{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T04:59:55Z","timestamp":1768280395254,"version":"3.49.0"},"reference-count":58,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2014,4,17]],"date-time":"2014-04-17T00:00:00Z","timestamp":1397692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Melatonin (MEL), a methoxyindole synthesized by the pineal gland, is a powerful antioxidant in tissues as well as within cells, with a fundamental role in ameliorating homeostasis in a number of specific pathologies. It acts both as a direct radical scavenger and by stimulating production\/activity of intracellular antioxidant enzymes. In this work, some chemical triggers, with different mechanisms of action, have been chosen to induce cell death in U937 hematopoietic cell line. Cells were pre-treated with 100 \u00b5M MEL and then exposed to hydrogen peroxide or staurosporine. Morphological analyses, TUNEL reaction and Orange\/PI double staining have been used to recognize ultrastructural apoptotic patterns and to evaluate DNA behavior. Chemical damage and potential MEL anti-apoptotic effects were quantified by means of Tali\u00ae Image-Based Cytometer, able to monitor cell viability and apoptotic events. After trigger exposure, chromatin condensation, micronuclei formation and DNA fragmentation have been observed, all suggesting apoptotic cell death. These events underwent a statistically significant decrease in samples pre-treated with MEL. After caspase inhibition and subsequent assessment of cell viability, we demonstrated that apoptosis occurs, at least in part, through the mitochondrial pathway and that MEL interacts at this level to rescue U937 cells from death.<\/jats:p>","DOI":"10.3390\/ijms15046625","type":"journal-article","created":{"date-parts":[[2014,4,17]],"date-time":"2014-04-17T12:21:27Z","timestamp":1397737287000},"page":"6625-6640","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Melatonin Prevents Chemical-Induced Haemopoietic Cell Death"],"prefix":"10.3390","volume":"15","author":[{"given":"Sara","family":"Salucci","sequence":"first","affiliation":[{"name":"DiSTeVA, University of Urbino Carlo Bo, Urbino 61029, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Burattini","sequence":"additional","affiliation":[{"name":"DiSTeVA, University of Urbino Carlo Bo, Urbino 61029, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michela","family":"Battistelli","sequence":"additional","affiliation":[{"name":"DiSTeVA, University of Urbino Carlo Bo, Urbino 61029, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Baldassarri","sequence":"additional","affiliation":[{"name":"DiSTeVA, University of Urbino Carlo Bo, Urbino 61029, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Curzi","sequence":"additional","affiliation":[{"name":"DiSTeVA, University of Urbino Carlo Bo, Urbino 61029, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aurelio","family":"Valmori","sequence":"additional","affiliation":[{"name":"IGM, CNR, Rizzoli Orthopaedic Institute, Bologna 40136, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabetta","family":"Falcieri","sequence":"additional","affiliation":[{"name":"DiSTeVA, University of Urbino Carlo Bo, Urbino 61029, Italy"},{"name":"IGM, CNR, Rizzoli Orthopaedic Institute, Bologna 40136, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2014,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/S0008-6363(02)00827-1","article-title":"Melatonin: A novel protective agent against oxidative injury of the ischemic\/reperfused heart","volume":"58","author":"Reiter","year":"2003","journal-title":"Cardiovasc. Res"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1034\/j.1600-079X.2003.00037.x","article-title":"Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interactions with the ABTS cation radical","volume":"34","author":"Tan","year":"2003","journal-title":"J. Pineal Res"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/j.1600-079X.2007.00514.x","article-title":"Protective effect of melatonin against hippocampal injury of rats with intermittent hypoxia","volume":"44","author":"Hung","year":"2008","journal-title":"J. Pineal Res"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/j.1600-079X.2007.00546.x","article-title":"Melatonin protects against endosulfan-induced oxidative tissue damage in rats","volume":"44","author":"Omurtag","year":"2008","journal-title":"J. Pineal Res"},{"key":"ref_5","first-page":"373","article-title":"The universal nature, unequal distribution and antioxidant functions of melatonin and its derivatives","volume":"13","author":"Reiter","year":"2013","journal-title":"Mini Rev. Med. Chem"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.tiv.2006.08.003","article-title":"Melatonin reduces early changes in intramitochondrial cardiolipin during apoptosis in U937 cell line","volume":"2","author":"Luchetti","year":"2007","journal-title":"Toxicol. in Vitro"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"635","DOI":"10.3109\/10715762.2013.808743","article-title":"The role of melatonin as an antioxidant in human lens epithelial cells","volume":"47","author":"Bai","year":"2013","journal-title":"Free Radic. Res"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1046\/j.1600-079X.2003.00092.x","article-title":"Regulation of antioxidant enzymes: A significant role for melatonin","volume":"36","author":"Rodriguez","year":"2004","journal-title":"J. Pineal Res"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-079X.1998.tb00359.x","article-title":"In vivo protection by melatonin against delta-aminolevulinic acid-induced oxidative damage and its antioxidant effect on the activity of haem enzymes","volume":"24","author":"Princ","year":"1998","journal-title":"J. Pineal Res"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1034\/j.1600-079X.2003.02112.x","article-title":"The chemistry of melatonin\u2019s interaction with reactive species","volume":"34","author":"Allegra","year":"2003","journal-title":"J. Pineal Res"},{"key":"ref_11","first-page":"127","article-title":"Prooxidant activity of melatonin promotes fas-induced cell death in human leukemic Jurkat cells","volume":"3","author":"Caluba","year":"2001","journal-title":"FEBS Lett"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1196\/annals.1378.050","article-title":"Intracellular pro-oxidant activity of melatonin deprives U937 cells of reduced glutathione without affecting glutathione peroxidase activity","volume":"1091","author":"Albertini","year":"2006","journal-title":"Ann. N. Y. Acad. Sci"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/jpi.12062","article-title":"Melatonin induces apoptosis through a caspase-dependent but reactive oxygen species-independent mechanism in human leukemia Molt-3 cells","volume":"55","author":"Perdomo","year":"2013","journal-title":"J. Pineal Res"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/j.1600-079X.2009.00727.x","article-title":"Synergistic antitumor effect of melatonin with several chemotherapeutic drugs on human Ewing sarcoma cancer cells. Potentiation of the extrinsic apoptotic pathway","volume":"48","author":"Martin","year":"2010","journal-title":"J. Pineal Res"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.canlet.2009.06.016","article-title":"Melatonin sensitizes human malignant glioma cells against TRAIL-induced cell death","volume":"287","author":"Martin","year":"2010","journal-title":"Cancer Lett"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s11010-011-0783-8","article-title":"Melatonin enhances hydrogen peroxide-induced apoptosis in human promyelocytic leukemia HL-60 cells","volume":"353","author":"Bejarano","year":"2011","journal-title":"Mol. Cell. Biochem"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1111\/j.1600-079X.2010.00851.x","article-title":"Melatonin sensitizes Caki renal cancer cells to kahweol-induced apoptosis through CHOP-mediated up-regulation of PUMA","volume":"50","author":"Um","year":"2011","journal-title":"J. Pineal Res"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.1600-079X.2011.00935.x","article-title":"Melatonin synergistically enhances cisplatin-induced apoptosis via the dephosphorylation of ERK\/p90 ribosomal S6 kinase\/heat shock protein 27 in SK-OV-3 cells","volume":"52","author":"Kim","year":"2012","journal-title":"J. Pineal Res"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1600-079X.2012.00974.x","article-title":"Melatonin potentiates chemotherapy-induced cytotoxicity and apoptosis in rat pancreatic tumor cells","volume":"53","author":"Uguz","year":"2012","journal-title":"J. Pineal Res"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"188","DOI":"10.4161\/cc.9.1.10407","article-title":"Metformin extends life span of HER-2\/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumorsin vivo","volume":"9","author":"Anisimov","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/j.1600-079X.2010.00791.x","article-title":"Melatonin and celecoxib improve the outcomes in hamsters with experimental pancreatic cancer","volume":"49","author":"Padillo","year":"2010","journal-title":"J. Pineal Res"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1152\/physrev.00018.2001","article-title":"Free radicals in the physiological control of cell function","volume":"82","author":"Droge","year":"2002","journal-title":"Physiol. Rev"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6597","DOI":"10.3390\/ijms14046597","article-title":"Mechanisms Involved in the Pro-Apoptotic Effect of Melatonin in Cancer Cells","volume":"14","author":"Rodriguez","year":"2013","journal-title":"Int. J. Mol. Sci"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.2741\/1667","article-title":"Reactive oxygen species in tumor progression","volume":"10","author":"Storz","year":"2005","journal-title":"Front. Biosci"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.biocel.2006.07.001","article-title":"Free radicals and antioxidants in normal physiological functions and human disease","volume":"39","author":"Valko","year":"2007","journal-title":"Int. J. Biochem. Cell Biol"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/j.1600-065X.2000.imr017506.x","article-title":"Apoptosis and its modulation during B lymphopoiesis in mouse bone marrow","volume":"175","author":"Lu","year":"2000","journal-title":"Immunol. Rev"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.coi.2007.04.007","article-title":"Apoptosis induced by the lymphocyte effector molecule perforin","volume":"19","author":"Bolitho","year":"2007","journal-title":"Curr. Opin. Immunol"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s11010-006-2956-4","article-title":"l-tryptophan administered orally at night modifies the melatonin plasma levels, phagocytosis and oxidative metabolism of ringdove (Streptopelia roseogrisea) heterophils","volume":"293","author":"Cubero","year":"2006","journal-title":"Mol. Cell. Biochem"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.0959-9673.2006.00474.x","article-title":"The role of melatonin in immune enhancement: Potential application in cancer","volume":"87","author":"Miller","year":"2006","journal-title":"Int. J. Exp. Pathol"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"493","DOI":"10.2174\/138945007780362764","article-title":"The apoptotic pathway as a therapeutic target in sepsis","volume":"8","author":"Swan","year":"2007","journal-title":"Curr. Drug Targets"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1196\/annals.1378.025","article-title":"Melatonin as an apoptosis antagonist","volume":"1090","author":"Radogna","year":"2006","journal-title":"Ann. N. Y. Acad. Sci"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1111\/j.1600-079X.2007.00455.x","article-title":"Melatonin antagonizes apoptosis via receptor interaction in U937 monocytic cells","volume":"43","author":"Radogna","year":"2007","journal-title":"J. Pineal Res"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.freeradbiomed.2008.09.017","article-title":"ERK MAPK activation mediates the antiapoptotic signaling of melatonin in UVB-stressed U937 cells","volume":"46","author":"Luchetti","year":"2009","journal-title":"Free Radic. Biol. Med"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1111\/j.1600-079X.2007.00532.x","article-title":"Melatonin antagonizes the intrinsic pathway of apoptosis via mitochondrial targeting of Bcl-2","volume":"44","author":"Radogna","year":"2008","journal-title":"J. Pineal Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/j.1600-079X.2005.00293.x","article-title":"Melatonin prevents apoptosis induced by UV-B treatment in U937 cell line","volume":"40","author":"Luchetti","year":"2006","journal-title":"J. Pineal Res"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1016\/j.micron.2010.07.002","article-title":"C2C12 myoblast sensitivity to different apoptotic chemical triggers","volume":"41","author":"Salucci","year":"2010","journal-title":"Micron"},{"key":"ref_37","first-page":"1073","article-title":"The peculiar apoptotic behavior of skeletal muscle cells","volume":"28","author":"Salucci","year":"2013","journal-title":"Histol. Histopathol"},{"key":"ref_38","first-page":"3659","article-title":"Assessment of GFP expression and viability using the tali image-based cytometer","volume":"17","author":"Remple","year":"2011","journal-title":"J. Vis. Exp."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/1097-0320(20010501)44:1<57::AID-CYTO1082>3.0.CO;2-O","article-title":"Supravital exposure to propidium iodide identifies apoptosis on adherent cells","volume":"1","author":"Zamai","year":"2001","journal-title":"Cytometry"},{"key":"ref_40","first-page":"21","article-title":"Morphological and biochemical patterns in skeletal muscle apoptosis","volume":"25","author":"Biagiotti","year":"2010","journal-title":"Histol. Histopathol"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.fct.2012.12.049","article-title":"Anti-apoptotic activity of hydroxytyrosol and hydroxytyrosyl laurate","volume":"55","author":"Burattini","year":"2013","journal-title":"Food Chem. Toxicol"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"532","DOI":"10.3390\/ijms14010532","article-title":"(UVB) Irradiation-Induced Apoptosis in Various Cell Lineages in Vitro","volume":"14","author":"Salucci","year":"2012","journal-title":"Int. J. Mol. Sci"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"421894","DOI":"10.1093\/ecam\/neq010","article-title":"In vitro ultramorphological assessment of apoptosis on CEMss induced by linoleic acid-rich fraction from typhonium flagelliforme tuber","volume":"2011","author":"Mohan","year":"2011","journal-title":"Evid. Based Complement. Alternat. Med"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3250","DOI":"10.1096\/fj.10-177527","article-title":"Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: Activation of caspase-9 in the absence of Apaf-1","volume":"25","author":"Manns","year":"2011","journal-title":"FASEB J"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e41945","DOI":"10.1371\/journal.pone.0041945","article-title":"Staurosporine induces necroptotic cell death under caspase-compromised conditions in U937 cells","volume":"7","author":"Dunai","year":"2012","journal-title":"PLoS One"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/j.1600-079X.2009.00721.x","article-title":"Visualization of melatonin\u2019s multiple mitochondrial levels of protection against mitochondrial Ca(2+)-mediated permeability transition and beyond in rat brain astrocytes","volume":"48","author":"Jou","year":"2010","journal-title":"J. Pineal Res"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1111\/j.1600-079X.2010.00759.x","article-title":"Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease","volume":"48","author":"Paradies","year":"2010","journal-title":"J. Pineal Res"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1016\/j.neuropharm.2012.08.018","article-title":"Caffeine increases mitochondrial function and blocks melatonin signaling to mitochondria in Alzheimer\u2019s mice and cells","volume":"63","author":"Dragicevic","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1096\/fj.99-0865fje","article-title":"Melatonin but not vitamins C and E maintains glutathione homeostasis in t-butyl hydroperoxide-induced mitochondrial oxidative stress","volume":"14","author":"Escames","year":"2000","journal-title":"FASEB J"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/jpi.12026","article-title":"Mitochondria and chloroplasts as the original sites of melatonin synthesis: A hypothesis related to melatonin\u2019s primary function and evolution in eukaryotes","volume":"54","author":"Tan","year":"2013","journal-title":"J. Pineal Res"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1002\/cbf.1775","article-title":"Corrections by melatonin of liver mitochondrial disorders under diabetes and acute intoxication in rats","volume":"29","author":"Cheshchevik","year":"2011","journal-title":"Cell Biochem. Funct"},{"key":"ref_52","first-page":"421","article-title":"Melatonin and succinate reduce rat liver mitochondrial dysfunction in diabetes","volume":"62","author":"Zavodnik","year":"2011","journal-title":"J. Physiol. Pharmacol"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.taap.2012.04.007","article-title":"Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: Protection by melatonin and cranberry flavonoids","volume":"261","author":"Cheshchevik","year":"2012","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/j.1600-079X.2010.00748.x","article-title":"Melatonin ameliorates cerulein-induced pancreatitis by the modulation of nuclear erythroid 2-related factor 2 and nuclear factor-kappaB in rats","volume":"48","author":"Jung","year":"2010","journal-title":"J. Pineal Res"},{"key":"ref_55","first-page":"935","article-title":"cDNA gene expression profile homology of antioxidants and their antiapoptotic and proapoptotic activities in human neuroblastoma cells","volume":"7","author":"Weinreb","year":"2003","journal-title":"FASEB J"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1196\/annals.1299.082","article-title":"Apoptotic GSH extrusion is associated with free radical generation","volume":"1010","author":"Cerella","year":"2003","journal-title":"Ann. N. Y. Acad. Sci"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1096\/fj.03-1031fje","article-title":"Direct inhibition of the mitochondrial permeability transition pore: A possible mechanism responsible for anti-apoptotic effects of melatonin","volume":"18","author":"Andrabi","year":"2004","journal-title":"FASEB J"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/cbin.10030","article-title":"Pharmacological doses of melatonin induce alterations in mitochondrial mass and potential, bcl-2 levels and K+ currents in UVB-exposed U937 cells","volume":"37","author":"Canonico","year":"2013","journal-title":"Cell Biol. Int."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/4\/6625\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:10:26Z","timestamp":1760217026000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/4\/6625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,17]]},"references-count":58,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2014,4]]}},"alternative-id":["ijms15046625"],"URL":"https:\/\/doi.org\/10.3390\/ijms15046625","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,17]]}}}