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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
dataset
posted on 2016-06-01, 00:00 authored by Guohui Li, Zaijun Zhang, Quan Quan, Renwang Jiang, Samuel
S.W. Szeto, Shuai Yuan, Wing-tak Wong, Herman H. C. Lam, Simon Ming-Yuen Lee, Ivan K. ChuHerein
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 switchand 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.