title: The Selective Sirtuin 1 Activator SRT2104 Reduces Endotoxin-Induced Cytokine Release and Coagulation Activation in Humans.
abstract: OBJECTIVE
  Sirtuin 1 influences gene expression and other cellular functions through deacetylation of histone and nonhistone proteins. We here sought to determine the effects of a small molecule sirtuin 1 activator, SRT2104, on inflammation and coagulation induced by lipopolysaccharide in humans.
  
  
  METHODS
  A randomized, double-blind, placebo-controlled study.
  
  
  METHODS
  An academic hospital.
  
  
  METHODS
  Twenty-four healthy humans.
  
  
  METHODS
  All subjects received an intravenous injection with lipopolysaccharide. Subjects were randomized to one of three groups (n=8 per group): 1) pretreatment with oral SRT2104 for 7 days (2 g/d), 2) pretreatment with a single SRT2104 dose (2 g), or 3) placebo.
  
  
  RESULTS
  SRT2104 attenuated lipopolysaccharide-induced release of the cytokines interleukin-6 (mean peak levels of 58.8% [p<0.05] and 80.9% [p=0.078] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment) and interleukin-8 (mean peak levels of 57.0% [p<0.05 vs placebo] and 77.1% [p<0.05 vs placebo] after single and repeated SRT2104 ingestion, respectively, while not affecting tumor necrosis factor-α and interleukin-10 release). SRT2104 also reduced the lipopolysaccharide-induced acute phase protein response (C-reactive protein). SRT2104 inhibited activation of coagulation, as reflected by lower plasma levels of the prothrombin fragment F1+2 (mean peak levels 57.9% [p<0.05] and 64.2% [p<0.05] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment). Activation of the vascular endothelium (plasma von Willebrand levels) and the fibrinolytic system (plasma tissue-type plasminogen activator and plasminogen activator inhibitor type I) was not influenced by SRT2104.
  
  
  CONCLUSIONS
  This is the first human study to demonstrate biological anti-inflammatory and anticoagulant responses consistent with the activation of sirtuin 1 by a small molecule.
authors.affiliation: 1Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, The Netherlands. 2Bioinformatics Laboratory, Department of Clinical Epidemiology, Academic Medical Center, Amsterdam, The Netherlands. 3GlaxoSmithKline, Durham, North Carolina. 4Sirtris, A GSK Company, Cambridge, MA.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: van der Meer
authors.forename: Brendon P
authors.initials: BP
authors.lastname: Scicluna
authors.forename: Perry D
authors.initials: PD
authors.lastname: Moerland
authors.forename: Jiang
authors.initials: J
authors.lastname: Lin
authors.forename: Eric W
authors.initials: EW
authors.lastname: Jacobson
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects*; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004311:Double-Blind Method; D004731:Endotoxins / Q000378:metabolism*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D056564:Sirtuin 1 / Q000096:biosynthesis*; D055815:Young Adult
chemical_list: D016207:Cytokines; D004731:Endotoxins; D006574:Heterocyclic Compounds, 2-Ring; D008070:Lipopolysaccharides; C584666:SRT2104; D056564:Sirtuin 1