Discovery, Synthesis, and Functional Characterization of a Novel Neuroprotective Natural Product from the Fruit of Alpinia oxyphylla for use in Parkinson's Disease Through LC/MS-Based Multivariate Data Analysis-Guided Fractionation
Discovery, Synthesis, and Functional Characterization of a Novel Neuroprotective Natural Product from the Fruit of Alpinia oxyphylla for use in Parkinson's Disease Through LC/MS-Based Multivariate Data Analysis-Guided Fractionation
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DOI：
10.1021/acs.jproteome.6b00152
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发表时间：
2016-08-01
影响因子：
4.4
通讯作者：
Chu, Ivan K.
中科院分区：
文献类型：
--
作者：
Li, Guohui;Zhang, Zaijun;Chu, Ivan K.
本文报道了一种新的先导化合物，oxyphylla A [（R）-4-（2-羟基-5-甲基苯基）-5-甲基己酸]（来自益智的果实）的发现，其作为抗帕金森病的神经保护剂。为了确定一个候选人从提取物的益智，我们采用了一个综合的策略相结合的液相色谱/质谱，生物活性导向分馏，和化学计量学分析。在扩大潜在神经保护成分的最终清单以进行更详细的化学和生物学表征之前，对入围候选物的神经保护作用进行了验证。尖叶甲具有很好的神经保护作用：（i）它改善体外化学诱导的原代神经元细胞损伤，（ii）减轻斑马鱼和小鼠体内化学诱导的多巴胺能神经元损失和行为障碍。定量蛋白质组学分析的oxyphylla A处理的原代小脑颗粒神经元，已中毒与1-甲基-4-苯基吡啶显示，oxyphylla A激活核因子红细胞2相关因子2（NRF 2）的主氧化还原开关，并触发级联的抗氧化反应。通过蛋白质印迹分析独立地验证这些观察结果。我们综合了代谢组学、化学计量学和药理学策略，有效地从A.同时避免了鉴定生物活性化合物通常所需的非靶向、劳动密集型步骤。我们成功地开发了一条合成路线，以尖叶甲应导致其可用于大规模的进一步功能开发和病理学研究。
Herein we report the discovery of a novel lead compound, oxyphylla A [(R)-4-(2-hydroxy-5-methylpheny1)-5-methylhexanoic acid] (from the fruit of Alpinia oxyphylla), which functions as a neuroprotective agent against Parkinson's disease. To identify a shortlist of candidates from the extract of A oxyphylla, we employed an integrated strategy combining liquid chromatography/ mass spectrometry, bioactivity-guided fractionation, and chemometric analysis. The neuroprotective effects of the shortlisted candidates were validated prior to scaling up the finalized list of potential neuroprotective constituents for more detailed chemical and biological characterization. Oxyphylla A has promising neuroprotective effects: (i) it ameliorates in vitro chemical-induced primary neuronal cell damage and (ii) alleviates chemical-induced dopaminergic neuron loss and behavioral impairment in both zebrafish and mice in vivo. Quantitative proteomics analyses of oxyphylla A-treated primary cerebellar granule neurons that had been intoxicated with 1-methyl-4-phenylpyridinium revealed that oxyphylla A activates nuclear factor-erythroid 2-related factor 2 (NRF2) a master redox switch and triggers a cascade of antioxidative responses. These observations were verified independently through western blot analyses. Our integrated metabolomics, chemometrics, and pharmacological strategy led to the efficient discovery of novel bioactive ingredients from A. oxyphylla while avoiding the nontargeting, labor-intensive steps usually required for identification of bioactive compounds. Our successful development of a synthetic route toward oxyphylla A should lead to its availability on a large scale for further functional development and pathological studies.