{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:46:10Z","timestamp":1789677970026,"version":"4.0.1"},"reference-count":45,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32071154, 32171102, 31770917, 82000819, and 31701025"],"award-info":[{"award-number":["32071154, 32171102, 31770917, 82000819, and 31701025"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>NF-E2-related factor 2 (Nrf2), the key transcription regulator of phase II enzymes, has been considered beneficial for neuronal protection. We previously designed a novel chalcone analog, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), that could specifically activate Nrf2 in vitro. Here, we report that Tak confers significant hippocampal neuronal protection both in vitro and in vivo. Treatment with Tak has no significant toxicity on cultured neuronal cells. Instead, Tak increases cellular ATP production by increasing mitochondrial function and decreases the levels of reactive oxygen species by activating Nrf2-mediated phase II enzyme expression. Tak pretreatment prevents glutamate-induced excitotoxic neuronal death accompanied by suppressed mitochondrial respiration, increased superoxide production, and activation of apoptosis. Further investigation indicates that the protective effect of Tak is mediated by the Akt signaling pathway. Meanwhile, Tak administration in mice can sufficiently abrogate scopolamine-induced cognitive impairment via decreasing hippocampal oxidative stress. In addition, consistent benefits are also observed in an energy stress mouse model under a high-fat diet, as the administration of Tak remarkably increases Akt signaling-mediated antioxidative enzyme expression and prevents hippocampal neuronal apoptosis without significant effect on the mouse metabolic status. Overall, our study demonstrates that Tak protects cognitive function by Akt-mediated Nrf2 activation to maintain redox status both vivo and in vitro, suggesting that Tak is a promising pharmacological candidate for the treatment of oxidative neuronal diseases.<\/jats:p>","DOI":"10.3390\/antiox10111811","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T08:19:20Z","timestamp":1636964360000},"page":"1811","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status"],"prefix":"10.3390","volume":"10","author":[{"given":"Yuting","family":"Cui","sequence":"first","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Xiong","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Zeng","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Science, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Zou","sequence":"additional","affiliation":[{"name":"National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi\u2019an Jiaotong University, Shannxi 710004, China"},{"name":"Shaanxi Provincial Clinical Research Center for Hepatic and Splenic Diseases, The Second Affiliated Hospital of Xi\u2019an Jiaotong University, Shannxi 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqiang","family":"Lv","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Gao","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijun","family":"Cao","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Science, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingjie","family":"Meng","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Science, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangang","family":"Long","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, 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Aging"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S22","DOI":"10.1002\/ana.410320706","article-title":"Free radical damage to protein and DNA: Mechanisms involved and relevant observations on brain undergoing oxidative stress","volume":"32","author":"Floyd","year":"1992","journal-title":"Ann. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.redox.2018.01.008","article-title":"13 reasons why the brain is susceptible to oxidative stress","volume":"15","author":"Cobley","year":"2018","journal-title":"Redox Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/jnc.14037","article-title":"Brain aging and neurodegeneration: From a mitochondrial point of view","volume":"143","author":"Grimm","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1126\/science.1128134","article-title":"Learning Induces Long-Term Potentiation in the Hippocampus","volume":"313","author":"Whitlock","year":"2006","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1111\/j.1460-9568.2006.04957.x","article-title":"Glutamate enhances proliferation and neu-rogenesis in human neural progenitor cell cultures derived from the fetal cortex","volume":"24","author":"Suzuki","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102069","DOI":"10.1016\/j.nicl.2019.102069","article-title":"Role of cerebral glutamate in post-stroke epileptogenesis","volume":"24","author":"Nicolo","year":"2019","journal-title":"NeuroImage: Clin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1089\/neu.2015.4373","article-title":"Glutamate Neurotransmission in Rodent Models of Traumatic Brain Injury","volume":"34","author":"Dorsett","year":"2017","journal-title":"J. Neurotrauma"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/sj.mp.4001551","article-title":"Glutamate as a therapeutic target in psychiatric disorders","volume":"9","author":"Javitt","year":"2004","journal-title":"Mol. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.neuint.2004.03.007","article-title":"Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer\u2019s disease","volume":"45","author":"Hynd","year":"2004","journal-title":"Neu-rochem. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/aps.2009.24","article-title":"Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegen-erative diseases","volume":"30","author":"Dong","year":"2009","journal-title":"Acta Pharmacol. Sinica"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2009.06.059","article-title":"Mechanism of glutamate-Induced neurotoxicity in HT22 mouse hippocampal cells","volume":"617","author":"Fukui","year":"2009","journal-title":"Eur. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.phymed.2007.02.001","article-title":"Glutamate-induced cell death in neuronal HT22 cells is attenuated by extracts from St. John\u2019s wort (Hypericum perforatum L.)","volume":"14","author":"Breyer","year":"2007","journal-title":"Phytomedicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1007\/s12640-017-9811-0","article-title":"Neuroprotective Effects of Kinetin Against Glutamate-Induced Oxidative Cytotoxicity in HT22 Cells: Involvement of Nrf2 and Heme Oxygenase","volume":"33","author":"Wei","year":"2017","journal-title":"Neurotox. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/cdd.2010.92","article-title":"Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons","volume":"18","author":"Tobaben","year":"2010","journal-title":"Cell Death Differ."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/cdd.2017.161","article-title":"The BCL-2 arbiters of apoptosis and their growing role as cancer targets","volume":"25","author":"Adams","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.biopsych.2013.04.025","article-title":"Scopolamine Rapidly Increases Mammalian Target of Rapamycin Complex 1 Signaling, Synaptogenesis, and Antidepressant Behavioral Responses","volume":"74","author":"Voleti","year":"2013","journal-title":"Biol. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1016\/j.neubiorev.2010.04.001","article-title":"The validity of scopolamine as a pharmacological model for cognitive impairment: A review of animal behavioral studies","volume":"34","author":"Klinkenberg","year":"2010","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111777","DOI":"10.1016\/j.ejmech.2019.111777","article-title":"A novel chalcone derivative as Nrf2 activator attenuates learning and memory impairment in a scopolamine-induced mouse model","volume":"185","author":"Kim","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.fct.2013.05.007","article-title":"Cognitive-enhancing effects of Rhus verniciflua bark extract and its active flavonoids with neuroprotective and anti-inflammatory activities","volume":"58","author":"Cho","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ejphar.2010.09.001","article-title":"Neuroprotective effects of chlorogenic acid on scopolamine-induced amnesia via anti-acetylcholinesterase and anti-oxidative activities in mice","volume":"649","author":"Kwon","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1038\/sj.npp.1301591","article-title":"Nasal Colivelin treatment ameliorates memory impairment related to Alzheimer\u2019s disease","volume":"33","author":"Yamada","year":"2008","journal-title":"Neuropsychopharmacology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1007\/s12035-018-1164-z","article-title":"Vdac1 Downregulation Causes Mitochondrial Disintegration Leading to Hippocampal Neuro-degeneration in Scopolamine-Induced Amnesic Mice","volume":"56","author":"Baghel","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1111\/j.1471-4159.2010.06865.x","article-title":"High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: Implications for decreased Nrf2 signaling","volume":"114","author":"Morrison","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1179\/1476830513Y.0000000092","article-title":"Damaging effects of a high-fat diet to the brain and cognition: A review of proposed mechanisms","volume":"17","author":"Freeman","year":"2013","journal-title":"Nutr. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.ejmech.2014.08.033","article-title":"Recent developments in biological activities of chalcones: A mini review","volume":"85","author":"Singh","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.freeradbiomed.2019.12.033","article-title":"Structure based modification of chalcone analogue activates Nrf2 in the human retinal pigment epithelial cell line ARPE-19","volume":"148","author":"Cui","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101948","DOI":"10.1016\/j.redox.2021.101948","article-title":"Htd2 deficiency-associated sup-pression of alpha-lipoic acid production provokes mitochondrial dysfunction and insulin resistance in adipocytes","volume":"41","author":"Zeng","year":"2021","journal-title":"Redox Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1002\/mnfr.201500490","article-title":"Punicalagin attenuates palmitate-induced lipotoxicity in HepG2 cells by activating the Keap1-Nrf2 antioxidant defense system","volume":"60","author":"Yan","year":"2016","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_30","first-page":"e52434","article-title":"Use of the open field maze to measure locomotor and anxiety-like behavior in mice","volume":"96","author":"Seibenhener","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1002\/9780470942390.mo150068","article-title":"Assessing Cognition in Mice","volume":"5","author":"Holter","year":"2015","journal-title":"Curr. Protoc. Mouse Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/nprot.2006.116","article-title":"Morris water maze: Procedures for assessing spatial and related forms of learning and memory","volume":"1","author":"Vorhees","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/nrn2421","article-title":"Brain foods: The effects of nutrients on brain function","volume":"9","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3389\/fnagi.2014.00026","article-title":"Cognitive decline due to excess synaptic Zn(2+) signaling in the hippocampus","volume":"6","author":"Takeda","year":"2014","journal-title":"Front. Aging Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms4672","article-title":"Cellular protection using Flt3 and PI3K\u03b1 inhibitors demonstrates multiple mechanisms of oxidative glutamate toxicity","volume":"5","author":"Kang","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10818","DOI":"10.3390\/molecules190810818","article-title":"Cudarflavone B Provides Neuroprotection against Glutamate-Induced Mouse Hippocampal HT22 Cell Damage through the Nrf2 and PI3K\/Akt Signaling Pathways","volume":"19","author":"Lee","year":"2014","journal-title":"Molecules"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1089\/ars.2008.2242","article-title":"The Nrf2\/ARE Pathway as a Potential Therapeutic Target in Neurodegenerative Disease","volume":"11","author":"Calkins","year":"2009","journal-title":"Antioxidants Redox Signal."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"16505","DOI":"10.1073\/pnas.0908397106","article-title":"Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer\u2019s disease","volume":"106","author":"Kanninen","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.neuint.2017.11.006","article-title":"Activation of the Nrf2 signaling pathway and neuroprotection of nigral dopaminergic neurons by a novel synthetic compound KMS992220","volume":"112","author":"Lee","year":"2018","journal-title":"Neurochem. Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1021\/jm2016073","article-title":"A Synthetic Chalcone as a Potent Inducer of Glutathione Biosynthesis","volume":"55","author":"Kachadourian","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/j.freeradbiomed.2010.06.002","article-title":"Mechanism for the protective effect of resveratrol against oxidative stress-induced neuronal death","volume":"49","author":"Fukui","year":"2010","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"197","DOI":"10.3164\/jcbn.2008029","article-title":"Integrative Survival Response Evoked by Heme Oxygenase-1 and Heme Metabolites","volume":"42","author":"Pae","year":"2008","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1017\/S0007114515000884","article-title":"Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain of db\/db mice: Role of AMP-activated protein kinase activation","volume":"113","author":"Zheng","year":"2015","journal-title":"Br. J. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.brainres.2011.12.063","article-title":"Insulin signaling, glucose metabolism and mitochondria: Major players in Alzheimer\u2019s disease and diabetes interrelation","volume":"1441","author":"Correia","year":"2012","journal-title":"Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"991","DOI":"10.2337\/db12-0209","article-title":"Mitochondria, Diabetes, and Alzheimer\u2019s Disease","volume":"61","author":"Milone","year":"2012","journal-title":"Diabetes"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/11\/1811\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:30:32Z","timestamp":1760167832000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/11\/1811"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,15]]},"references-count":45,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["antiox10111811"],"URL":"https:\/\/doi.org\/10.3390\/antiox10111811","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,15]]}}}