title: Phloretin suppresses thrombin-mediated leukocyte-platelet-endothelial interactions.
abstract: METHODS
  Thrombin playing a pivotal role in coagulation cascade may influence the onset and progression of atherosclerosis as a pro-inflammatory mediator. This study investigated whether phloretin found in apple tree leaves, severed a linkage between thrombosis and atherosclerosis by thrombin.
  
  
  RESULTS
  Human endothelial cells were pre-treated with 1-20 μM phloretin and stimulated with 10 U/mL thrombin. Phloretin attenuated adhesion of THP-1 monocytes and platelets to thrombin-inflamed endothelial cells with concurrent inhibition of protease-activated receptor (PAR-1) induction. The thrombin induction of endothelial CD40, endothelial integrin β3 and P-selectin, and monocytic CD40L was dampened by phloretin. Additionally, phloretin inhibited monocyte secretion of MCP-1, IL-6 and IL-8 responsible for pro-inflammatory activity of thrombin inducing endothelial CD40. The monocyte COX-2 induction and PGE2 secretion due to thrombin were down-regulated by phloretin, deterring endothelial CD40 expression. Thrombin promoted production of PAI-1 and tissue factor in monocytes was attenuated by phloretin through blocking PAR-1 and CD40. Thrombin up-regulated the induction of endothelial connective tissue growth factor independent of PAR-1 activation, which was reversed by phloretin.
  
  
  CONCLUSIONS
  Phloretin disturbed tethering and stable adhesion of monocytes and platelets onto endothelium during increased thrombosis by thrombin. Phloretin would be a potent agent preventing thrombosis and atherosclerosis.
authors: Department of Food and Nutrition, Hallym University, Chuncheon, Republic of Korea.
authors: Min Soo
authors: MS
authors: Kim
authors: Sin-Hye
authors: SH
authors: Park
authors: Seon-Young
authors: SY
authors: Han
authors: Yun-Ho
authors: YH
authors: Kim
authors: Eun-Jung
authors: EJ
authors: Lee
authors: Jung Han
authors: JH
authors: Yoon Park
authors: Young-Hee
authors: YH
authors: Kang
mesh_terms: D001792:Blood Platelets / Q000187:drug effects*; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects; D010693:Phloretin / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000187:drug effects; D044463:Receptor, PAR-1 / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D017395:Plasminogen Activator Inhibitor 1; D044463:Receptor, PAR-1; C051321:SERPINE1 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D013917:Thrombin; D015232:Dinoprostone; D010693:Phloretin
keywords: CD40; Phloretin; Platelet; Protease-activated receptor-1; Thrombin