Abstract
Diabetic encephalopathy (DE) is a complication of diabetes, especially type 2 diabetes (T2D), characterized by damage in the central nervous system and cognitive impairment, which has gained global attention. Despite the extensive research aimed at enhancing our understanding of DE, the underlying mechanism of occurrence and development of DE has not been established. Mounting evidence has demonstrated a close correlation between DE and various factors, such as Alzheimer’s disease-like pathological changes, insulin resistance, inflammation, and oxidative stress. Of interest, nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor with antioxidant properties that is crucial in maintaining redox homeostasis and regulating inflammatory responses. The activation and regulatory mechanisms of NRF2 are a relatively complex process. NRF2 is involved in the regulation of multiple metabolic pathways and confers neuroprotective functions. Multiple studies have provided evidence demonstrating the significant involvement of NRF2 as a critical transcription factor in the progression of DE. Additionally, various molecules capable of activating NRF2 expression have shown potential in ameliorating DE. Therefore, it is intriguing to consider NRF2 as a potential target for the treatment of DE. In this review, we aim to shed light on the role and the possible underlying mechanism of NRF2 in DE. Furthermore, we provide an overview of the current research landscape and address the challenges associated with using NRF2 activators as potential treatment options for DE.
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Abbreviations
- DE:
-
Diabetic encephalopathy
- T2D:
-
Type 2 diabetes
- NRF2:
-
Nuclear factor erythroid 2-related factor 2
- IR:
-
Insulin resistance
- NFE2L2:
-
Nuclear factor erythroid 2-like 2
- ARE:
-
Antioxidant response element
- KEAP1:
-
Kelch-like-ECH-associated protein 1
- CBP:
-
CAMP response element binding protein
- βTrCP:
-
β-Transducin repeat protein
- RARα:
-
Retinoic acid receptor alpha
- CTR:
-
C-terminal region
- NTR:
-
N-terminal region
- ROS:
-
Reactive oxygen species
- MAF:
-
Musculoaponeurotic fibrosarcoma
- NQO1:
-
NAD(P)H: quinone dehydrogenase 1
- HO-1:
-
Heme oxygenase 1
- G6PD:
-
Carbohydrate metabolism gene: glucose-6-phosphate dehydrogenase
- GCLC:
-
Glutamate-cysteine ligase catalytic subunit
- GCLM:
-
Glutamate-cysteine ligase modifier subunit
- LC3:
-
Microtubule-associated protein 1A/1B-light chain 3
- ER:
-
Endoplasmic reticulum
- MAPK:
-
P38-mitogen-activated protein kinase
- GSK-3:
-
Glycogen synthase kinase 3
- PI3K:
-
Phosphoinositide kinase
- AMPK:
-
AMP-activated protein kinase
- PKC:
-
Protein kinase C
- NLS:
-
Nuclear localization sequence
- NF-κB:
-
Nuclear factor kappa B
- HDAC3:
-
Histone deacetylase 3
- Aβ:
-
Amyloid beta
- BBB:
-
Blood-brain barrier
- TNF-α:
-
Tumor necrosis factor-alpha
- IL-6:
-
Interleukin-6
- GPX4:
-
Glutathione peroxidation Enzyme 4
- SLC7A11:
-
Solute carrier family 7 member 11
- BACE1:
-
Beta-site APP cleaving enzyme 1
- APP:
-
Amyloid precursor protein
- NDP52:
-
Nuclear point protein 52
- SFN:
-
Sulforaphane
- SOD:
-
Superoxide dismutase
- GSTA2:
-
Glutathione S-transferase A2
- ZDF:
-
Zucker diabetic fatty
- MGO:
-
Methylglyoxal
- FTL:
-
Ferritin light chain
- FTH1:
-
Ferritin heavy chain 1
- SLC40A1:
-
Solute carrier family 40 member 1
- PPAR:
-
Peroxisome proliferator-activated receptor
- cav-1:
-
Caveolin-1
- PCr:
-
Phosphocreatine
- NGR1:
-
Notoginsenoside R1
- BBR:
-
Berberine
- SiPE:
-
S. inappendiculata Polyphenol-rich extract
- QCSPIONs:
-
Quercetin-conjugated superparamagnetic iron oxide nanoparticles
- Trx-1:
-
Thioredoxin-1
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This work was financially supported by the National Natural Science Foundation of China (No. 81873169, 82104967), Hunan Youth Science and Technology Innovation Talent Project (No.2022RC1220), China Postdoctoral Science Foundation (No.2022M711733), Hunan Provincial Natural Science Foundation of China (No.2020JJ4803,2022JJ40728), Hunan Flagship Department of Integrated Traditional Chinese and Western Medicine, and Hunan Scientific Research Program of traditional Chinese Medicine (No.2021192), and the Scientific Research Launch Project for new employees of the Second Xiangya Hospital of Central South University.
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W.J.P and X.C conceived the study. X.C drafted the manuscript. Y.J.T and Z.Y.Z contributed to drafting the manuscript and interpreting the data. H.L.L and Z.Y.Z performed the literature search. Z.Z and S.H collected the data. All authors read and approved the final manuscript.
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Cheng, X., Tan, Y., Li, H. et al. Mechanistic Insights and Potential Therapeutic Implications of NRF2 in Diabetic Encephalopathy. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04097-5
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DOI: https://doi.org/10.1007/s12035-024-04097-5