title: Isolation, identification, and biological evaluation of Nrf2-ARE activator from the leaves of green perilla (Perilla frutescens var. crispa f. viridis).
abstract: The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is a cellular defense system against oxidative stress. Activation of this pathway increases expression of antioxidant enzymes. Epidemiological studies have demonstrated that the consumption of fruits and vegetables is associated with reduced risk of contracting a variety of human diseases. The aim of this study is to find Nrf2-ARE activators in dietary fruits and vegetables. We first attempted to compare the potency of ARE activation in six fruit and six vegetables extracts. Green perilla (Perilla frutescens var. crispa f. viridis) extract exhibited high ARE activity. We isolated the active fraction from green perilla extract through bioactivity-guided fractionation. Based on nuclear magnetic resonance and mass spectrometric analysis, the active ingredient responsible for the ARE activity was identified as 2',3'-dihydroxy-4',6'-dimethoxychalcone (DDC). DDC induced the expression of antioxidant enzymes, such as γ-glutamylcysteine synthetase (γ-GCS), NAD(P)H: quinone oxidoreductase-1 (NQO1), and heme oxygenase-1. DDC inhibited the formation of intracellular reactive oxygen species and the cytotoxicity induced by 6-hydroxydopamine. Inhibition of the p38 mitogen-activated protein kinase pathway abolished ARE activation, the induction of γ-GCS and NQO1, and the cytoprotective effect brought about by DDC. Thus, this study demonstrated that DDC contained in green perilla enhanced cellular resistance to oxidative damage through activation of the Nrf2-ARE pathway.
authors: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Yasuhiko
authors: Y
authors: Izumi
authors: Atsuko
authors: A
authors: Matsumura
authors: Seiko
authors: S
authors: Wakita
authors: Ken-ichi
authors: K
authors: Akagi
authors: Hiroyuki
authors: H
authors: Fukuda
authors: Toshiaki
authors: T
authors: Kume
authors: Kazuhiro
authors: K
authors: Irie
authors: Yuki
authors: Y
authors: Takada-Takatori
authors: Hachiro
authors: H
authors: Sugimoto
authors: Tadashi
authors: T
authors: Hashimoto
authors: Akinori
authors: A
authors: Akaike
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000302:isolation & purification* / Q000494:pharmacology; D019610:Cytoprotection; D004790:Enzyme Induction / Q000187:drug effects; D005638:Fruit / Q000737:chemistry; D017930:Genes, Reporter; D005978:Glutathione / Q000378:metabolism; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D016716:PC12 Cells; D031344:Perilla frutescens / Q000737:chemistry*; D010936:Plant Extracts / Q000302:isolation & purification* / Q000494:pharmacology; D018515:Plant Leaves / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects*; D014675:Vegetables / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C576910:2',3'-dihydroxy-4',6'-dimethoxychalcone; D047188:Chalcones; D051267:NF-E2-Related Factor 2; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D049409:Luciferases, Firefly; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione