title: Hyperoside attenuates hydrogen peroxide-induced L02 cell damage via MAPK-dependent Keap₁-Nrf₂-ARE signaling pathway.
abstract: The flavonoid hyperoside has been reported to elicit cytoprotection against oxidative stress partly by increasing the activity of antioxidant enzymes, such as glutathione peroxidase, superoxide dismutase and catalase. However, the cellular and molecular mechanisms underlying this effect remain unclear. Here, hepatic L02 cells exposed to H(2)O(2) (100 μM) were used to demonstrate that hyperoside protected cells by significantly inhibiting overproduction of intracellular ROS, depletion of the mitochondrial membrane potential and leakage of lactate dehydrogenase. Hyperoside further enhanced the cellular antioxidant defense system through increasing the activity of heme oxygenase-1 (HO-1), and by up-regulating HO-1 expression. Meanwhile, real time PCR, western blot and immunofluorescence studies revealed that hyperoside stimulated nuclear translocation of the Nrf(2) transcription factor in a dose-dependent manner, and this effect was significantly suppressed by pharmacological inhibition of the mitogen-activated protein kinases (MAPK) p38 and ERK. Collectively, our data provide the first description of the mechanism underlying hyperoside's ability to attenuate H(2)O(2)-induced cell damage, namely this compound interacts with the MAPK-dependent Keap(1)-Nrf(2)-ARE signaling pathway to up-regulate HO-1 expression and enhance intracellular antioxidant activity.
authors.affiliation: Department of Pharmacy, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Xing
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Chen
authors.forename: Feng-Jun
authors.initials: FJ
authors.lastname: Sun
authors.forename: Hui-Qing
authors.initials: HQ
authors.lastname: Shi
authors.forename: Pei-Yuan
authors.initials: PY
authors.lastname: Xia
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000975:Antioxidants / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D019610:Cytoprotection; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000633:toxicity; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D020218:Response Elements; D015398:Signal Transduction; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C021304:hyperoside; D011794:Quercetin; D006861:Hydrogen Peroxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases