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
| Autor: | Quan Quan, Zaijun Zhang, Samuel S. W. Szeto, Herman H.C. Lam, Ivan K. Chu, Guohui Li, Ren-Wang Jiang, Simon Ming-Yuen Lee, Shuai Yuan, Wing Tak Wong |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Quantitative proteomics Dopamine Agents Pharmacology Chemical Fractionation Proteomics 01 natural sciences Biochemistry Neuroprotection Mass Spectrometry 03 medical and health sciences chemistry.chemical_compound Cresols Mice Liquid chromatography–mass spectrometry In vivo Drug Discovery Animals Caproates Zebrafish Natural product biology Drug discovery Plant Extracts Dopaminergic Neurons 010401 analytical chemistry Alpinia Parkinson Disease General Chemistry biology.organism_classification 0104 chemical sciences 030104 developmental biology Neuroprotective Agents chemistry Nerve Degeneration Chromatography Liquid |
| Zdroj: | Journal of proteome research. 15(8) |
| ISSN: | 1535-3907 |
| Popis: | Herein we report the discovery of a novel lead compound, oxyphylla A [(R)-4-(2-hydroxy-5-methylphenyl)-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. |
| Databáze: | OpenAIRE |
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