Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation
作者全名："Li, Lin; Li, Wen-Jun; Zheng, Xiang-Ru; Liu, Qing-Long; Du, Qian; Lai, Yu-Jie; Liu, Song-Qing"
作者地址："[Li, Lin; Li, Wen-Jun; Liu, Qing-Long; Du, Qian; Liu, Song-Qing] Chongqing Med Univ, Dept Pharm, Affiliated Hosp 3, Shuanghu Rd, Chongqing 401120, Peoples R China; [Zheng, Xiang-Ru] Chongqing Med Univ, Dept Hepatobiliary & Pancreat Surg, Affiliated Hosp 3, Chongqing 401120, Peoples R China; [Lai, Yu-Jie] Chongqing Med Univ, Dept Neurol, Affiliated Hosp 3, Chongqing 401120, Peoples R China"
通信作者："Liu, SQ (通讯作者)，Chongqing Med Univ, Dept Pharm, Affiliated Hosp 3, Shuanghu Rd, Chongqing 401120, Peoples R China.; Lai, YJ (通讯作者)，Chongqing Med Univ, Dept Neurol, Affiliated Hosp 3, Chongqing 401120, Peoples R China."
ESI学科分类：MOLECULAR BIOLOGY & GENETICS
关键词：Alzheimer's disease; Eriodictyol; Ferroptosis; VDR; Nrf2
摘要："Background Alzheimer's disease (AD) is the most common type of neurodegenerative disease in the contemporary era, and it is still clinically incurable. Eriodictyol, a natural flavonoid compound that is mainly present in citrus fruits and some Chinese herbal medicines, has been reported to exert anti-inflammatory, antioxidant, anticancer and neuroprotective effects. However, few studies have examined the anti-AD effect and molecular mechanism of eriodictyol. Methods APP/PS1 mice were treated with eriodictyol and the cognitive function of mice was assessed using behavioral tests. The level of amyloid-beta (A beta) aggregation and hyperphosphorylation of Tau in the mouse brain were detected by preforming a histological analysis and Western blotting. HT-22 cells induced by amyloid-beta peptide (1-42) (A beta(1-42)) oligomers were treated with eriodictyol, after which cell viability was determined and the production of p-Tau was tested using Western blotting. Then, the characteristics of ferroptosis, including iron aggregation, lipid peroxidation and the expression of glutathione peroxidase type 4 (GPX4), were determined both in vivo and in vitro using Fe straining, Western blotting and qPCR assays. Additionally, the expression level of vitamin D receptor (VDR) and the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway were tested using Western blotting and qPCR assays. Afterward, HT-22 cells with VDR knockout were used to explore the potential mechanisms, and the relationship between VDR and Nrf2 was further assessed by performing a coimmunoprecipitation assay and bioinformatics analysis. Results Eriodictyol obviously ameliorated cognitive deficits in APP/PS1 mice, and suppressed A beta aggregation and Tau phosphorylation in the brains of APP/PS1 mice. Moreover, eriodictyol inhibited Tau hyperphosphorylation and neurotoxicity in HT-22 cells induced by A beta(1-42) oligomer. Furthermore, eriodictyol exerted an antiferroptosis effect both in vivo and in vitro, and its mechanism may be associated with the activation of the Nrf2/HO-1 signaling pathway. Additionally, further experiments explained that the activation of Nrf2/HO-1 signaling pathway by eriodictyol treatment mediated by VDR. Conclusions Eriodictyol alleviated memory impairment and AD-like pathological changes by activating the Nrf2/HO-1 signaling pathway through a mechanism mediated by VDR, which provides a new possibility for the treatment of AD."
基金机构：Application and Development Project from Chongqing Science and Technology Commission [cstc2020jscx-msxmX0123]; Chongqing Basic Research and Frontier Exploration Project [cstc2018jcyjAX0170]; National Natural Science Foundation of China 
基金资助正文："This work was supported by Application and Development Project from Chongqing Science and Technology Commission (No. cstc2020jscx-msxmX0123), Chongqing Basic Research and Frontier Exploration Project (No. cstc2018jcyjAX0170) and National Natural Science Foundation of China (No. 81801071)."