"J. Pineal Res."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Stefani, L.C., Muller, S., Torres, I.L.S., Razzolini, B., Rozisky, J.R., Fregni, F., Markus, R., and Caumo, W. (2013). A Phase II, Randomized, Double-Blind, Placebo Controlled, Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074107"},{"key":"ref_93","unstructured":"Kumar, R., Kumari, K., Janweja, S., Kumar, R., Verma, M., Sharma, A., Paliwal, B., and Kishan, R. (2021). Role of Melatonin in Attenuation of Hemodynamic Response to Intubation and Anesthetic Requirements: A Randomized, Controlled, Double-Blind Study. Braz. J. Anesthesiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1002\/jcp.27090","article-title":"Regulation Effects of Melatonin on Bone Marrow Mesenchymal Stem Cell Differentiation","volume":"234","author":"Wang","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1159\/000347160","article-title":"The Concept of the Immune-Pineal Axis Tested in Patients Undergoing an Abdominal Hysterectomy","volume":"20","author":"Levandovski","year":"2013","journal-title":"Neuroimmunomodulation"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.1007\/s00018-017-2609-7","article-title":"Melatonin as a Mitochondria-Targeted Antioxidant: One of Evolution\u2019s Best Ideas","volume":"74","author":"Reiter","year":"2017","journal-title":"Cell Mol. Life Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"249","DOI":"10.3389\/fendo.2019.00249","article-title":"Melatonin Synthesis and Function: Evolutionary History in Animals and Plants","volume":"10","author":"Zhao","year":"2019","journal-title":"Front. Endocrinol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12143\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:28:25Z","timestamp":1760167705000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12143"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,10]]},"references-count":97,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222212143"],"URL":"https:\/\/doi.org\/10.3390\/ijms222212143","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,10]]}}}