{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:13:27Z","timestamp":1790018007219,"version":"4.0.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T34GM062756"],"award-info":[{"award-number":["T34GM062756"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R25GM119975"],"award-info":[{"award-number":["R25GM119975"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T34GM146637"],"award-info":[{"award-number":["T34GM146637"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21NS106949"],"award-info":[{"award-number":["R21NS106949"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS091616"],"award-info":[{"award-number":["R01NS091616"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS125775"],"award-info":[{"award-number":["R01NS125775"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Neuregulin-1 (NRG-1) is a growth factor that has been investigated for its neuroprotective properties following ischemic stroke. While NRG-1 has shown considerable promise in reducing neuronal damage, the molecular mechanisms underlying its protective effects remain unclear. This study aimed to examine the impact of NRG-1 treatment on ischemia-induced gene expression following permanent middle cerebral artery occlusion (MCAO) in rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Rats were treated with either NRG-1 or vehicle then sacrificed 3 and 12\u202fh after permanent MCAO. RNA isolated from the peri-infarct cortex (ischemic penumbra) was hybridized to an Affymetrix Rat Genome 2.0 ST Microarray Gene Chip. Gene expression was analyzed using the Affymetrix Transcriptome Analysis Console (TAC) 4.0 software and the STRING Protein\u2013Protein Interaction Networks database.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NRG-1 treatment upregulated transcriptional programs promoting cell survival and anti-inflammatory signaling. CREB1 and FOXO1 transcription factor pathways, which are associated with anti-inflammatory signaling, cell proliferation, reduced apoptosis, and decreased oxidative stress, were upregulated. Consistent with the transcriptomic findings, Luminex multiplex transcription factor assays validated the increased CREB1 and FOXO1 activity in NRG-1-treated MCAO brains.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings provide novel insight into the molecular mechanisms by which NRG-1 mediates neuroprotection, highlighting its role in activating transcriptional programs that promote neuronal survival and resilience following ischemic injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnmol.2026.1741120","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T11:50:53Z","timestamp":1773402653000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Transcriptomic identification of CREB1 and FOXO1 activation in neuregulin-1-mediated neuroprotection after stroke"],"prefix":"10.3389","volume":"19","author":[{"given":"Kimberly R.","family":"Bennett","sequence":"first","affiliation":[{"name":"Department of Bioengineering, Bourns College of Engineering, University of California, Riverside","place":["Riverside, CA, United States"]},{"name":"Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology","place":["Cambridge, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique C.","family":"Surles-Zeigler","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Howard University College of Medicine","place":["Washington, DC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine J.","family":"Augello","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Bourns College of Engineering, University of California, Riverside","place":["Riverside, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etchi","family":"Ako","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Bourns College of Engineering, University of California, Riverside","place":["Riverside, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakeem","family":"Omotayo","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Bourns College of Engineering, University of California, Riverside","place":["Riverside, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory D.","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Howard University College of Medicine","place":["Washington, DC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor G. J.","family":"Rodgers","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Bourns College of Engineering, University of California, Riverside","place":["Riverside, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byron D.","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Bourns College of Engineering, University of California, Riverside","place":["Riverside, CA, United States"]},{"name":"Division of Biomedical Sciences, School of Medicine, University of California, Riverside","place":["Riverside, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.brainresbull.2018.10.013","article-title":"Adiponectin confers neuroprotection against cerebral ischemia-reperfusion injury through activating the cAMP\/PKA-CREB-BDNF signaling","volume":"143","author":"Bai","year":"2018","journal-title":"Brain Res. Bull."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1097\/00004647-199908000-00001","article-title":"Inflammatory mediators and stroke: new opportunities for novel therapeutics","volume":"19","author":"Barone","year":"1999","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2632","DOI":"10.1161\/STROKEAHA.117.017112","article-title":"Translational stroke research: vision and opportunities","volume":"48","author":"Bosetti","year":"2017","journal-title":"Stroke"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1126\/science.1094637","article-title":"Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase","volume":"303","author":"Brunet","year":"2004","journal-title":"Science"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"024","DOI":"10.23937\/2469-5866\/1410024","article-title":"Neuregulin in health and disease","volume":"4","author":"Cespedes","year":"2018","journal-title":"Int. J. Brain Disord. Treat."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1089\/scd.2010.0465","article-title":"SIRT1 deficiency downregulates PTEN\/JNK\/FOXO1 pathway to block reactive oxygen species-induced apoptosis in mouse embryonic stem cells","volume":"20","author":"Chae","year":"2011","journal-title":"Stem Cells Dev."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.bbrc.2008.11.110","article-title":"Resveratrol protects cardiomyocytes from hypoxia-induced apoptosis through the SIRT1-FoxO1 pathway","volume":"378","author":"Chen","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/s0166-2236(99)01401-0","article-title":"Pathobiology of ischaemic stroke: an integrated view","volume":"22","author":"Dirnagl","year":"1999","journal-title":"Trends Neurosci."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.1161\/strokeaha.108.541128","article-title":"Update of the stroke therapy academic industry roundtable preclinical recommendations","volume":"40","author":"Fisher","year":"2009","journal-title":"Stroke"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.brainres.2005.11.090","article-title":"Expression analysis systematic explorer (EASE) analysis reveals differential gene expression in permanent and transient focal stroke rat models","volume":"1071","author":"Ford","year":"2006","journal-title":"Brain Res."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"D87","DOI":"10.1093\/nar\/gkz1001","article-title":"JASPAR 2020: update of the open-access database of transcription factor binding profiles","volume":"48","author":"Fornes","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.neuroscience.2015.08.047","article-title":"Neuregulin 1 protects against ischemic brain injury via ErbB4 receptors by increasing GABAergic transmission","volume":"307","author":"Guan","year":"2015","journal-title":"Neuroscience"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1097\/WNR.0000000000000308","article-title":"SIRT1 attenuates severe ischemic damage by preserving cerebral blood flow","volume":"26","author":"Hattori","year":"2015","journal-title":"Neuroreport"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/j.neuropharm.2010.07.017","article-title":"Glial growth factor 2 promotes functional recovery with treatment initiated up to 7 days after permanent focal ischemic stroke","volume":"59","author":"Iaci","year":"2010","journal-title":"Neuropharmacology"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1002\/jnr.23699","article-title":"An optimized dosing regimen of cimaglermin (neuregulin 1\u03b23, glial growth factor 2) enhances molecular markers of neuroplasticity and functional recovery after permanent ischemic stroke in rats","volume":"94","author":"Iaci","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/s12974-019-1516-2","article-title":"Neuroinflammation: friend and foe for ischemic stroke","volume":"16","author":"Jayaraj","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"D412","DOI":"10.1093\/nar\/gkn760","article-title":"STRING 8\u2014a global view on proteins and their functional interactions in 630 organisms","volume":"37","author":"Jensen","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.brainres.2010.01.046","article-title":"Acute estradiol protects CA1 neurons from ischemia-induced apoptotic cell death via the PI3K\/Akt pathway","volume":"1321","author":"Jover-Mengual","year":"2010","journal-title":"Brain Res."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.neulet.2008.07.064","article-title":"Neuregulin attenuated cerebral ischemia-Creperfusion injury via inhibiting apoptosis and upregulating aquaporin-4","volume":"443","author":"Li","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.brainres.2007.09.037","article-title":"Neuroprotection by neuregulin-1 in a rat model of permanent focal cerebral ischemia","volume":"1184","author":"Li","year":"2007","journal-title":"Brain Res."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1152\/physrev.1999.79.4.1431","article-title":"Ischemic cell death in brain neurons","volume":"79","author":"Lipton","year":"1999","journal-title":"Physiol. Rev."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"569392","DOI":"10.1155\/2015\/569392","article-title":"FoxO proteins in the nervous system","volume":"2015","author":"Maiese","year":"2015","journal-title":"Anal. Cell. Pathol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"448","DOI":"10.4103\/1673-5374.291382","article-title":"Targeting the core of neurodegeneration: FoxO, mTOR, and SIRT1","volume":"16","author":"Maiese","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e41","DOI":"10.1161\/CIR.0000000000001303","article-title":"2025 heart disease and stroke statistics: a report of US and global data from the American Heart Association","volume":"151","author":"Martin","year":"2025","journal-title":"Circulation"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s10571-016-0355-2","article-title":"Sirt1: role under the condition of ischemia\/hypoxia","volume":"37","author":"Meng","year":"2017","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1038\/378386a0","article-title":"Multiple essential functions of neuregulin in development","volume":"378","author":"Meyer","year":"1995","journal-title":"Nature"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.lfs.2018.12.017","article-title":"The protective effect of zeranol in cerebral ischemia reperfusion via p-CREB overexpression","volume":"217","author":"Mohamed","year":"2019","journal-title":"Life Sci."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1007\/s12031-019-01362-4","article-title":"Neuroprotection by exogenous and endogenous neuregulin-1 in mouse models of focal ischemic stroke","volume":"69","author":"Noll","year":"2019","journal-title":"J. Mol. Neurosci."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"13500","DOI":"10.1093\/nar\/gku1228","article-title":"Prediction of DNA binding motifs from 3D models of transcription factors; identifying TLX3 regulated genes","volume":"42","author":"Pujato","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref30","first-page":"427","article-title":"Acute neuronal injury and blood genomic profiles in a nonhuman primate model for ischemic stroke","volume":"62","author":"Rodriguez-Mercado","year":"2012","journal-title":"Comp. Med."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1016\/j.neurobiolaging.2003.10.012","article-title":"Neuregulin-1 reduces ischemia-induced brain damage in rats","volume":"25","author":"Shyu","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1186\/s12974-016-0703-7","article-title":"Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway","volume":"13","author":"Simmons","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"e0197092","DOI":"10.1371\/journal.pone.0197092","article-title":"Transcriptomic analysis of neuregulin-1 regulated genes following ischemic stroke by computational identification of promoter binding sites: a role for the ETS-1 transcription factor","volume":"13","author":"Surles-Zeigler","year":"2018","journal-title":"PLoS One"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.jns.2015.06.055","article-title":"Spatio-temporal assessment of the neuroprotective effects of neuregulin-1 on ischemic stroke lesions using MRI","volume":"357","author":"Wang","year":"2015","journal-title":"J. Neurol. Sci."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"6413","DOI":"10.4049\/jimmunol.1001829","article-title":"The role of the transcription factor CREB in immune function","volume":"185","author":"Wen","year":"2010","journal-title":"J. Immunol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/sj.jcbfm.9600212","article-title":"Extended therapeutic window and functional recovery after intraarterial administration of neuregulin-1 after focal ischemic stroke","volume":"26","author":"Xu","year":"2006","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.nbd.2005.01.027","article-title":"Neuroprotection by neuregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression","volume":"19","author":"Xu","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/j.bbrc.2004.07.149","article-title":"Neuregulin-1 is neuroprotective and attenuates inflammatory responses induced by ischemic stroke","volume":"322","author":"Xu","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"2369","DOI":"10.1038\/sj.emboj.7600244","article-title":"Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase","volume":"23","author":"Yeung","year":"2004","journal-title":"EMBO J."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"113362","DOI":"10.1016\/j.expneurol.2020.113362","article-title":"ENT1 inhibition attenuates apoptosis by activation of cAMP\/pCREB\/Bcl2 pathway after MCAO in rats","volume":"331","author":"Zhang","year":"2020","journal-title":"Exp. Neurol."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2026.1741120\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T11:50:54Z","timestamp":1773402654000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2026.1741120\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,13]]},"references-count":40,"alternative-id":["10.3389\/fnmol.2026.1741120"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2026.1741120","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,13]]},"article-number":"1741120"}}