{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T05:23:30Z","timestamp":1787289810750,"version":"build-2736575974"},"reference-count":24,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T00:00:00Z","timestamp":1572480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Space Agency \u201cProject RASC","award":["2015-008-R.0"],"award-info":[{"award-number":["2015-008-R.0"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Studies on the relationship between reactive oxygen species (ROS)\/manganese superoxide dismutase (MnSOD) and sphingomyelinase (SMase) are controversial. It has been demonstrated that SMase increases the intracellular ROS level and induces gene expression for MnSOD protein. On the other hand, some authors showed that ROS modulate the activation of SMase. The human recombinant manganese superoxide dismutase (rMnSOD) exerting a radioprotective effect on normal cells, qualifies as a possible pharmaceutical tool to prevent and\/or cure damages derived from accidental exposure to ionizing radiation. This study aimed to identify neutral SMase (nSMase) as novel molecule connecting rMnSOD to its radiation protective effects. We used a new, and to this date, unique, experimental model to assess the effect of both radiation and rMnSOD in the brain of mice, within a collaborative project among Italian research groups and the Joint Institute for Nuclear Research, Dubna (Russia). Mice were exposed to a set of minor \u03b3 radiation and neutrons and a spectrum of neutrons, simulating the radiation levels to which cosmonauts will be exposed during deep-space, long-term missions. Groups of mice were treated or not-treated (controls) with daily subcutaneous injections of rMnSOD during a period of 10 days. An additional group of mice was also pretreated with rMnSOD for three days before irradiation, as a model for preventive measures. We demonstrate that rMnSOD significantly protects the midbrain cells from radiation-induced damage, inducing a strong upregulation of nSMase gene and protein expression. Pretreatment with rMnSOD before irradiation protects the brain with a value of very high nSMase activity, indicating that high levels of activity might be sufficient to exert the rMnSOD preventive role. In conclusion, the protective effect of rMnSOD from radiation-induced brain damage may require nSMase enzyme.<\/jats:p>","DOI":"10.3390\/ijms20215431","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T06:33:29Z","timestamp":1572503609000},"page":"5431","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["RETRACTED: Neutral Sphingomyelinase Modulation in the Protective\/Preventive Role of rMnSOD from Radiation-Induced Damage in the Brain"],"prefix":"10.3390","volume":"20","author":[{"given":"Samuela","family":"Cataldi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4439-6882","authenticated-orcid":false,"given":"Antonella","family":"Borrelli","sequence":"additional","affiliation":[{"name":"Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS \u201cFondazione G. Pascale\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5344-4890","authenticated-orcid":false,"given":"Maria","family":"Ceccarini","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8934-6312","authenticated-orcid":false,"given":"Irina","family":"Nakashidze","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1562-4495","authenticated-orcid":false,"given":"Michela","family":"Codini","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg","family":"Belov","sequence":"additional","affiliation":[{"name":"Laboratory of Radiation Biology, Joint Institute for Nuclear Research, 141980 Dubna, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Laboratory of Radiation Biology, Joint Institute for Nuclear Research, 141980 Dubna, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Krasavin","sequence":"additional","affiliation":[{"name":"Laboratory of Radiation Biology, Joint Institute for Nuclear Research, 141980 Dubna, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Ferri","sequence":"additional","affiliation":[{"name":"Division of Pathological Anatomy and Histology, Department of Experimental Medicine, School of Medicine and Surgery, University of Perugia, 06126 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2456-6300","authenticated-orcid":false,"given":"Carmela","family":"Conte","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9010-4150","authenticated-orcid":false,"given":"Federica","family":"Patria","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Traina","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9637-6579","authenticated-orcid":false,"given":"Tommaso","family":"Beccari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"Mancini","sequence":"additional","affiliation":[{"name":"Laedhexa Biotechnologies Inc., San Francisco, CA QB3@953, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9070-4807","authenticated-orcid":false,"given":"Francesco","family":"Curcio","sequence":"additional","affiliation":[{"name":"Dipartimento di Area Medica, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Ambesi-Impiombato","sequence":"additional","affiliation":[{"name":"Dipartimento di Area Medica, University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5745-5343","authenticated-orcid":false,"given":"Elisabetta","family":"Albi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1084\/jem.180.2.525","article-title":"Ionizingradiationacts on cellular membranes to generate ceramide and initiate apoptosis","volume":"180","author":"Kan","year":"1994","journal-title":"J. Exp. Med."},{"key":"ref_2","first-page":"4340","article-title":"Decreasing the apoptotic threshold of tumor cells through protein kinase C inhibition and sphingomyelinaseactivation increases tumor killing by ionizingradiation","volume":"57","author":"Chmura","year":"1997","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Albi, E., Cataldi, S., Lazzarini, A., Codini, M., Beccari, T., Ambesi-Impiombato, F.S., and Curcio, F. (2017). Radiation and thyroid cancer. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18050911"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1016\/j.freeradbiomed.2006.01.035","article-title":"Sphingolipid signaling and redox regulation","volume":"40","author":"Won","year":"2016","journal-title":"Free Radic Biol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.cellsig.2004.02.003","article-title":"Ceramide-induced enhancement of secretory phospholipase A2 expression via generation of reactive oxygen species in tumor necrosis factor-alpha-stimulated mesangial cells","volume":"16","author":"Kitatani","year":"2004","journal-title":"Cell Signal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1161\/01.CIR.0000035650.05921.50","article-title":"Dual effect of ceramide on human endothelial cells: Induction of oxidative stress and transcriptional upregulation of endothelial nitric oxide synthase","volume":"106","author":"Li","year":"2002","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1159\/000315104","article-title":"Ceramide in redox signaling and cardiovascular diseases","volume":"26","author":"Li","year":"2010","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1002\/jcp.22611","article-title":"Neutral sphingomyelinase, NADPH oxidase and reactive oxygen species. Role in acute hypoxic pulmonary vasoconstriction","volume":"226","author":"Frazziano","year":"2011","journal-title":"J. Cell. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Jazvin\u0161\u0107akJembrek, M., Hof, P.R., and \u0160imi\u0107, G. (2015). Ceramides in Alzheimer\u2019s disease: Key mediators of neuronal apoptosis induced by oxidative stress and A\u03b2 accumulation. Oxid. Med. Cell. Longev., 346783.","DOI":"10.1155\/2015\/346783"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chen, Y.Y., Hsu, M.J., Sheu, J.R., Lee, L.W., and Hsieh, C.Y. (2013). Andrographolide, a Novel NF-\u03baB Inhibitor, Induces Vascular Smooth Muscle Cell Apoptosis via a Ceramide-p47phox-ROSSignaling Cascade. Evid. Based. Complement. Alternat. Med., 2013.","DOI":"10.1155\/2013\/821813"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1046\/j.1471-4159.1999.0730513.x","article-title":"Induction of the manganese superoxide dismutase gene by sphingomyelinase and ceramide","volume":"73","author":"Pahan","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"He, X., and Schuchman, E.H. (2018). Ceramide and ischemia\/reperfusion injury. J. Lipids., 2018.","DOI":"10.1155\/2018\/3646725"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1089\/ars.2007.1692","article-title":"Ceramide: A novel player in reactive oxygen species-induced signaling?","volume":"9","author":"Dumitru","year":"2007","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1124\/mol.62.6.1446","article-title":"Overexpression of protein kinase Czeta confers protection against antileukemic drugs by inhibiting the redox-dependentsphingomyelinaseactivation","volume":"62","author":"Bezombes","year":"2002","journal-title":"Mol. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.freeradbiomed.2008.10.030","article-title":"A recombinant MnSOD is radioprotective for normal cells and radiosensitizing for tumor cells","volume":"46","author":"Borrelli","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1667\/RR3081","article-title":"Mitochondrial localization of superoxide dismutase is required for decreasing radiation cellular damage","volume":"160","author":"Epperly","year":"2003","journal-title":"Radiat. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Borrelli, A., Schiattarella, A., Bonelli, P., Tuccillo, F.M., Buonaguro, F.M., and Mancini, A. (2014). The functional role of MnSOD as a biomarker of human diseases and therapeutic potential of a new isoform of a human recombinant MnSOD. Biomed. Res. Int., 2014.","DOI":"10.1155\/2014\/476789"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1002\/jcp.24840","article-title":"Effect ofrMnSODon survival signaling in pediatric high risk T-cell acute lymphoblastic leukaemia","volume":"230","author":"Pica","year":"2015","journal-title":"J. Cell Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cataldi, S., Codini, M., Hunot, S., L\u00e9geron, F.P., Ferri, I., Siccu, P., Sidoni, A., Ambesi-Impiombato, F.S., Beccari, T., and Curcio, F. (2016). e-Cadherin in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson Disease. Mediators Inflamm., 2016.","DOI":"10.1155\/2016\/3937057"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1089\/ast.2010.0461","article-title":"Thyroid cell growth: Sphingomyelin metabolism as non-invasive marker for cell damage acquired during spaceflight","volume":"10","author":"Albi","year":"2018","journal-title":"Astrobiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1016\/j.stemcr.2018.03.025","article-title":"INK4a\/ARF Expression Impairs Neurogenesis in theBrainof Irradiated Mice","volume":"10","author":"Le","year":"2018","journal-title":"Stem. Cell Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1002\/mrm.27112","article-title":"Diffusion MRI monitoring of specific structures in the irradiated ratbrain","volume":"80","author":"Constanzo","year":"2018","journal-title":"Magn. Reson. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.biochi.2017.11.011","article-title":"VDR independent induction of acid-sphingomyelinase by 1,23(OH)2 D3 in gastric cancer cells: Impact on apoptosis and cell morphology","volume":"146","author":"Albi","year":"2018","journal-title":"Biochimie"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s12944-016-0351-z","article-title":"Acid sphingomyelinaseas target of LyciumChinense: Promising new action for cell health","volume":"15","author":"Ceccarini","year":"2016","journal-title":"Lipids. Health. Dis."}],"updated-by":[{"DOI":"10.3390\/ijms27062812","type":"retraction","label":"Retraction","source":"publisher","updated":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T00:00:00Z","timestamp":1572480000000}},{"DOI":"10.3390\/ijms27062812","type":"retraction","label":"Retraction","source":"publisher","updated":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000}}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/21\/5431\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T04:24:13Z","timestamp":1787286253000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/21\/5431"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,31]]},"references-count":24,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["ijms20215431"],"URL":"https:\/\/doi.org\/10.3390\/ijms20215431","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,31]]}}}