Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Xuzhou Engineering Research Center of Medical Genetics and Transformation, Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Diabetes. 2024 Sep 1;73(9):1513-1526. doi: 10.2337/db23-0969.
Diabetic encephalopathy (DE) is a severe complication of the central nervous system associated with diabetes. In this study, we investigated the regulatory role of mammalian target of rapamycin (mTOR) on nuclear factor κB (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 phosphorylated mTOR, phosphorylated NF-κB, and histone deacetylase 2 (HDAC2) and increased the expression of brain-derived neurotrophic factor and synaptic-related proteins. Furthermore, protein-protein interaction and the Gene Ontology 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 inhibitor, to alleviate DE, complementing mTOR/NF-κB signaling inhibition. Analysis of luteolin's target proteins and their interactions suggest an 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.
糖尿病脑病（DE）是一种与糖尿病相关的严重中枢神经系统并发症。在本研究中，我们研究了雷帕霉素靶蛋白（mTOR）对 DE 小鼠核因子κB（NF-κB）的调节作用，以及木犀草素的神经保护作用和治疗机制。木犀草素是一种具有抗炎、抗氧化和神经保护作用的天然类黄酮化合物。结果表明，木犀草素治疗可改善 DE 小鼠的认知障碍程度。它还降低了磷酸化 mTOR、磷酸化 NF-κB 和组蛋白去乙酰化酶 2（HDAC2）的水平，并增加了脑源性神经营养因子和突触相关蛋白的表达。此外，蛋白质-蛋白质相互作用和基因本体分析表明，木犀草素通过 mTOR/NF-κB 信号级联参与 HDAC2 表达的调控网络。我们的生物信息学和分子对接结果表明，木犀草素也可能直接靶向 HDAC2，作为 HDAC2 抑制剂，以减轻 DE，补充 mTOR/NF-κB 信号抑制。木犀草素靶蛋白及其相互作用的分析表明其对 HDAC2 和认知有影响。总之，DE 中的 mTOR/NF-κB 信号级联调节 HDAC2 和 tau 过度磷酸化，而木犀草素被发现可逆转这些作用，证明其在 DE 中的保护作用。
