Liu Wei, Chen Xiao, Zhao Jing, Yang Chen, Huang Guanqin, Zhang Zhen, Liu Jianjun
Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
Front Pharmacol. 2024 Jul 24;15:1423060. doi: 10.3389/fphar.2024.1423060. eCollection 2024.
Alzheimer's disease (AD) has an increasing prevalence, complicated pathogenesis and no effective cure. Emerging evidences show that flavonoid compounds such as xanthohumol (Xn) could play an important role as a dietary supplement or traditional Chinese herbal medicine in the management of diseases such as AD. This study aims to analyze the target molecules of Xn in the prevention and treatment of AD, and its potential mechanism from the perspective of metabolites. APP/PS1 mice 2- and 6-months old were treated with Xn for 3 months, respectively, the younger animals to test for AD-like brain disease prevention and the older animals to address therapeutic effects on the disease. Memantine (Mem) was selected as positive control. Behavioral tests were performed to assess the course of cognitive function. Urine samples were collected and analyzed by high-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) coupled with online Compound Discoverer software. Morris Water Maze (MWM) tests showed that Xn, like Mem, had a therapeutic but not a preventive effect on cognitive impairment. The expression levels of urinary metabolites appeared to show an opposite trend at different stages of Xn treatment, downregulated in the prevention phase while upregulated in the therapy phase. In addition, the metabolic mechanisms of Xn during preventive treatment were also different from that during therapeutic treatment. The signaling pathways metabolites nordiazepam and genistein were specifically regulated by Xn but not by Mem in the disease prevention stage. The signaling pathway metabolite ascorbic acid was specifically regulated by Xn in the therapeutic stage. In conclusion, dietary treatment with Xn altered the urinary metabolite profile at different stages of administration in APP/PS1 mice. The identified potential endogenous metabolic biomarkers and signal pathways open new avenues to investigate the pathogenesis and treatment of AD.
阿尔茨海默病（AD）的患病率不断上升，发病机制复杂，且尚无有效治愈方法。新出现的证据表明，诸如黄腐酚（Xn）等类黄酮化合物作为膳食补充剂或传统中药，在AD等疾病的管理中可能发挥重要作用。本研究旨在从代谢物角度分析Xn在预防和治疗AD中的靶分子及其潜在机制。分别对2月龄和6月龄的APP/PS1小鼠进行为期3个月的Xn治疗，较年幼的动物用于测试AD样脑部疾病的预防效果，较年长的动物用于评估对该疾病的治疗效果。选择美金刚（Mem）作为阳性对照。进行行为测试以评估认知功能进程。收集尿液样本，采用高效液相色谱（HPLC）与串联质谱（MS/MS）联用在线Compound Discoverer软件进行分析。莫里斯水迷宫（MWM）测试表明，Xn与Mem一样，对认知障碍有治疗作用，但无预防作用。尿液代谢物的表达水平在Xn治疗的不同阶段似乎呈现相反趋势，在预防阶段下调，而在治疗阶段上调。此外，Xn在预防性治疗期间的代谢机制也与治疗性治疗期间不同。在疾病预防阶段，信号通路代谢物去甲西泮和染料木黄酮受Xn特异性调节，而不受Mem调节。信号通路代谢物抗坏血酸在治疗阶段受Xn特异性调节。总之，用Xn进行饮食治疗改变了APP/PS1小鼠给药不同阶段的尿液代谢物谱。所确定的潜在内源性代谢生物标志物和信号通路为研究AD的发病机制和治疗开辟了新途径。
