title: Astragalin inhibits airway eotaxin-1 induction and epithelial apoptosis through modulating oxidative stress-responsive MAPK signaling.
abstract: BACKGROUND
  Eotaxin proteins are a potential therapeutic target in treating the peribronchial eosinophilia associated with allergic airway diseases. Since inflammation is often associated with an increased generation of reactive oxygen species (ROS), oxidative stress is a mechanistically imperative factor in asthma. Astragalin (kaempferol-3-O-glucoside) is a flavonoid with anti-inflammatory activity and newly found in persimmon leaves and green tea seeds. This study elucidated that astragalin inhibited endotoxin-induced oxidative stress leading to eosinophilia and epithelial apoptosis in airways.
  
  
  METHODS
  Airway epithelial BEAS-2B cells were exposed to lipopolysaccharide (LPS) in the absence and presence of 1-20 μM astragalin. Western blot and immunocytochemical analyses were conducted to determine induction of target proteins. Cell and nuclear staining was also performed for ROS production and epithelial apoptosis.
  
  
  RESULTS
  When airway epithelial cells were exposed to 2 μg/ml LPS, astragalin nontoxic at ≤ 20 μM suppressed cellular induction of Toll-like receptor 4 (TLR4) and ROS production enhanced by LPS. Both LPS and H2O2 induced epithelial eotaxin-1 expression, which was blocked by astragalin. LPS activated and induced PLCγ1, PKCβ2, and NADPH oxidase subunits of p22phox and p47phox in epithelial cells and such activation and induction were demoted by astragalin or TLR4 inhibition antagonizing eotaxin-1 induction. H2O2-upregulated phosphorylation of JNK and p38 MAPK was dampened by adding astragalin to epithelial cells, while this compound enhanced epithelial activation of Akt and ERK. H2O2 and LPS promoted epithelial apoptosis concomitant with nuclear condensation or caspase-3 activation, which was blunted by astragalin.
  
  
  CONCLUSIONS
  Astragalin ameliorated oxidative stress-associated epithelial eosinophilia and apoptosis through disturbing TLR4-PKCβ2-NADPH oxidase-responsive signaling. Therefore, astragalin may be a potent agent antagonizing endotoxin-induced oxidative stress leading to airway dysfunction and inflammation.
authors: In-Hee
authors: IH
authors: Cho
authors: Ju-Hyun
authors: JH
authors: Gong
authors: Min-Kyung
authors: MK
authors: Kang
authors: Eun-Jung
authors: EJ
authors: Lee
authors: Jung Han Yoon
authors: JH
authors: Park
authors: Sang-Jae
authors: SJ
authors: Park
authors: Department of Food and Nutrition, Hallym University, Chuncheon, South Korea. yhkang@hallym.ac.kr.
authors: Young-Hee
authors: YH
authors: Kang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001980:Bronchi; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000037:antagonists & inhibitors*; D029788:Diospyros; D004789:Enzyme Activation / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects; D004847:Epithelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D044949:Kaempferols / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018515:Plant Leaves; D028321:Plant Preparations / Q000494:pharmacology*; D064546:Protein Kinase C beta / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C515456:CCL11 protein, human; D054413:Chemokine CCL11; D044949:Kaempferols; D008070:Lipopolysaccharides; D016877:Oxidants; D028321:Plant Preparations; D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C001579:astragalin; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D064546:Protein Kinase C beta; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D051966:Phospholipase C gamma; D053148:Caspase 3