title: 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.
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. 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.
authors.affiliation: Department of Chemistry, The University of Hong Kong , Hong Kong, China.|State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau , Avenue Padre Tomás Pereira S.J., Taipa, Macao, China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau , Avenue Padre Tomás Pereira S.J., Taipa, Macao, China.|Institute of New Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of Traditional Chinese Medicine & New Drug Research, College of Pharmacy, Jinan University , Guangdong, China.
authors.forename: Zaijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, The University of Hong Kong , Hong Kong, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Quan
authors.affiliation: Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University , Guangzhou 510632, P. R. China.
authors.forename: Renwang
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Department of Chemistry, The University of Hong Kong , Hong Kong, China.
authors.forename: Samuel S W
authors.initials: SS
authors.lastname: Szeto
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau , Avenue Padre Tomás Pereira S.J., Taipa, Macao, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University , Hong Kong, China.
authors.forename: Wing-Tak
authors.initials: WT
authors.lastname: Wong
authors.affiliation: Department of Chemistry, The University of Hong Kong , Hong Kong, China.
authors.forename: Herman H C
authors.initials: HH
authors.lastname: Lam
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau , Avenue Padre Tomás Pereira S.J., Taipa, Macao, China.
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Department of Chemistry, The University of Hong Kong , Hong Kong, China.
authors.forename: Ivan K
authors.initials: IK
authors.lastname: Chu
mesh_terms: D032429:Alpinia / Q000737:chemistry*; D000818:Animals; D002208:Caproates / Q000302:isolation & purification / Q000494:pharmacology; D005591:Chemical Fractionation; D002853:Chromatography, Liquid; D003408:Cresols / Q000302:isolation & purification / Q000494:pharmacology; D015259:Dopamine Agents / Q000302:isolation & purification / Q000627:therapeutic use; D059290:Dopaminergic Neurons / Q000187:drug effects; D055808:Drug Discovery; D013058:Mass Spectrometry; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000302:isolation & purification* / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy*; D010936:Plant Extracts / Q000737:chemistry / Q000627:therapeutic use; D015027:Zebrafish
chemical_list: D002208:Caproates; D003408:Cresols; D015259:Dopamine Agents; D018696:Neuroprotective Agents; D010936:Plant Extracts; C000624958:oxyphylla A; C481311:5-methylhexanoic acid
keywords: NRF2; Parkinson’s disease; natural products; neuroprotective; proteomics