title: Dihydromyricetin ameliorates the oxidative stress response induced by methylglyoxal via the AMPK/GLUT4 signaling pathway in PC12 cells.
abstract: Dihydromyricetin (DMY), the major bioactive flavonoid ingredient extracted from the leaves of Ampelopsis grossedentata (Hand.-Mazz) W.T. Wang, displays multiple pharmacological activities, including oxidation resistance, antitumor properties and free radical scavenging capacities. However, the role of DMY in methylglyoxal (MG)-induced diabetes-associated cognitive decline and its underlying molecular mechanisms are unclear. The aim of the present study was to evaluate the effects of DMY on oxidative stress and glucose transport activity in a MG-induced PC12 cell line and to explore the related mechanisms. The effects of DMY on cell survival and apoptosis were examined, and the dysregulation of intracellular Ca(2+) was determined. Oxidative stress was evaluated by monitoring ROS production and the glutathione to glutathione disulfide ratio. The effects of DMY on glucose metabolism were investigated using a fluorescently labeled deoxyglucose analog and by measuring ATP and lactate production. Western blot analysis was performed to examine the protein levels of glyoxalase I (Glo-1), glucose transporter 4 (GLUT4), AMP-activated protein kinase (AMPKα) and phosphorylated AMPKα (p-AMPKα). The results revealed that DMY suppressed cellular oxidative stress in PC12 cells and balanced glucose metabolism. Additionally, DMY reduced GLUT4 translocation dysfunction and increased Glo-1 and p-AMPKα expression. We found that DMY protected PC12 cells against MG-induced apoptosis and glycometabolic disorders, at least in part by restraining the hyperactivation of p-AMPK activity and normalizing the translocation of GLUT4 from the intracellular compartment, resulting in a balance in glucose uptake. This result indicates that DMY may serve as a novel and effective candidate agent to treat diabetic encephalopathy by reducing the toxicity of MG.
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, 151 Malianwa North Road, Beijing 100194, PR China.
authors.forename: Baoping
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, 151 Malianwa North Road, Beijing 100194, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Le
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, 151 Malianwa North Road, Beijing 100194, PR China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Pan
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, 151 Malianwa North Road, Beijing 100194, PR China.
authors.forename: Keping
authors.initials: K
authors.lastname: Hu
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, 151 Malianwa North Road, Beijing 100194, PR China. Electronic address: xulijia@hotmail.com.
authors.forename: Lijia
authors.initials: L
authors.lastname: Xu
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, 151 Malianwa North Road, Beijing 100194, PR China.
authors.forename: Peigen
authors.initials: P
authors.lastname: Xiao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D044948:Flavonols / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D005978:Glutathione; D020287:In Situ Nick-End Labeling; D019344:Lactic Acid / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D044948:Flavonols; D051275:Glucose Transporter Type 4; D017382:Reactive Oxygen Species; C495694:Slc2a4 protein, rat; D019344:Lactic Acid; D011765:Pyruvaldehyde; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D005978:Glutathione; D005947:Glucose; C472036:dihydromyricetin; D002118:Calcium
keywords: Diabetic encephalopathy; Dihydromyricetin; Glycometabolism; Methylglyoxal