title: Pharmacological actions of nobiletin in the modulation of platelet function.
abstract: OBJECTIVE
  The discovery that flavonoids are capable of inhibiting platelet function has led to their investigation as potential antithrombotic agents. However, despite the range of studies on the antiplatelet properties of flavonoids, little is known about the mechanisms by which flavonoids inhibit platelet function. In this study, we aimed to explore the pharmacological effects of a polymethoxy flavonoid, nobiletin, in the modulation of platelet function.
  
  
  METHODS
  The ability of nobiletin to modulate platelet function was explored by using a range of in vitro and in vivo experimental approaches. Aggregation, dense granule secretion and spreading assays were performed using washed platelets. Fibrinogen binding, α-granule secretion and calcium mobilization assays were performed using platelet-rich plasma and whole blood was used in impedance aggregometry and thrombus formation experiments. The effect of nobiletin in vivo was assessed by measuring tail bleeding time using C57BL/6 mice.
  
  
  RESULTS
  Nobiletin was shown to suppress a range of well-established activatory mechanisms, including platelet aggregation, granule secretion, integrin modulation, calcium mobilization and thrombus formation. Nobiletin extended bleeding time in mice and reduced the phosphorylation of PKB (Akt) and PLCγ2 within the collagen receptor (glycoprotein VI)-stimulated pathway, in addition to increasing the levels of cGMP and phosphorylation of vasodilator-stimulated phosphoprotein, a protein whose activity is associated with inhibitory cyclic nucleotide signalling.
  
  
  CONCLUSIONS
  This study provides insight into the underlying molecular mechanisms through which nobiletin modulates haemostasis and thrombus formation. Therefore, nobiletin may represent a potential antithrombotic agent of dietary origins.
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.|School of Pharmacy, University of Reading, Reading, UK.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Vaiyapuri
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.
authors.forename: Harvey
authors.initials: H
authors.lastname: Roweth
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.
authors.forename: Marfoua S
authors.initials: MS
authors.lastname: Ali
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Unsworth
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Stainer
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.
authors.forename: Gagan D
authors.initials: GD
authors.lastname: Flora
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.
authors.forename: Marilena
authors.initials: M
authors.lastname: Crescente
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.
authors.forename: Chris I
authors.initials: CI
authors.lastname: Jones
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.|Department of Physiology, National University of Singapore, Singapore.
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Moraes
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gibbins
mesh_terms: D000818:Animals; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D008810:Mice, Inbred C57BL; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013927:Thrombosis / Q000139:chemically induced
chemical_list: D047309:Flavones; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen; C008661:nobiletin; D051057:Proto-Oncogene Proteins c-akt; D006152:Cyclic GMP; D002118:Calcium