Evidence mapPaperPMID 42467274Full record

ArticleMetabolic brain disease2026

Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis.

Xiaoqin Tan, Yanru Gao, Lingyu Zhang, Yubin He, Qing X Li, Yan Dong

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Article in Metabolic brain disease, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

6 authors.

Xiaoqin TanMedical Department, City University of Wuhan, Wuhan, Hubei Province, China. xqtan@wic.edu.cn.ORCID 0000-0001-7929-1178
Yanru GaoMedical Department, City University of Wuhan, Wuhan, Hubei Province, China.ORCID 0009-0008-2917-1301
Lingyu ZhangScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.ORCID 0009-0006-7810-8160
Yubin HeMedical Department, City University of Wuhan, Wuhan, Hubei Province, China.ORCID 0009-0009-8632-1457
Qing X LiDepartment of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, Hawaii, USA. qingl@hawaii.edu.ORCID 0000-0003-4589-2869
Yan DongScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China. dondy001@gzucm.edu.cn.ORCID 0000-0003-0915-6223

Funding

the USDA Hatch Project HAW05044-R
6 · The paper itself

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.

Indexed as

Cognitive DysfunctionDiabetes Mellitus, Type 2Glycogen Synthase Kinase 3 betaLuteolinNF-E2-Related Factor 2Oxidative StressAnimalsApoptosisBrainDiabetes Mellitus, ExperimentalMaleMiceMice, Inbred C57BLNeuroprotective AgentsSignal TransductionGlycogen Synthase Kinase 3 betaGsk3b protein, mousehomoorientinLuteolinNeuroprotective AgentsNfe2l2 protein, mouseNF-E2-Related Factor 2Diabetic cognitive dysfunctionGSK3β/Nrf2 axisIsoorientinNeuroprotectionOxidative stress

Identifiers

PMID42467274

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.