Background

The pathophysiology of diabetic encephalopathy (DE), a significant diabetes-related pathological complication of the central nervous system, is poorly understood. Ferroptosis is an iron-dependent regulated necrotic cell death process that mediates the development of neurodegenerative and diabetes-related lesions. Quercetin (QE) has anti-ferroptotic effects in various other diseases. Quercetin (QE) exerts anti-ferroptotic effects in various diseases. However, the roles of ferroptosis in DE and the potential anti-ferroptotic mechanisms of QE are unclear.

Purpose

This study aimed to investigate if quercetin can ameliorate DE by inhibiting ferroptosis and to elucidate the potential anti-ferroptotic mechanisms of QE, thus providing a new perspective on the pathogenesis and prevention of DE.

Methods

The spontaneously type 2 diabetic Goto-Kakizak rats and high glucose (HG)-induced PC12 cells were used as animal and in vitro models, respectively. The Morris water maze test was performed to evaluate the cognition of rats. Pathological damage was examined using hematoxylin and eosin staining. Mitochondrial damage was assessed using transmission electron microscopy. Lipid peroxidation was evaluated by examining the levels of malondialdehyde, superoxide dismutase, and glutathione. Additionally, the contents of iron ions were quantified. Immunofluorescence and western blotting were carried out to poke the protein levels. Network pharmacology analysis was conducted to construct a protein-protein interaction network for the therapeutic targets of QE in DE. Additionally, molecular docking and cell thermostability displacement experiments were performed to examine the target of QE.

Results

QE alleviated cognitive impairment, decreased lipid peroxidation and iron deposition in the hippocampus, and upregulated the Nrf2/HO-1 signaling pathway. HG-induced ferroptosis in PC12 cells resulted in decreased cell viability accompanied by lipid peroxidation and iron deposition. QE mitigated HG-induced ferroptosis by upregulating the Nrf2/HO-1 pathway, which was partially suppressed upon Nrf2 inhibition. Network pharmacology analysis further indicated that the Nrf2/HO-1 signaling pathway is a key target of QE. Molecular docking experiments revealed that QE binds to KEAP1 through four hydrogen bonds. Moreover, QE altered the thermostability of KEAP1.

Conclusion

These results indicated that QE inhibits ferroptosis in the hippocampal neurons by binding to KEAP1 and subsequently upregulating the Nrf2/HO-1 signaling pathway.

中文翻译：

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槲皮素：一种通过抑制海马铁死亡治疗糖尿病脑病的有前途的疗法

背景

糖尿病性脑病 (DE) 的病理生理学是中枢神经系统的一种重要的糖尿病相关病理并发症，人们对其了解甚少。Ferroptosis 是一种铁依赖性调节性坏死细胞死亡过程，可介导神经退行性和糖尿病相关病变的发展。槲皮素 (QE) 在多种其他疾病中具有抗铁死亡作用。槲皮素 (QE) 在多种疾病中发挥抗铁死亡作用。然而，铁死亡在 DE 中的作用以及 QE 的潜在抗铁死亡机制尚不清楚。

目的

本研究旨在探讨槲皮素是否可以通过抑制铁死亡来改善 DE，并阐明 QE 潜在的抗铁死亡机制，从而为 DE 的发病机制和预防提供新的视角。

方法

自发性 2 型糖尿病 Goto-Kakizak 大鼠和高葡萄糖 (HG) 诱导的 PC12 细胞分别用作动物和体外模型。Morris 水迷宫试验用于评估大鼠的认知能力。使用苏木精和伊红染色检查病理损伤。使用透射电子显微镜评估线粒体损伤。通过检查丙二醛、超氧化物歧化酶和谷胱甘肽的水平来评估脂质过氧化。此外，对铁离子的含量进行了量化。进行免疫荧光和蛋白质印迹以检测蛋白质水平。进行网络药理学分析以构建 DE 中 QE 治疗靶点的蛋白质-蛋白质相互作用网络。此外，

结果

QE 减轻了认知障碍，减少了海马体中的脂质过氧化和铁沉积，并上调了 Nrf2/HO-1 信号通路。HG 诱导的 PC12 细胞铁死亡导致细胞活力降低，并伴有脂质过氧化和铁沉积。QE 通过上调 Nrf2/HO-1 通路来减轻 HG 诱导的铁死亡，该通路在 Nrf2 抑制时被部分抑制。网络药理学分析进一步表明 Nrf2/HO-1 信号通路是 QE 的关键靶点。分子对接实验表明，QE 通过四个氢键与 KEAP1 结合。此外，QE 改变了 KEAP1 的热稳定性。

结论

这些结果表明，QE 通过与 KEAP1 结合并随后上调 Nrf2/HO-1 信号通路来抑制海马神经元的铁死亡。