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DB23-0969 Supplemental_online-only_material.pdf (249.42 kB)

Regulatory Role of NF-κB on HDAC2 and Tau Hyperphosphorylation in Diabetic Encephalopathy and the Therapeutic Potential of Luteolin

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posted on 2024-06-13, 13:37 authored by Qian Fu, Yilin Song, Zhaoke Ling, Jie Liu, Qingqing Kong, Xin Hao., Ting Xu, Qiang Zhang, Yi Liu

Abstract

Diabetic encephalopathy (DE) is a severe complication of the central nervous system associated with diabetes. This research aims to investigate the regulatory role of mammalian target of rapamycin (mTOR) on nuclear factor kappa-B (NF-κB) in mice with DE, and the neuroprotective effect and therapeutic mechanisms of luteolin, a natural flavonoid compound with anti-inflammatory, antioxidant, and neuroprotective properties. The results indicated that treatment with luteolin improved the degree of cognitive impairment in mice with DE. It also decreased the levels of p-mTOR, p-NF-κB and histone deacetylase 2 (HDAC2) and increased the expression of brain-derived neurotrophic factor (BDNF) and synaptic-related proteins. Furthermore, protein-protein interaction (PPI) and the Gene Ontology (GO) analysis revealed that luteolin was involved in the regulatory network of HDAC2 expression through the mTOR/NF-κB signaling cascade. Our bioinformatics and molecular docking results indicated that luteolin may also directly target HDAC2, as an HDAC2 inhibitors, to alleviate DE, complementing mTOR/NF-κB signaling inhibition. Analysis of luteolin's target genes and their interactions suggested effect on HDAC2 and cognition. In conclusion, HDAC2 and tau hyperphosphorylation are regulated by the mTOR/NF-κB signaling cascade in DE, and luteolin is found to reverse these effects, demonstrating its protective role in DE.


Article Highlights

• Luteolin's neuroprotective effect on diabetic encephalopathy, targeting mTOR/NF-κB signaling.

• Demonstrating decreases in p-mTOR, p-NF-κB, and HDAC2, and increases in BDNF and synaptic proteins.

• Highlighting Luteolin's potential direct targeting to HDAC2, in order to provide a new approach for DE treatment.

Funding

Ministry of Science and Technology of the People's Republic of China > National Natural Science Foundation of China 82271228

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