Gastrodin attenuates high fructose-induced sweet taste preference decrease by inhibiting hippocampal neural stem cell ferroptosis.

Chuan-Feng Tang, Hong Ding, Ya-Qian Wu, Zi-An Miao, Zi-Xuan Wang, Wen-Xuan Wang, Ying Pan, Ling-Dong Kong
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Abstract

Introduction: High fructose intake has been implicated as a risk factor for behavioral disorders, potentially through cell ferroptosis induction in the central nervous system. Neural stem cells (NSCs) are crucial for maintaining hippocampal neurogenesis to resist behavioral alterations. Gastrodin, derived from the traditional Chinese herb Gastrodia elata, has neuroprotective effect.

Objectives: This study aimed to elucidate the underlying mechanism by which high fructose induces sweet taste preference and assesses the impact of gastrodin on hippocampal NSC ferroptosis.

Methods: Mice and cultured NSCs were treated with high fructose and/or gastrodin, respectively. NSC ferroptosis was evaluated by assay of lipid peroxidation and DNA double-strand breaks. Transcriptome sequencing (RNA-seq), Western blotting, and chromatin immunoprecipitation (ChIP) were employed to explore the potential mechanism underlying high fructose-induced NSC ferroptosis and the modulation of gastrodin. Simultaneously, specific gene expression was regulated by lentivirus injection into the hippocampus of mice.

Results: Our data showed that gastrodin mitigated sweet taste preference decline and hippocampal NSC ferroptosis in high fructose-fed mice, being consistent with reduction of reactive oxygen species (ROS) and iron accumulation in hippocampal NSC mitochondria. Mechanistically, we identified CDGSH iron-sulfur domain 1 (CISD1) as a mediator of NSC ferroptosis, with its expression being augmented by high fructose. Overexpression of Zic family member 2 (ZIC2) increased the transcription of Cisd1 gene. Additionally, overexpression of Zic2 with lentiviral vectors in hippocampus showed the decreased sweet taste preference in mice, consistently up-regulated CISD1 protein expression and reduced hippocampal NSC number. Gastrodin downregulated ZIC2 expression to inhibit CISD1 transcription in its attenuation of high fructose-induced NSC ferroptosis and sweet taste preference decrease.

Conclusion: Collectively, high fructose can drive hippocampal NSC ferroptosis by upregulating ZIC2 and CISD1 expression, thereby contributing to the decline in sweet taste preference. Gastrodin emerges as a promising agent for mitigating NSC ferroptosis and improving sweet taste preference.

Abstract Image

天麻素通过抑制海马神经干细胞的铁凋亡减轻高果糖诱导的甜味偏好降低。
导言:高果糖摄入量被认为是行为失调的风险因素,可能是通过诱导中枢神经系统的细胞铁变态反应。神经干细胞(NSCs)是维持海马神经发生以抵御行为改变的关键。从传统中草药天麻中提取的天麻素具有神经保护作用:本研究旨在阐明高果糖诱导甜味偏好的内在机制,并评估天麻素对海马神经干细胞铁突变的影响:方法:分别用高果糖和/或胃泌素处理小鼠和培养的NSCs。方法:分别用高果糖和/或胃泌素处理小鼠和培养的神经干细胞,通过检测脂质过氧化和DNA双链断裂来评估神经干细胞的铁变态反应。研究人员采用转录组测序(RNA-seq)、Western 印迹和染色质免疫沉淀(ChIP)等方法探讨了高果糖诱导 NSC 铁变态反应的潜在机制以及天麻素的调节作用。同时,通过向小鼠海马注射慢病毒来调控特定基因的表达:结果:我们的数据显示,胃泌素能缓解高果糖喂养小鼠的甜味偏好下降和海马间充质干细胞铁突变,这与海马间充质干细胞线粒体中活性氧(ROS)和铁积累的减少是一致的。从机理上讲,我们发现 CDGSH 铁硫结构域 1(CISD1)是 NSC 铁突变的介质,高果糖会增强其表达。过表达 Zic 家族成员 2(ZIC2)会增加 Cisd1 基因的转录。此外,用慢病毒载体在海马中过表达 Zic2 会降低小鼠对甜味的偏好,并持续上调 CISD1 蛋白表达和减少海马 NSC 数量。Gastrodin 通过下调 ZIC2 的表达来抑制 CISD1 的转录,从而减轻高果糖诱导的 NSC 铁突变和甜味偏好下降:总之,高果糖可通过上调 ZIC2 和 CISD1 的表达来驱动海马 NSC 铁细胞沉积,从而导致甜味偏好下降。天麻素是一种很有前景的药物,可减轻海马神经节铁质沉积和改善甜味偏好。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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