Academic Journal
Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis.
| Τίτλος: | Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis. |
|---|---|
| Συγγραφείς: | 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. |
| Πηγή: | Metabolic brain disease [Metab Brain Dis] 2026 Jul 17; Vol. 41 (1). Date of Electronic Publication: 2026 Jul 17. |
| Τύπος έκδοσης: | Journal Article; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | 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- |
| Ιατρικοί όροι (MeSH): | 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 |
| Περίληψη: | 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. |
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| 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 |
| Βάση Δεδομένων: | MEDLINE |
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