Academic Journal
Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis.
| Title: | Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis. |
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| Authors: | Tan X; Medical Department, City University of Wuhan, Wuhan, Hubei Province, China. xqtan@wic.edu.cn., Gao Y; Medical Department, City University of Wuhan, Wuhan, Hubei Province, China., Zhang L; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China., He Y; Medical Department, City University of Wuhan, Wuhan, Hubei Province, China., Li QX; Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, Hawaii, USA. qingl@hawaii.edu.; Hawaii Pacific Neuroscience, 2230 Liliha Street, Honolulu, 96817, HI, USA. qingl@hawaii.edu., Dong Y; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China. dondy001@gzucm.edu.cn. |
| Source: | Metabolic brain disease [Metab Brain Dis] 2026 Jul 17; Vol. 41 (1). Date of Electronic Publication: 2026 Jul 17. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Springer Country of Publication: United States NLM ID: 8610370 Publication Model: Electronic Cited Medium: Internet ISSN: 1573-7365 (Electronic) Linking ISSN: 08857490 NLM ISO Abbreviation: Metab Brain Dis Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2005- : Amsterdam : Springer Original Publication: New York : Plenum, c1986- |
| MeSH Terms: | Oxidative Stress*/drug effects , Glycogen Synthase Kinase 3 beta*/metabolism , NF-E2-Related Factor 2*/metabolism , Luteolin*/pharmacology , Luteolin*/therapeutic use , Diabetes Mellitus, Type 2*/metabolism , Diabetes Mellitus, Type 2*/drug therapy , Diabetes Mellitus, Type 2*/complications , Cognitive Dysfunction*/metabolism , Cognitive Dysfunction*/drug therapy , Cognitive Dysfunction*/etiology, Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/drug therapy ; Signal Transduction/drug effects ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/therapeutic use ; Apoptosis/drug effects ; Brain/drug effects ; Brain/metabolism ; Animals ; Mice ; Male ; Mice, Inbred C57BL |
| Abstract: | Type 2 diabetes-associated cognitive dysfunction (TDACD) is a recognized metabolic brain disorder with limited therapeutic options. This preclinical study investigated whether isoorientin (ISO) confers neuroprotection in TDACD and examined the involvement of the glycogen synthase kinase-3β/nuclear factor erythroid 2-related factor 2 (GSK3β/Nrf2) pathway in its effects. A mouse model of TDACD was induced by high-fat diet and streptozotocin. Mice were administered ISO for six weeks. The systemic metabolism and cognitive behavior were evaluated. The synaptic protein expression, apoptosis, tau phosphorylation, oxidative stress in the brain were detected to identify the pathological signature. The activity of GSK3β and the expression of its downstream targets Nrf2 and heme oxygenase-1 (HO-1) were analyzed to elucidate the mechanism. ISO improved systemic glucose metabolism and alleviated hepatic steatosis, and reversed cognitive deficits. In the brain, ISO restored synaptic proteins (PSD-95, BDNF, soluble α-synuclein), exerted anti-apoptotic effects (increased Bcl-2/Bax ratio, decreased cleaved caspase-3), and attenuated oxidative stress and mitochondrial damage. Mechanistically, ISO inhibited GSK3β activity, promoted Nrf2 nuclear accumulation, upregulated HO-1 expression, and reduced tau phosphorylation at Ser396. These findings demonstrate that ISO exerts a neuroprotective effect in TDACD model by inhibiting oxidative stress via GSK3β/Nrf2 pathway, and highlight ISO as a potential therapeutic candidate for TDACD. (© 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) |
| Competing Interests: | Declarations. Ethics approval: This study was approved by the Ethical Committee of Medical Research of ZHBY Biotech Co., Ltd (Nanchang, China) (Approval No.: LL-202312260004) and the Ethical Committee of Medical Research of City University of Wuhan (Wuhan, China) (Approval No.: CVW2025006). Consent to publish: All authors have reviewed and approved the manuscript for submission. Competing interests: The authors declare no competing interests. |
| References: | Aarsland D, Batzu L, Halliday GM et al (2021) Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers 7:47. https://doi.org/10.1038/s41572-021-00280-3. (PMID: 10.1038/s41572-021-00280-334210995) Abdulwahab DA, El-Missiry MA, Shabana S et al (2021) Melatonin protects the heart and pancreas by improving glucose homeostasis, oxidative stress, inflammation and apoptosis in T2DM-induced rats. Heliyon 7:e06474. https://doi.org/10.1016/j.heliyon.2021.e06474. (PMID: 10.1016/j.heliyon.2021.e06474337485047970364) Alqahtani SM, Al-Kuraishy HM, Al-Gareeb AI et al (2025) Targeting of PP2A/GSK3β/PTEN axis in Alzheimer disease: the mooting evidence, divine, and devil. Cell Mol Neurobiol 45:36. https://doi.org/10.1007/s10571-025-01554-0. (PMID: 10.1007/s10571-025-01554-04025134812008108) Cao Y, Li M, Gu L et al (2023) Chinese traditional formula Kaixin San suppressed ferroptosis of hippocampal neurons and cardiomyocytes in mice with paradoxical sleep deprivation. J Ethnopharmacol 304:116034. https://doi.org/10.1016/j.jep.2022.116034. (PMID: 10.1016/j.jep.2022.11603436529245) Chen X, Liu Y, Zhu J et al (2016) GSK-3β downregulates Nrf2 in cultured cortical neurons and in a rat model of cerebral ischemia-reperfusion. Sci Rep 6:20196. https://doi.org/10.1038/srep20196. (PMID: 10.1038/srep20196268381644738318) Dai P, Yu Y, Sun Q et al (2024) Abnormal changes of brain function and structure in patients with T2DM-related cognitive impairment: a neuroimaging meta-analysis and an independent validation. Nutr Diabetes 14:91. https://doi.org/10.1038/s41387-024-00348-5. (PMID: 10.1038/s41387-024-00348-53952844211554684) Dhaliwal J, Dhaliwal N, Akhtar A et al (2022) Tetramethylpyrazine attenuates cognitive impairment via suppressing oxidative stress, neuroinflammation, and apoptosis in type 2 diabetic rats. Neurochem Res 47:2431–2444. https://doi.org/10.1007/s11064-022-03640-x. (PMID: 10.1007/s11064-022-03640-x35665448) Gan Y, Li X, Han S et al (2023) Targeting Mcl-1 degradation by bergenin inhibits tumorigenesis of colorectal cancer cells. Pharmaceuticals 16. https://doi.org/10.3390/ph16020241. (PMID: 10.3390/ph16020241) Gao X, Sun H, Wei Y et al (2024a) Protective effect of melatonin against metabolic disorders and neuropsychiatric injuries in type 2 diabetes mellitus mice. Phytomedicine 131:155805. https://doi.org/10.1016/j.phymed.2024.155805. (PMID: 10.1016/j.phymed.2024.15580538851097) Gao Y, Yu H, Liu Y et al (2024b) GSK-3β activation mediates apolipoprotein E4-associated cognitive impairment in type 2 diabetes mellitus: a multicenter, cross-sectional study. J Diabetes 16:e13470. https://doi.org/10.1111/1753-0407.13470. (PMID: 10.1111/1753-0407.1347037700547) Goodman LD, Ralhan I, Li X et al (2024) Tau is required for glial lipid droplet formation and resistance to neuronal oxidative stress. Nat Neurosci 27:1918–1933. https://doi.org/10.1038/s41593-024-01740-1. (PMID: 10.1038/s41593-024-01740-13918770611809452) Guo M, Ye Y, Li X et al (2025) Kirenol alleviates cerebral ischemic injury by promoting synaptic plasticity via HDAC2-mediated BDNF expression. Phytomedicine 143:156605. https://doi.org/10.1016/j.phymed.2025.156605. (PMID: 10.1016/j.phymed.2025.15660540446576) Hamzé R, Delangre E, Tolu S et al (2022) Type 2 diabetes mellitus and Alzheimer’s disease: shared molecular mechanisms and potential common therapeutic targets. Int J Mol Sci 23. https://doi.org/10.3390/ijms232315287. (PMID: 10.3390/ijms232315287) Han C, Kong X, Xia X et al (2023) Effects of ginseng peptides on the hypoglycemic activity and gut microbiota of a type 2 diabetes mellitus mice model. J Funct Foods 111:105897. https://doi.org/10.1016/j.jff.2023.105897. (PMID: 10.1016/j.jff.2023.105897) He C, Wang K, Xia J et al (2023) Natural exosomes-like nanoparticles in mung bean sprouts possesses anti-diabetic effects via activation of PI3K/Akt/GLUT4/GSK-3β signaling pathway. J Nanobiotechnol 21:349. https://doi.org/10.1186/s12951-023-02120-w. (PMID: 10.1186/s12951-023-02120-w) He D, Hao Z, Zhao M et al (2025a) Structural and functional brain abnormal alteration in patients with type 2 diabetes mellitus: a coordinate-based meta-analysis. Transl Psychiatry 15:269. https://doi.org/10.1038/s41398-025-03488-z. (PMID: 10.1038/s41398-025-03488-z4077017412328820) He L, Gao Y, Ju C et al (2025b) Collagen peptides alleviate hyperglycemia in mice by modulating insulin resistance, glucose metabolism and gut microbiota. Int J Biol Macromol 301:140498. https://doi.org/10.1016/j.ijbiomac.2025.140498. (PMID: 10.1016/j.ijbiomac.2025.14049839889980) He S, Lu JJ, Wu JJ et al (2025c) Altered cerebellar activity and cognitive deficits in Type 2 diabetes: insights from resting-state fMRI. Brain Res 1856:149586. https://doi.org/10.1016/j.brainres.2025.149586. (PMID: 10.1016/j.brainres.2025.14958640113193) Huang W, Wu D, Cai C et al (2024) Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetes. Redox Biol 71:103104. https://doi.org/10.1016/j.redox.2024.103104. (PMID: 10.1016/j.redox.2024.1031043843068310914584) John CM, Mohamed Yusof NIS, Abdul Aziz SH et al (2018) Maternal cognitive impairment associated with gestational diabetes mellitus-a review of potential contributing mechanisms. Int J Mol Sci 19. https://doi.org/10.3390/ijms19123894. (PMID: 10.3390/ijms19123894) Koivisto H, Maguire C, Tanila H (2025) Novel object recognition task for mice: is it a test for memory, object neophobia or innate preference? Behav Brain Res 491:115649. https://doi.org/10.1016/j.bbr.2025.115649. (PMID: 10.1016/j.bbr.2025.11564940414309) La Vitola P, Szegö EM, Pinto-Costa R et al (2024) Mitochondrial oxidant stress promotes α-synuclein aggregation and spreading in mice with mutated glucocerebrosidase. NPJ Parkinsons Dis 10:233. https://doi.org/10.1038/s41531-024-00842-8. (PMID: 10.1038/s41531-024-00842-83966335411634889) Lai S, Wang P, Gong J et al (2023) New insights into the role of GSK-3β in the brain: from neurodegenerative disease to tumorigenesis. PeerJ 11:e16635. https://doi.org/10.7717/peerj.16635. (PMID: 10.7717/peerj.166353810756210722984) Li Y, Zhao Y, Tan X et al (2020) Isoorientin inhibits inflammation in macrophages and endotoxemia mice by regulating glycogen synthase kinase 3β. Mediators Inflamm 2020: 8704146. https://doi.org/10.1155/2020/8704146. Li Q, Zhao Y, Guo H et al (2023) Impaired lipophagy induced-microglial lipid droplets accumulation contributes to the buildup of TREM1 in diabetes-associated cognitive impairment. Autophagy 19:2639–2656. https://doi.org/10.1080/15548627.2023.2213984. (PMID: 10.1080/15548627.2023.22139843720411910472854) Liang Z, Zhang B, Su WW et al (2016) C-Glycosylflavones alleviate Tau phosphorylation and amyloid neurotoxicity through GSK3β inhibition. ACS Chem Neurosci 7:912–923. https://doi.org/10.1021/acschemneuro.6b00059. (PMID: 10.1021/acschemneuro.6b00059272138247355085) Linseman DA, Butts BD, Precht TA et al (2004) Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci 24:9993–10002. https://doi.org/10.1523/jneurosci.2057-04.2004. (PMID: 10.1523/jneurosci.2057-04.2004155257856730230) Liu G, Yang C, Wang X et al (2023) Oxygen metabolism abnormality and Alzheimer’s disease: an update. Redox Biol 68:102955. https://doi.org/10.1016/j.redox.2023.102955. (PMID: 10.1016/j.redox.2023.1029553795659810665957) Luo A, Xie Z, Wang Y et al (2022) Type 2 diabetes mellitus-associated cognitive dysfunction: advances in potential mechanisms and therapies. Neurosci Biobehav Rev 137:104642. https://doi.org/10.1016/j.neubiorev.2022.104642. (PMID: 10.1016/j.neubiorev.2022.10464235367221) Mayor E (2023) Neurotrophic effects of intermittent fasting, calorie restriction and exercise: a review and annotated bibliography. Front Aging 4:1161814. https://doi.org/10.3389/fragi.2023.1161814. (PMID: 10.3389/fragi.2023.11618143733404510273285) Murakami S, Kusano Y, Okazaki K et al (2023) NRF2 signalling in cytoprotection and metabolism. Br J Pharmacol. https://doi.org/10.1111/bph.16246. (PMID: 10.1111/bph.1624637715470) Numakawa T, Kajihara R (2025) The role of brain-derived neurotrophic factor as an essential mediator in neuronal functions and the therapeutic potential of its mimetics for neuroprotection in neurologic and psychiatric disorders. Molecules 30. https://doi.org/10.3390/molecules30040848. (PMID: 10.3390/molecules30040848) Patibandla C, van Aalten L, Dinkova-Kostova AT et al (2024) Inhibition of glycogen synthase kinase-3 enhances NRF2 protein stability, nuclear localisation and target gene transcription in pancreatic beta cells. Redox Biol 71. https://doi.org/10.1016/j.redox.2024.103117. (PMID: 10.1016/j.redox.2024.103117) Raza A, Saleem S, Imran S et al (2025) From metabolic dysregulation to neurodegenerative pathology: the role of hyperglycemia, oxidative stress, and blood-brain barrier breakdown in T2D-driven Alzheimer’s disease. Metab Brain Dis 40:276. https://doi.org/10.1007/s11011-025-01700-z. (PMID: 10.1007/s11011-025-01700-z4100379612474712) Sahoo S, Padhy AA, Kumari V et al (2022) Role of ubiquitin-proteasome and autophagy-lysosome pathways in α-synuclein aggregate clearance. Mol Neurobiol 59:5379–5407. https://doi.org/10.1007/s12035-022-02897-1. (PMID: 10.1007/s12035-022-02897-135699874) Salazar M, Rojo AI, Velasco D et al (2006) Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 281:14841–14851. https://doi.org/10.1074/jbc.M513737200. (PMID: 10.1074/jbc.M51373720016551619) Shen Z, Li ZY, Yu MT et al (2023) Metabolic perspective of astrocyte dysfunction in Alzheimer’s disease and type 2 diabetes brains. Biomed Pharmacother 158:114206. https://doi.org/10.1016/j.biopha.2022.114206. (PMID: 10.1016/j.biopha.2022.11420636916433) Shi X, Zhou XZ, Chen G et al (2024) Targeting the postsynaptic scaffolding protein PSD-95 enhances BDNF signaling to mitigate depression-like behaviors in mice. Sci Signal 17:eadn4556. https://doi.org/10.1126/scisignal.adn4556. (PMID: 10.1126/scisignal.adn45563868782611223518) Soni D, Kumar P (2022) GSK-3β-mediated regulation of Nrf2/HO-1 signaling as a new therapeutic approach in the treatment of movement disorders. Pharmacol Rep 74:557–569. https://doi.org/10.1007/s43440-022-00390-z. (PMID: 10.1007/s43440-022-00390-z35882765) Tan X, Liang Z, Li Y et al (2021) Isoorientin, a GSK-3β inhibitor, rescues synaptic dysfunction, spatial memory deficits and attenuates pathological progression in APP/PS1 model mice. Behav Brain Res 398:112968. https://doi.org/10.1016/j.bbr.2020.112968. (PMID: 10.1016/j.bbr.2020.11296833069740) Tang W, Yan C, He S et al (2023) Neuron-targeted overexpression of caveolin-1 alleviates diabetes-associated cognitive dysfunction via regulating mitochondrial fission-mitophagy axis. Cell Commun Signal 21:357. https://doi.org/10.1186/s12964-023-01328-5. (PMID: 10.1186/s12964-023-01328-53810266210722701) Thakkar H, Chatterjee S, Verma A et al (2025) Malondialdehyde-mediated alpha-synuclein aggregation: a plausible etiology of Parkinson’s disease in oxidative stress. Chem Res Toxicol 38:573–582. https://doi.org/10.1021/acs.chemrestox.4c00348. (PMID: 10.1021/acs.chemrestox.4c0034840190040) Thorp EB, Flanagan ME, Popko B et al (2022) Resolving inflammatory links between myocardial infarction and vascular dementia. Semin Immunol 59:101600. https://doi.org/10.1016/j.smim.2022.101600. (PMID: 10.1016/j.smim.2022.1016003522756710234261) Urkon M, Ferencz E, Szász JA et al (2025) Antidiabetic GLP-1 receptor agonists have neuroprotective properties in experimental animal models of Alzheimer’s disease. Pharmaceuticals 18. https://doi.org/10.3390/ph18050614. (PMID: 10.3390/ph18050614) Verma A, Sharma M, Alam O et al (2026) Type 3 diabetes: a molecular link between cerebral insulin resistance and neurodegeneration via AGE-RAGE signaling. Eur J Neurosci 63:e70364. https://doi.org/10.1111/ejn.70364. (PMID: 10.1111/ejn.7036441459736) Wang JT, Wang XR, Ren JQ et al (2024) S-9-PAHSA’s neuroprotective effect mediated by CAIII suppresses apoptosis and oxidative stress in a mouse model of type 2 diabetes. CNS Neurosci Ther 30:e14594. https://doi.org/10.1111/cns.14594. (PMID: 10.1111/cns.145943833253810853598) Wang R, Liu X, Yang K et al (2025) Bioactive component screening and mechanistic study of the anti-diabetic activity of Lophatherum gracile Brongn extract. Curr Issues Mol Biol 47. https://doi.org/10.3390/cimb47090779. (PMID: 10.3390/cimb47090779) Wen P, Sun Z, Gou F et al (2025) Oxidative stress and mitochondrial impairment: key drivers in neurodegenerative disorders. Ageing Res Rev 104:102667. https://doi.org/10.1016/j.arr.2025.102667. (PMID: 10.1016/j.arr.2025.10266739848408) Xiang J, Ran LY, Zeng XX et al (2021) LiCl attenuates impaired learning and memory of APP/PS1 mice, which in mechanism involves α7 nAChRs and Wnt/β-catenin pathway. J Cell Mol Med 25:10698–10710. https://doi.org/10.1111/jcmm.17006. (PMID: 10.1111/jcmm.17006347085228581309) Yang K, Chen Z, Gao J et al (2017) The key roles of GSK-3β in regulating mitochondrial activity. Cell Physiol Biochem 44:1445–1459. https://doi.org/10.1159/000485580. (PMID: 10.1159/00048558029190615) Yen YC, Gassen NC, Zellner A et al (2015) Glycogen synthase kinase-3β inhibition in the medial prefrontal cortex mediates paradoxical amphetamine action in a mouse model of ADHD. Front Behav Neurosci 9:67. https://doi.org/10.3389/fnbeh.2015.00067. (PMID: 10.3389/fnbeh.2015.00067258525084367184) Zhang W, Sun C, Huang Y et al (2025) Inflammation levels in type 2 diabetes mellitus patients with mild cognitive impairment: assessment followed by amelioration via dapagliflozin therapy. J Diabetes Complications 39:109017. https://doi.org/10.1016/j.jdiacomp.2025.109017. (PMID: 10.1016/j.jdiacomp.2025.10901740228375) Zhao Y, He C, Hu S et al (2024) Anti-oxidative stress and cognitive improvement of a semi-synthetic isoorientin-based GSK-3β inhibitor in rat pheochromocytoma cell PC12 and scopolamine-induced AD model mice via AKT/GSK-3β/Nrf2 pathway. Exp Neurol 380:114881. https://doi.org/10.1016/j.expneurol.2024.114881. (PMID: 10.1016/j.expneurol.2024.11488138996864) Zhou S, Wang P, Qiao Y et al (2016) Genetic and pharmacologic targeting of glycogen synthase kinase 3β reinforces the Nrf2 antioxidant defense against podocytopathy. J Am Soc Nephrol 27:2289–2308. https://doi.org/10.1681/asn.2015050565. (PMID: 10.1681/asn.201505056526647425) |
| Grant Information: | HAW05044-R the USDA Hatch Project |
| Contributed Indexing: | Keywords: Diabetic cognitive dysfunction; GSK3β/Nrf2 axis; Isoorientin; Neuroprotection; Oxidative stress |
| Substance Nomenclature: | EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) 0 (NF-E2-Related Factor 2) KUX1ZNC9J2 (Luteolin) A37342TIX1 (homoorientin) 0 (Nfe2l2 protein, mouse) EC 2.7.11.1 (Gsk3b protein, mouse) 0 (Neuroprotective Agents) |
| Entry Date(s): | Date Created: 20260717 Date Completed: 20260717 Latest Revision: 20260720 |
| Update Code: | 20260720 |
| DOI: | 10.1007/s11011-026-01938-1 |
| PMID: | 42467274 |
| Database: | MEDLINE |
| FullText | Links: – Type: other Url: https://resolver.ebsco.com:443/public/rma-ftfapi/ejs/direct?AccessToken=4156BAEF9D55A507AD51&Show=Object Text: Availability: 0 CustomLinks: – Url: https://dx.doi.org/doi:10.1007/s11011-026-01938-1 Name: EDS - Springer Nature Journals (s7799221) Category: fullText Text: View record at Springer |
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| Items | – Name: Title Label: Title Group: Ti Data: Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AU" term="%22Tan+X%22">Tan X</searchLink>; Medical Department, City University of Wuhan, Wuhan, Hubei Province, China. xqtan@wic.edu.cn.<br /><searchLink fieldCode="AU" term="%22Gao+Y%22">Gao Y</searchLink>; Medical Department, City University of Wuhan, Wuhan, Hubei Province, China.<br /><searchLink fieldCode="AU" term="%22Zhang+L%22">Zhang L</searchLink>; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.<br /><searchLink fieldCode="AU" term="%22He+Y%22">He Y</searchLink>; Medical Department, City University of Wuhan, Wuhan, Hubei Province, China.<br /><searchLink fieldCode="AU" term="%22Li+QX%22">Li QX</searchLink>; Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, Hawaii, USA. qingl@hawaii.edu.; Hawaii Pacific Neuroscience, 2230 Liliha Street, Honolulu, 96817, HI, USA. qingl@hawaii.edu.<br /><searchLink fieldCode="AU" term="%22Dong+Y%22">Dong Y</searchLink>; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China. dondy001@gzucm.edu.cn. – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%228610370%22">Metabolic brain disease</searchLink> [Metab Brain Dis] 2026 Jul 17; Vol. 41 (1). <i>Date of Electronic Publication: </i>2026 Jul 17. – Name: TypePub Label: Publication Type Group: TypPub Data: Journal Article; Research Support, Non-U.S. Gov't – Name: Language Label: Language Group: Lang Data: English – Name: TitleSource Label: Journal Info Group: Src Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Springer%22">Springer </searchLink><i>Country of Publication: </i>United States <i>NLM ID: </i>8610370 <i>Publication Model: </i>Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1573-7365 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2208857490%22">08857490 </searchLink><i>NLM ISO Abbreviation: </i>Metab Brain Dis <i>Subsets: </i>MEDLINE – Name: PublisherInfo Label: Imprint Name(s) Group: PubInfo Data: <i>Publication</i>: 2005- : Amsterdam : Springer<br /><i>Original Publication</i>: New York : Plenum, c1986- – Name: SubjectMESH Label: MeSH Terms Group: Su Data: <searchLink fieldCode="MM" term="%22Oxidative+Stress%22">Oxidative Stress*</searchLink>/<searchLink fieldCode="MM" term="%22Oxidative+Stress+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Glycogen+Synthase+Kinase+3+beta%22">Glycogen Synthase Kinase 3 beta*</searchLink>/<searchLink fieldCode="MM" term="%22Glycogen+Synthase+Kinase+3+beta+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22NF-E2-Related+Factor+2%22">NF-E2-Related Factor 2*</searchLink>/<searchLink fieldCode="MM" term="%22NF-E2-Related+Factor+2+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Luteolin%22">Luteolin*</searchLink>/<searchLink fieldCode="MM" term="%22Luteolin+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Luteolin%22">Luteolin*</searchLink>/<searchLink fieldCode="MM" term="%22Luteolin+therapeutic+use%22">therapeutic use</searchLink> <br /><searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2%22">Diabetes Mellitus, Type 2*</searchLink>/<searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2%22">Diabetes Mellitus, Type 2*</searchLink>/<searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2+drug+therapy%22">drug therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2%22">Diabetes Mellitus, Type 2*</searchLink>/<searchLink fieldCode="MM" term="%22Diabetes+Mellitus%2C+Type+2+complications%22">complications</searchLink> <br /><searchLink fieldCode="MM" term="%22Cognitive+Dysfunction%22">Cognitive Dysfunction*</searchLink>/<searchLink fieldCode="MM" term="%22Cognitive+Dysfunction+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Cognitive+Dysfunction%22">Cognitive Dysfunction*</searchLink>/<searchLink fieldCode="MM" term="%22Cognitive+Dysfunction+drug+therapy%22">drug therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Cognitive+Dysfunction%22">Cognitive Dysfunction*</searchLink>/<searchLink fieldCode="MM" term="%22Cognitive+Dysfunction+etiology%22">etiology</searchLink><br /><searchLink fieldCode="MH" term="%22Diabetes+Mellitus%2C+Experimental%22">Diabetes Mellitus, Experimental</searchLink>/<searchLink fieldCode="MH" term="%22Diabetes+Mellitus%2C+Experimental+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Diabetes+Mellitus%2C+Experimental%22">Diabetes Mellitus, Experimental</searchLink>/<searchLink fieldCode="MH" term="%22Diabetes+Mellitus%2C+Experimental+drug+therapy%22">drug therapy</searchLink> ; <searchLink fieldCode="MH" term="%22Signal+Transduction%22">Signal Transduction</searchLink>/<searchLink fieldCode="MH" term="%22Signal+Transduction+drug+effects%22">drug effects</searchLink> ; <searchLink fieldCode="MH" term="%22Neuroprotective+Agents%22">Neuroprotective Agents</searchLink>/<searchLink fieldCode="MH" term="%22Neuroprotective+Agents+pharmacology%22">pharmacology</searchLink> ; <searchLink fieldCode="MH" term="%22Neuroprotective+Agents%22">Neuroprotective Agents</searchLink>/<searchLink fieldCode="MH" term="%22Neuroprotective+Agents+therapeutic+use%22">therapeutic use</searchLink> ; <searchLink fieldCode="MH" term="%22Apoptosis%22">Apoptosis</searchLink>/<searchLink fieldCode="MH" term="%22Apoptosis+drug+effects%22">drug effects</searchLink> ; <searchLink fieldCode="MH" term="%22Brain%22">Brain</searchLink>/<searchLink fieldCode="MH" term="%22Brain+drug+effects%22">drug effects</searchLink> ; <searchLink fieldCode="MH" term="%22Brain%22">Brain</searchLink>/<searchLink fieldCode="MH" term="%22Brain+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%2C+Inbred+C57BL%22">Mice, Inbred C57BL</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Type 2 diabetes-associated cognitive dysfunction (TDACD) is a recognized metabolic brain disorder with limited therapeutic options. This preclinical study investigated whether isoorientin (ISO) confers neuroprotection in TDACD and examined the involvement of the glycogen synthase kinase-3β/nuclear factor erythroid 2-related factor 2 (GSK3β/Nrf2) pathway in its effects. A mouse model of TDACD was induced by high-fat diet and streptozotocin. Mice were administered ISO for six weeks. The systemic metabolism and cognitive behavior were evaluated. The synaptic protein expression, apoptosis, tau phosphorylation, oxidative stress in the brain were detected to identify the pathological signature. The activity of GSK3β and the expression of its downstream targets Nrf2 and heme oxygenase-1 (HO-1) were analyzed to elucidate the mechanism. ISO improved systemic glucose metabolism and alleviated hepatic steatosis, and reversed cognitive deficits. In the brain, ISO restored synaptic proteins (PSD-95, BDNF, soluble α-synuclein), exerted anti-apoptotic effects (increased Bcl-2/Bax ratio, decreased cleaved caspase-3), and attenuated oxidative stress and mitochondrial damage. Mechanistically, ISO inhibited GSK3β activity, promoted Nrf2 nuclear accumulation, upregulated HO-1 expression, and reduced tau phosphorylation at Ser396. These findings demonstrate that ISO exerts a neuroprotective effect in TDACD model by inhibiting oxidative stress via GSK3β/Nrf2 pathway, and highlight ISO as a potential therapeutic candidate for TDACD.<br /> (© 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) – Name: Abstract Label: Competing Interests Group: Ab Data: Declarations. Ethics approval: This study was approved by the Ethical Committee of Medical Research of ZHBY Biotech Co., Ltd (Nanchang, China) (Approval No.: LL-202312260004) and the Ethical Committee of Medical Research of City University of Wuhan (Wuhan, China) (Approval No.: CVW2025006). Consent to publish: All authors have reviewed and approved the manuscript for submission. Competing interests: The authors declare no competing interests. – Name: Ref Label: References Group: RefInfo Data: Aarsland D, Batzu L, Halliday GM et al (2021) Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers 7:47. https://doi.org/10.1038/s41572-021-00280-3. (PMID: <searchLink fieldCode="PM" term="%2210%2E1038%2Fs41572-021-00280-334210995%22">10.1038/s41572-021-00280-334210995)</searchLink><br />Abdulwahab DA, El-Missiry MA, Shabana S et al (2021) Melatonin protects the heart and pancreas by improving glucose homeostasis, oxidative stress, inflammation and apoptosis in T2DM-induced rats. Heliyon 7:e06474. https://doi.org/10.1016/j.heliyon.2021.e06474. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Eheliyon%2E2021%2Ee06474337485047970364%22">10.1016/j.heliyon.2021.e06474337485047970364)</searchLink><br />Alqahtani SM, Al-Kuraishy HM, Al-Gareeb AI et al (2025) Targeting of PP2A/GSK3β/PTEN axis in Alzheimer disease: the mooting evidence, divine, and devil. Cell Mol Neurobiol 45:36. https://doi.org/10.1007/s10571-025-01554-0. (PMID: <searchLink fieldCode="PM" term="%2210%2E1007%2Fs10571-025-01554-04025134812008108%22">10.1007/s10571-025-01554-04025134812008108)</searchLink><br />Cao Y, Li M, Gu L et al (2023) Chinese traditional formula Kaixin San suppressed ferroptosis of hippocampal neurons and cardiomyocytes in mice with paradoxical sleep deprivation. J Ethnopharmacol 304:116034. https://doi.org/10.1016/j.jep.2022.116034. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Ejep%2E2022%2E11603436529245%22">10.1016/j.jep.2022.11603436529245)</searchLink><br />Chen X, Liu Y, Zhu J et al (2016) GSK-3β downregulates Nrf2 in cultured cortical neurons and in a rat model of cerebral ischemia-reperfusion. Sci Rep 6:20196. https://doi.org/10.1038/srep20196. (PMID: <searchLink fieldCode="PM" term="%2210%2E1038%2Fsrep20196268381644738318%22">10.1038/srep20196268381644738318)</searchLink><br />Dai P, Yu Y, Sun Q et al (2024) Abnormal changes of brain function and structure in patients with T2DM-related cognitive impairment: a neuroimaging meta-analysis and an independent validation. Nutr Diabetes 14:91. https://doi.org/10.1038/s41387-024-00348-5. (PMID: <searchLink fieldCode="PM" term="%2210%2E1038%2Fs41387-024-00348-53952844211554684%22">10.1038/s41387-024-00348-53952844211554684)</searchLink><br />Dhaliwal J, Dhaliwal N, Akhtar A et al (2022) Tetramethylpyrazine attenuates cognitive impairment via suppressing oxidative stress, neuroinflammation, and apoptosis in type 2 diabetic rats. Neurochem Res 47:2431–2444. https://doi.org/10.1007/s11064-022-03640-x. (PMID: <searchLink fieldCode="PM" term="%2210%2E1007%2Fs11064-022-03640-x35665448%22">10.1007/s11064-022-03640-x35665448)</searchLink><br />Gan Y, Li X, Han S et al (2023) Targeting Mcl-1 degradation by bergenin inhibits tumorigenesis of colorectal cancer cells. Pharmaceuticals 16. https://doi.org/10.3390/ph16020241. (PMID: <searchLink fieldCode="PM" term="%2210%2E3390%2Fph16020241%22">10.3390/ph16020241)</searchLink><br />Gao X, Sun H, Wei Y et al (2024a) Protective effect of melatonin against metabolic disorders and neuropsychiatric injuries in type 2 diabetes mellitus mice. Phytomedicine 131:155805. https://doi.org/10.1016/j.phymed.2024.155805. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Ephymed%2E2024%2E15580538851097%22">10.1016/j.phymed.2024.15580538851097)</searchLink><br />Gao Y, Yu H, Liu Y et al (2024b) GSK-3β activation mediates apolipoprotein E4-associated cognitive impairment in type 2 diabetes mellitus: a multicenter, cross-sectional study. J Diabetes 16:e13470. https://doi.org/10.1111/1753-0407.13470. (PMID: <searchLink fieldCode="PM" term="%2210%2E1111%2F1753-0407%2E1347037700547%22">10.1111/1753-0407.1347037700547)</searchLink><br />Goodman LD, Ralhan I, Li X et al (2024) Tau is required for glial lipid droplet formation and resistance to neuronal oxidative stress. Nat Neurosci 27:1918–1933. https://doi.org/10.1038/s41593-024-01740-1. (PMID: <searchLink fieldCode="PM" term="%2210%2E1038%2Fs41593-024-01740-13918770611809452%22">10.1038/s41593-024-01740-13918770611809452)</searchLink><br />Guo M, Ye Y, Li X et al (2025) Kirenol alleviates cerebral ischemic injury by promoting synaptic plasticity via HDAC2-mediated BDNF expression. Phytomedicine 143:156605. https://doi.org/10.1016/j.phymed.2025.156605. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Ephymed%2E2025%2E15660540446576%22">10.1016/j.phymed.2025.15660540446576)</searchLink><br />Hamzé R, Delangre E, Tolu S et al (2022) Type 2 diabetes mellitus and Alzheimer’s disease: shared molecular mechanisms and potential common therapeutic targets. Int J Mol Sci 23. https://doi.org/10.3390/ijms232315287. (PMID: <searchLink fieldCode="PM" term="%2210%2E3390%2Fijms232315287%22">10.3390/ijms232315287)</searchLink><br />Han C, Kong X, Xia X et al (2023) Effects of ginseng peptides on the hypoglycemic activity and gut microbiota of a type 2 diabetes mellitus mice model. J Funct Foods 111:105897. https://doi.org/10.1016/j.jff.2023.105897. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Ejff%2E2023%2E105897%22">10.1016/j.jff.2023.105897)</searchLink><br />He C, Wang K, Xia J et al (2023) Natural exosomes-like nanoparticles in mung bean sprouts possesses anti-diabetic effects via activation of PI3K/Akt/GLUT4/GSK-3β signaling pathway. J Nanobiotechnol 21:349. https://doi.org/10.1186/s12951-023-02120-w. (PMID: <searchLink fieldCode="PM" term="%2210%2E1186%2Fs12951-023-02120-w%22">10.1186/s12951-023-02120-w)</searchLink><br />He D, Hao Z, Zhao M et al (2025a) Structural and functional brain abnormal alteration in patients with type 2 diabetes mellitus: a coordinate-based meta-analysis. Transl Psychiatry 15:269. https://doi.org/10.1038/s41398-025-03488-z. (PMID: <searchLink fieldCode="PM" term="%2210%2E1038%2Fs41398-025-03488-z4077017412328820%22">10.1038/s41398-025-03488-z4077017412328820)</searchLink><br />He L, Gao Y, Ju C et al (2025b) Collagen peptides alleviate hyperglycemia in mice by modulating insulin resistance, glucose metabolism and gut microbiota. Int J Biol Macromol 301:140498. https://doi.org/10.1016/j.ijbiomac.2025.140498. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Eijbiomac%2E2025%2E14049839889980%22">10.1016/j.ijbiomac.2025.14049839889980)</searchLink><br />He S, Lu JJ, Wu JJ et al (2025c) Altered cerebellar activity and cognitive deficits in Type 2 diabetes: insights from resting-state fMRI. Brain Res 1856:149586. https://doi.org/10.1016/j.brainres.2025.149586. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Ebrainres%2E2025%2E14958640113193%22">10.1016/j.brainres.2025.14958640113193)</searchLink><br />Huang W, Wu D, Cai C et al (2024) Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetes. Redox Biol 71:103104. https://doi.org/10.1016/j.redox.2024.103104. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Eredox%2E2024%2E1031043843068310914584%22">10.1016/j.redox.2024.1031043843068310914584)</searchLink><br />John CM, Mohamed Yusof NIS, Abdul Aziz SH et al (2018) Maternal cognitive impairment associated with gestational diabetes mellitus-a review of potential contributing mechanisms. Int J Mol Sci 19. https://doi.org/10.3390/ijms19123894. (PMID: <searchLink fieldCode="PM" term="%2210%2E3390%2Fijms19123894%22">10.3390/ijms19123894)</searchLink><br />Koivisto H, Maguire C, Tanila H (2025) Novel object recognition task for mice: is it a test for memory, object neophobia or innate preference? Behav Brain Res 491:115649. https://doi.org/10.1016/j.bbr.2025.115649. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Ebbr%2E2025%2E11564940414309%22">10.1016/j.bbr.2025.11564940414309)</searchLink><br />La Vitola P, Szegö EM, Pinto-Costa R et al (2024) Mitochondrial oxidant stress promotes α-synuclein aggregation and spreading in mice with mutated glucocerebrosidase. NPJ Parkinsons Dis 10:233. https://doi.org/10.1038/s41531-024-00842-8. (PMID: <searchLink fieldCode="PM" term="%2210%2E1038%2Fs41531-024-00842-83966335411634889%22">10.1038/s41531-024-00842-83966335411634889)</searchLink><br />Lai S, Wang P, Gong J et al (2023) New insights into the role of GSK-3β in the brain: from neurodegenerative disease to tumorigenesis. PeerJ 11:e16635. https://doi.org/10.7717/peerj.16635. (PMID: <searchLink fieldCode="PM" term="%2210%2E7717%2Fpeerj%2E166353810756210722984%22">10.7717/peerj.166353810756210722984)</searchLink><br />Li Y, Zhao Y, Tan X et al (2020) Isoorientin inhibits inflammation in macrophages and endotoxemia mice by regulating glycogen synthase kinase 3β. Mediators Inflamm 2020: 8704146. https://doi.org/10.1155/2020/8704146.<br />Li Q, Zhao Y, Guo H et al (2023) Impaired lipophagy induced-microglial lipid droplets accumulation contributes to the buildup of TREM1 in diabetes-associated cognitive impairment. Autophagy 19:2639–2656. https://doi.org/10.1080/15548627.2023.2213984. (PMID: <searchLink fieldCode="PM" term="%2210%2E1080%2F15548627%2E2023%2E22139843720411910472854%22">10.1080/15548627.2023.22139843720411910472854)</searchLink><br />Liang Z, Zhang B, Su WW et al (2016) C-Glycosylflavones alleviate Tau phosphorylation and amyloid neurotoxicity through GSK3β inhibition. ACS Chem Neurosci 7:912–923. https://doi.org/10.1021/acschemneuro.6b00059. (PMID: <searchLink fieldCode="PM" term="%2210%2E1021%2Facschemneuro%2E6b00059272138247355085%22">10.1021/acschemneuro.6b00059272138247355085)</searchLink><br />Linseman DA, Butts BD, Precht TA et al (2004) Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci 24:9993–10002. https://doi.org/10.1523/jneurosci.2057-04.2004. (PMID: <searchLink fieldCode="PM" term="%2210%2E1523%2Fjneurosci%2E2057-04%2E2004155257856730230%22">10.1523/jneurosci.2057-04.2004155257856730230)</searchLink><br />Liu G, Yang C, Wang X et al (2023) Oxygen metabolism abnormality and Alzheimer’s disease: an update. Redox Biol 68:102955. https://doi.org/10.1016/j.redox.2023.102955. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Eredox%2E2023%2E1029553795659810665957%22">10.1016/j.redox.2023.1029553795659810665957)</searchLink><br />Luo A, Xie Z, Wang Y et al (2022) Type 2 diabetes mellitus-associated cognitive dysfunction: advances in potential mechanisms and therapies. Neurosci Biobehav Rev 137:104642. https://doi.org/10.1016/j.neubiorev.2022.104642. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Eneubiorev%2E2022%2E10464235367221%22">10.1016/j.neubiorev.2022.10464235367221)</searchLink><br />Mayor E (2023) Neurotrophic effects of intermittent fasting, calorie restriction and exercise: a review and annotated bibliography. Front Aging 4:1161814. https://doi.org/10.3389/fragi.2023.1161814. (PMID: <searchLink fieldCode="PM" term="%2210%2E3389%2Ffragi%2E2023%2E11618143733404510273285%22">10.3389/fragi.2023.11618143733404510273285)</searchLink><br />Murakami S, Kusano Y, Okazaki K et al (2023) NRF2 signalling in cytoprotection and metabolism. Br J Pharmacol. https://doi.org/10.1111/bph.16246. (PMID: <searchLink fieldCode="PM" term="%2210%2E1111%2Fbph%2E1624637715470%22">10.1111/bph.1624637715470)</searchLink><br />Numakawa T, Kajihara R (2025) The role of brain-derived neurotrophic factor as an essential mediator in neuronal functions and the therapeutic potential of its mimetics for neuroprotection in neurologic and psychiatric disorders. Molecules 30. https://doi.org/10.3390/molecules30040848. (PMID: <searchLink fieldCode="PM" term="%2210%2E3390%2Fmolecules30040848%22">10.3390/molecules30040848)</searchLink><br />Patibandla C, van Aalten L, Dinkova-Kostova AT et al (2024) Inhibition of glycogen synthase kinase-3 enhances NRF2 protein stability, nuclear localisation and target gene transcription in pancreatic beta cells. Redox Biol 71. https://doi.org/10.1016/j.redox.2024.103117. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Eredox%2E2024%2E103117%22">10.1016/j.redox.2024.103117)</searchLink><br />Raza A, Saleem S, Imran S et al (2025) From metabolic dysregulation to neurodegenerative pathology: the role of hyperglycemia, oxidative stress, and blood-brain barrier breakdown in T2D-driven Alzheimer’s disease. Metab Brain Dis 40:276. https://doi.org/10.1007/s11011-025-01700-z. (PMID: <searchLink fieldCode="PM" term="%2210%2E1007%2Fs11011-025-01700-z4100379612474712%22">10.1007/s11011-025-01700-z4100379612474712)</searchLink><br />Sahoo S, Padhy AA, Kumari V et al (2022) Role of ubiquitin-proteasome and autophagy-lysosome pathways in α-synuclein aggregate clearance. Mol Neurobiol 59:5379–5407. https://doi.org/10.1007/s12035-022-02897-1. (PMID: <searchLink fieldCode="PM" term="%2210%2E1007%2Fs12035-022-02897-135699874%22">10.1007/s12035-022-02897-135699874)</searchLink><br />Salazar M, Rojo AI, Velasco D et al (2006) Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 281:14841–14851. https://doi.org/10.1074/jbc.M513737200. (PMID: <searchLink fieldCode="PM" term="%2210%2E1074%2Fjbc%2EM51373720016551619%22">10.1074/jbc.M51373720016551619)</searchLink><br />Shen Z, Li ZY, Yu MT et al (2023) Metabolic perspective of astrocyte dysfunction in Alzheimer’s disease and type 2 diabetes brains. Biomed Pharmacother 158:114206. https://doi.org/10.1016/j.biopha.2022.114206. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Ebiopha%2E2022%2E11420636916433%22">10.1016/j.biopha.2022.11420636916433)</searchLink><br />Shi X, Zhou XZ, Chen G et al (2024) Targeting the postsynaptic scaffolding protein PSD-95 enhances BDNF signaling to mitigate depression-like behaviors in mice. Sci Signal 17:eadn4556. https://doi.org/10.1126/scisignal.adn4556. (PMID: <searchLink fieldCode="PM" term="%2210%2E1126%2Fscisignal%2Eadn45563868782611223518%22">10.1126/scisignal.adn45563868782611223518)</searchLink><br />Soni D, Kumar P (2022) GSK-3β-mediated regulation of Nrf2/HO-1 signaling as a new therapeutic approach in the treatment of movement disorders. Pharmacol Rep 74:557–569. https://doi.org/10.1007/s43440-022-00390-z. (PMID: <searchLink fieldCode="PM" term="%2210%2E1007%2Fs43440-022-00390-z35882765%22">10.1007/s43440-022-00390-z35882765)</searchLink><br />Tan X, Liang Z, Li Y et al (2021) Isoorientin, a GSK-3β inhibitor, rescues synaptic dysfunction, spatial memory deficits and attenuates pathological progression in APP/PS1 model mice. Behav Brain Res 398:112968. https://doi.org/10.1016/j.bbr.2020.112968. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Ebbr%2E2020%2E11296833069740%22">10.1016/j.bbr.2020.11296833069740)</searchLink><br />Tang W, Yan C, He S et al (2023) Neuron-targeted overexpression of caveolin-1 alleviates diabetes-associated cognitive dysfunction via regulating mitochondrial fission-mitophagy axis. Cell Commun Signal 21:357. https://doi.org/10.1186/s12964-023-01328-5. (PMID: <searchLink fieldCode="PM" term="%2210%2E1186%2Fs12964-023-01328-53810266210722701%22">10.1186/s12964-023-01328-53810266210722701)</searchLink><br />Thakkar H, Chatterjee S, Verma A et al (2025) Malondialdehyde-mediated alpha-synuclein aggregation: a plausible etiology of Parkinson’s disease in oxidative stress. Chem Res Toxicol 38:573–582. https://doi.org/10.1021/acs.chemrestox.4c00348. (PMID: <searchLink fieldCode="PM" term="%2210%2E1021%2Facs%2Echemrestox%2E4c0034840190040%22">10.1021/acs.chemrestox.4c0034840190040)</searchLink><br />Thorp EB, Flanagan ME, Popko B et al (2022) Resolving inflammatory links between myocardial infarction and vascular dementia. Semin Immunol 59:101600. https://doi.org/10.1016/j.smim.2022.101600. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Esmim%2E2022%2E1016003522756710234261%22">10.1016/j.smim.2022.1016003522756710234261)</searchLink><br />Urkon M, Ferencz E, Szász JA et al (2025) Antidiabetic GLP-1 receptor agonists have neuroprotective properties in experimental animal models of Alzheimer’s disease. Pharmaceuticals 18. https://doi.org/10.3390/ph18050614. (PMID: <searchLink fieldCode="PM" term="%2210%2E3390%2Fph18050614%22">10.3390/ph18050614)</searchLink><br />Verma A, Sharma M, Alam O et al (2026) Type 3 diabetes: a molecular link between cerebral insulin resistance and neurodegeneration via AGE-RAGE signaling. Eur J Neurosci 63:e70364. https://doi.org/10.1111/ejn.70364. (PMID: <searchLink fieldCode="PM" term="%2210%2E1111%2Fejn%2E7036441459736%22">10.1111/ejn.7036441459736)</searchLink><br />Wang JT, Wang XR, Ren JQ et al (2024) S-9-PAHSA’s neuroprotective effect mediated by CAIII suppresses apoptosis and oxidative stress in a mouse model of type 2 diabetes. CNS Neurosci Ther 30:e14594. https://doi.org/10.1111/cns.14594. (PMID: <searchLink fieldCode="PM" term="%2210%2E1111%2Fcns%2E145943833253810853598%22">10.1111/cns.145943833253810853598)</searchLink><br />Wang R, Liu X, Yang K et al (2025) Bioactive component screening and mechanistic study of the anti-diabetic activity of Lophatherum gracile Brongn extract. Curr Issues Mol Biol 47. https://doi.org/10.3390/cimb47090779. (PMID: <searchLink fieldCode="PM" term="%2210%2E3390%2Fcimb47090779%22">10.3390/cimb47090779)</searchLink><br />Wen P, Sun Z, Gou F et al (2025) Oxidative stress and mitochondrial impairment: key drivers in neurodegenerative disorders. Ageing Res Rev 104:102667. https://doi.org/10.1016/j.arr.2025.102667. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Earr%2E2025%2E10266739848408%22">10.1016/j.arr.2025.10266739848408)</searchLink><br />Xiang J, Ran LY, Zeng XX et al (2021) LiCl attenuates impaired learning and memory of APP/PS1 mice, which in mechanism involves α7 nAChRs and Wnt/β-catenin pathway. J Cell Mol Med 25:10698–10710. https://doi.org/10.1111/jcmm.17006. (PMID: <searchLink fieldCode="PM" term="%2210%2E1111%2Fjcmm%2E17006347085228581309%22">10.1111/jcmm.17006347085228581309)</searchLink><br />Yang K, Chen Z, Gao J et al (2017) The key roles of GSK-3β in regulating mitochondrial activity. Cell Physiol Biochem 44:1445–1459. https://doi.org/10.1159/000485580. (PMID: <searchLink fieldCode="PM" term="%2210%2E1159%2F00048558029190615%22">10.1159/00048558029190615)</searchLink><br />Yen YC, Gassen NC, Zellner A et al (2015) Glycogen synthase kinase-3β inhibition in the medial prefrontal cortex mediates paradoxical amphetamine action in a mouse model of ADHD. Front Behav Neurosci 9:67. https://doi.org/10.3389/fnbeh.2015.00067. (PMID: <searchLink fieldCode="PM" term="%2210%2E3389%2Ffnbeh%2E2015%2E00067258525084367184%22">10.3389/fnbeh.2015.00067258525084367184)</searchLink><br />Zhang W, Sun C, Huang Y et al (2025) Inflammation levels in type 2 diabetes mellitus patients with mild cognitive impairment: assessment followed by amelioration via dapagliflozin therapy. J Diabetes Complications 39:109017. https://doi.org/10.1016/j.jdiacomp.2025.109017. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Ejdiacomp%2E2025%2E10901740228375%22">10.1016/j.jdiacomp.2025.10901740228375)</searchLink><br />Zhao Y, He C, Hu S et al (2024) Anti-oxidative stress and cognitive improvement of a semi-synthetic isoorientin-based GSK-3β inhibitor in rat pheochromocytoma cell PC12 and scopolamine-induced AD model mice via AKT/GSK-3β/Nrf2 pathway. Exp Neurol 380:114881. https://doi.org/10.1016/j.expneurol.2024.114881. (PMID: <searchLink fieldCode="PM" term="%2210%2E1016%2Fj%2Eexpneurol%2E2024%2E11488138996864%22">10.1016/j.expneurol.2024.11488138996864)</searchLink><br />Zhou S, Wang P, Qiao Y et al (2016) Genetic and pharmacologic targeting of glycogen synthase kinase 3β reinforces the Nrf2 antioxidant defense against podocytopathy. J Am Soc Nephrol 27:2289–2308. https://doi.org/10.1681/asn.2015050565. 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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1007/s11011-026-01938-1 Languages: – Code: eng Text: English Subjects: – SubjectFull: Diabetes Mellitus, Experimental metabolism Type: general – SubjectFull: Diabetes Mellitus, Experimental drug therapy Type: general – SubjectFull: Signal Transduction drug effects Type: general – SubjectFull: Neuroprotective Agents pharmacology Type: general – SubjectFull: Neuroprotective Agents therapeutic use Type: general – SubjectFull: Apoptosis drug effects Type: general – SubjectFull: Brain drug effects Type: general – SubjectFull: Brain metabolism Type: general – SubjectFull: Animals Type: general – SubjectFull: Mice Type: general – SubjectFull: Male Type: general – SubjectFull: Mice, Inbred C57BL Type: general – SubjectFull: Oxidative Stress drug effects Type: general – SubjectFull: Glycogen Synthase Kinase 3 beta metabolism Type: general – SubjectFull: NF-E2-Related Factor 2 metabolism Type: general – SubjectFull: Luteolin pharmacology Type: general – SubjectFull: Luteolin therapeutic use Type: general – SubjectFull: Diabetes Mellitus, Type 2 metabolism Type: general – SubjectFull: Diabetes Mellitus, Type 2 drug therapy Type: general – SubjectFull: Diabetes Mellitus, Type 2 complications Type: general – SubjectFull: Cognitive Dysfunction metabolism Type: general – SubjectFull: Cognitive Dysfunction drug therapy Type: general – SubjectFull: Cognitive Dysfunction etiology Type: general Titles: – TitleFull: Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Tan X – PersonEntity: Name: NameFull: Gao Y – PersonEntity: Name: NameFull: Zhang L – PersonEntity: Name: NameFull: He Y – PersonEntity: Name: NameFull: Li QX – PersonEntity: Name: NameFull: Dong Y IsPartOfRelationships: – BibEntity: Dates: – D: 17 M: 07 Text: 2026 Jul 17 Type: published Y: 2026 Identifiers: – Type: issn-electronic Value: 1573-7365 Numbering: – Type: volume Value: 41 – Type: issue Value: 1 Titles: – TitleFull: Metabolic brain disease Type: main |
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