PUBLICATION
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
- Authors
- Li, G., Zhang, Z., Quan, Q., Jiang, R.W., Szeto, S.S., Yuan, S., Wong, W.T., Lam, H.H., Lee, S.M., Chu, I.K.
- ID
- ZDB-PUB-160602-14
- Date
- 2016
- Source
- Journal of Proteome Research 15(8): 2595-606 (Journal)
- Registered Authors
- Szeto, Samuel
- Keywords
- natural products, neuroprotective, NRF2, Parkinson’s disease, proteomics
- MeSH Terms
-
- Alpinia/chemistry*
- Animals
- Caproates/isolation & purification
- Caproates/pharmacology
- Chemical Fractionation
- Chromatography, Liquid
- Cresols/isolation & purification
- Cresols/pharmacology
- Dopamine Agents/isolation & purification
- Dopamine Agents/therapeutic use
- Dopaminergic Neurons/drug effects
- Drug Discovery*
- Mass Spectrometry
- Mice
- Nerve Degeneration/drug therapy
- Nerve Degeneration/prevention & control
- Neuroprotective Agents/isolation & purification*
- Neuroprotective Agents/pharmacology
- Parkinson Disease/drug therapy*
- Plant Extracts/chemistry
- Plant Extracts/therapeutic use
- Zebrafish
- PubMed
- 27246451 Full text @ J. Proteome Res.
Citation
Li, G., Zhang, Z., Quan, Q., Jiang, R.W., Szeto, S.S., Yuan, S., Wong, W.T., Lam, H.H., Lee, S.M., Chu, I.K. (2016) 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. Journal of Proteome Research. 15(8):2595-606.
Abstract
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. oxyphyllawhile avoiding the non-targeting, 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 large scale for further functional development and pathological studies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping