{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T09:54:25Z","timestamp":1771581265277,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["NS092810"],"award-info":[{"award-number":["NS092810"]}]},{"name":"National Institutes of Health","award":["NS103810"],"award-info":[{"award-number":["NS103810"]}]},{"name":"Pittsburgh Institute of Brain Disorders and Recovery","award":["NS092810"],"award-info":[{"award-number":["NS092810"]}]},{"name":"Pittsburgh Institute of Brain Disorders and Recovery","award":["NS103810"],"award-info":[{"award-number":["NS103810"]}]},{"name":"Department of Neurology of the University of Pittsburgh","award":["NS092810"],"award-info":[{"award-number":["NS092810"]}]},{"name":"Department of Neurology of the University of Pittsburgh","award":["NS103810"],"award-info":[{"award-number":["NS103810"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Aldo-keto reductase (AKR) 1C15, a member of the AKR superfamily, was recently identified and cloned, and reported to alleviate oxidative stress in endothelial cells in rodent lungs. However, its expression and role in the brain and ischemic brain diseases have not been investigated. AKR1C15 expression was detected with real-time PCR. Mouse ischemic stroke and ischemic preconditioning (IPC) were established with middle cerebral artery occlusion (MCAO) for 1 h or 12 min, respectively. Recombinant AKR1C15 was administered intraperitoneally, and stroke outcome was evaluated with neurobehavioral tests and infarct volumes. Rat primary brain cell cultures were subjected to oxygen\u2013glucose deprivation (OGD) to mimic ischemic injury. Cell survival or in vitro blood\u2013brain barrier (BBB) permeability was measured, and nitric oxide (NO) release was detected. Immunostaining and Western blotting were used to evaluate oxidative-stress-related protein expression. AKR1C15 administration decreased the infarct volume and neurological deficits 2d post-stroke, and its early (1-h) administration after IPC abolished the protection of IPC against stroke. In rat primary brain cell cultures, AKR1C15 was most abundantly expressed in brain microvascular endothelial cells (BMVECs) and microglia. Its expression decreased upon OGD in most cell types except for BMVECs and microglia. In primary neuronal cultures, AKR1C15 treatment prevented OGD-induced cell death accompanied by decreased levels of 4-hydroxynonenal, 8-hydroxy-2\u2032-deoxyguanosine, and heme oxygenase-1. In BMVEC cultures, AKR1C15 treatment protected against OGD-induced cell death and in vitro BBB leakage. In primary microglial cultures, AKR1C15 reduced the release of NO upon proinflammatory stimulation. Our results provide a characterization of the novel antioxidant AKR1C15 and demonstrate its protective role against ischemic injury, both in vivo and in vitro. AKR1C15 may be a promising agent for ischemic stroke treatment.<\/jats:p>","DOI":"10.3390\/antiox12040909","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T03:49:17Z","timestamp":1681271357000},"page":"909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Aldo-Keto Reductase 1C15 Characterization and Protection in Ischemic Brain Injury"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0418-3014","authenticated-orcid":false,"given":"Tuo","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15216, USA"},{"name":"Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA 15216, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianqian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15216, USA"},{"name":"Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA 15216, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Fadoul","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15216, USA"},{"name":"Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA 15216, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nour","family":"Alraqmany","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15216, USA"},{"name":"Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA 15216, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milos","family":"Ikonomovic","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15216, USA"},{"name":"Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15216, USA"},{"name":"Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15216, USA"},{"name":"Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA 15216, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,11]]},"reference":[{"key":"ref_1","unstructured":"CDC (2023, March 01). Stroke Facts, Available online: https:\/\/www.cdc.gov\/stroke\/facts.htm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1179\/135100007X162211","article-title":"Role of 4-hydroxynonenal and its metabolites in signaling","volume":"12","author":"Dwivedi","year":"2007","journal-title":"Redox Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1089\/ars.1999.1.3-255","article-title":"4-Hydroxynonenal as a biological signal: Molecular basis and pathophysiological implications","volume":"1","author":"Parola","year":"1999","journal-title":"Antioxid. Redox Signal."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"113142","DOI":"10.1016\/j.expneurol.2019.113142","article-title":"Ischemic preconditioning provides long-lasting neuroprotection against ischemic stroke: The role of Nrf2","volume":"325","author":"Yang","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.redox.2018.05.001","article-title":"Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation","volume":"17","author":"Yang","year":"2018","journal-title":"Redox Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1523\/JNEUROSCI.4043-13.2014","article-title":"Omega-3 fatty acids protect the brain against ischemic injury by activating Nrf2 and upregulating heme oxygenase 1","volume":"34","author":"Zhang","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Smathers, R.L., Fritz, K.S., Galligan, J.J., Shearn, C.T., Reigan, P., Marks, M.J., and Petersen, D.R. (2012). Characterization of 4-HNE modified L-FABP reveals alterations in structural and functional dynamics. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038459"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0098-2997(03)00009-8","article-title":"Basic aspects of the biochemical reactivity of 4-hydroxynonenal","volume":"24","author":"Schaur","year":"2003","journal-title":"Mol. Asp. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1038\/cdd.2013.138","article-title":"Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance","volume":"20","author":"Dalleau","year":"2013","journal-title":"Cell. Death Differ."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/1476-4598-8-121","article-title":"Lack of functional and expression homology between human and mouse aldo-keto reductase 1C enzymes: Implications for modelling human cancers","volume":"8","author":"Velica","year":"2009","journal-title":"Mol. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4769","DOI":"10.1158\/0008-5472.CAN-08-4533","article-title":"AKR1C isoforms represent a novel cellular target for jasmonates alongside their mitochondrial-mediated effects","volume":"69","author":"Davies","year":"2009","journal-title":"Cancer Res."},{"key":"ref_12","first-page":"505","article-title":"The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs","volume":"63","author":"Desmond","year":"2003","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1749-6632.2009.03700.x","article-title":"Steroid hormone transforming aldo-keto reductases and cancer","volume":"1155","author":"Penning","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3223","DOI":"10.1021\/bi00177a012","article-title":"Structure and tissue-specific expression of the aldo-keto reductase superfamily","volume":"33","author":"Qin","year":"1994","journal-title":"Biochemistry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.cbi.2010.12.018","article-title":"Protective effect of rat aldo-keto reductase (AKR1C15) on endothelial cell damage elicited by 4-hydroxy-2-nonenal","volume":"191","author":"Matsunaga","year":"2011","journal-title":"Chem. Biol. Interact."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.abb.2007.05.008","article-title":"Enzymatic characteristics of an aldo-keto reductase family protein (AKR1C15) and its localization in rat tissues","volume":"465","author":"Endo","year":"2007","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1186\/1743-422X-10-358","article-title":"Roles and functions of HIV-1 Tat protein in the CNS: An overview","volume":"10","author":"Bagashev","year":"2013","journal-title":"Virol. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s12975-010-0019-3","article-title":"Enhanced Delivery of Erythropoietin Across the Blood-Brain Barrier for Neuroprotection against Ischemic Neuronal Injury","volume":"1","author":"Zhang","year":"2010","journal-title":"Transl. Stroke Res."},{"key":"ref_19","doi-asserted-by":"crossref","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":"ref_20","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.pneurobio.2013.11.005","article-title":"Preconditioning provides neuroprotection in models of CNS disease: Paradigms and clinical significance","volume":"114","author":"Stetler","year":"2014","journal-title":"Prog. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1161\/01.STR.20.1.84","article-title":"Reversible middle cerebral artery occlusion without craniectomy in rats","volume":"20","author":"Longa","year":"1989","journal-title":"Stroke"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1177\/0271678X18764083","article-title":"Protective effects of sulforaphane in experimental vascular cognitive impairment: Contribution of the Nrf2 pathway","volume":"39","author":"Mao","year":"2019","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"102125","DOI":"10.1016\/j.pneurobio.2021.102125","article-title":"Adiponectin ameliorates hypoperfusive cognitive deficits by boosting a neuroprotective microglial response","volume":"205","author":"Miao","year":"2021","journal-title":"Prog. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10523","DOI":"10.1038\/ncomms10523","article-title":"Rapid endothelial cytoskeletal reorganization enables early blood-brain barrier disruption and long-term ischaemic reperfusion brain injury","volume":"7","author":"Shi","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Gorini, F., Ambrosio, S., Lania, L., Majello, B., and Amente, S. (2023). The Intertwined Role of 8-oxodG and G4 in Transcription Regulation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032031"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.pneurobio.2012.09.003","article-title":"Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection","volume":"100","author":"Zhang","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1007\/s12975-020-00857-2","article-title":"Microglial Responses to Brain Injury and Disease: Functional Diversity and New Opportunities","volume":"12","author":"Lyu","year":"2021","journal-title":"Transl. Stroke Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1161\/STROKEAHA.119.028398","article-title":"Transforming Growth Factor Beta-Activated Kinase 1-Dependent Microglial and Macrophage Responses Aggravate Long-Term Outcomes After Ischemic Stroke","volume":"51","author":"Wang","year":"2020","journal-title":"Stroke"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.1161\/STROKEAHA.112.659656","article-title":"Microglia\/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia","volume":"43","author":"Hu","year":"2012","journal-title":"Stroke"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1111\/cns.13899","article-title":"Phagocytic microglia and macrophages in brain injury and repair","volume":"28","author":"Yu","year":"2022","journal-title":"CNS Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1042\/bj3260625","article-title":"Comparative anatomy of the aldo-keto reductase superfamily","volume":"326","author":"Jez","year":"1997","journal-title":"Biochem. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/S0009-2797(02)00193-X","article-title":"The aldo-keto reductase superfamily homepage","volume":"143\u2013144","author":"Hyndman","year":"2003","journal-title":"Chem. Biol. Interact."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.cbi.2010.12.017","article-title":"Roles of rat and human aldo-keto reductases in metabolism of farnesol and geranylgeraniol","volume":"191","author":"Endo","year":"2011","journal-title":"Chem. Biol. Interact."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.3390\/biom5042247","article-title":"4-Hydroxy-nonenal-A Bioactive Lipid Peroxidation Product","volume":"5","author":"Schaur","year":"2015","journal-title":"Biomolecules"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnagi.2020.00001","article-title":"Electrophile Signaling and Emerging Immuno- and Neuro-modulatory Electrophilic Pharmaceuticals","volume":"12","author":"Poganik","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1042\/bj3510067","article-title":"Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: Functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones","volume":"351","author":"Penning","year":"2000","journal-title":"Biochem. J."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/4\/909\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:13:48Z","timestamp":1760123628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/4\/909"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,11]]},"references-count":36,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["antiox12040909"],"URL":"https:\/\/doi.org\/10.3390\/antiox12040909","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,11]]}}}