{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:33:46Z","timestamp":1787027626227,"version":"build-2736575974"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T00:00:00Z","timestamp":1721001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Brescia to Rosaria Ingrassia","award":["60%-14-1550"],"award-info":[{"award-number":["60%-14-1550"]}]},{"name":"University of Brescia to Rosaria Ingrassia","award":["60%-14-1585"],"award-info":[{"award-number":["60%-14-1585"]}]},{"name":"Alessandra Valerio","award":["60%-14-1550"],"award-info":[{"award-number":["60%-14-1550"]}]},{"name":"Alessandra Valerio","award":["60%-14-1585"],"award-info":[{"award-number":["60%-14-1585"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: The regulation of divalent metal transporter-1 (DMT1) by insulin has been previously described in Langerhans cells and significant neuroprotection was found by insulin and insulin-like growth factor 1 treatment during experimental cerebral ischemia in acute ischemic stroke patients and in a rat 6-OHDA model of Parkinson\u2019s disease, where DMT1 involvement is described. According to the regulation of DMT1, previously described as a target gene of NF-kB in the early phase of post-ischemic neurodegeneration, both in vitro and in vivo, and because insulin controls the NFkB signaling with protection from ischemic cell death in rat cardiomyocytes, we evaluated the role of insulin in relation to DMT1 expression and function during ischemic neurodegeneration. Methods: Insulin neuroprotection is evaluated in differentiated human neuroblastoma cells, SK-N-SH, and in primary mouse cortical neurons exposed to oxygen glucose deprivation (OGD) for 8 h or 3 h, respectively, with or without 300 nM insulin. The insulin neuroprotection during OGD was evaluated in both cellular models in terms of cell death, and in SK-N-SH for DMT1 protein expression and acute ferrous iron treatment, performed in acidic conditions, known to promote the maximum DMT1 uptake as a proton co-transporter; and the transactivation of 1B\/DMT1 mouse promoter, already known to be responsive to NF-kB, was analyzed in primary mouse cortical neurons. Results: Insulin neuroprotection during OGD was concomitant to the down-regulation of both DMT1 protein expression and 1B\/DMT1 mouse promoter transactivation. We also showed the insulin-dependent protection from cell death after acute ferrous iron treatment. In conclusion, although preliminary, this evaluation highlights the peculiar role of DMT1 as a possible pharmacological target, involved in neuroprotection by insulin during in vitro neuronal ischemia and acute ferrous iron uptake.<\/jats:p>","DOI":"10.3390\/biom14070856","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T18:17:32Z","timestamp":1721067452000},"page":"856","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Ischemic Neuroprotection by Insulin with Down-Regulation of Divalent Metal Transporter 1 (DMT1) Expression and Ferrous Iron-Dependent Cell Death"],"prefix":"10.3390","volume":"14","author":[{"given":"Francesca","family":"Fenaroli","sequence":"first","affiliation":[{"name":"Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5844-2256","authenticated-orcid":false,"given":"Alessandra","family":"Valerio","sequence":"additional","affiliation":[{"name":"Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6559-903X","authenticated-orcid":false,"given":"Rosaria","family":"Ingrassia","sequence":"additional","affiliation":[{"name":"Section of Biotechnologies, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/41343","article-title":"Cloning and characterization of a mammalian proton-coupled metal-ion transporter","volume":"388","author":"Gunshin","year":"1997","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/ng0897-383","article-title":"Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene","volume":"16","author":"Fleming","year":"1997","journal-title":"Nat. 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