OBJECTIVES: 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. DESIGN: A randomized, double-blind, placebo-controlled study. SETTING: An academic hospital. SUBJECTS:Twenty-four healthy humans. INTERVENTIONS: 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. MEASUREMENTS AND MAIN 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.
RCT Entities:
OBJECTIVES: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. DESIGN: A randomized, double-blind, placebo-controlled study. SETTING: An academic hospital. SUBJECTS: Twenty-four healthy humans. INTERVENTIONS: 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. MEASUREMENTS AND MAIN 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: Evandro Fei Fang; Morten Scheibye-Knudsen; Katrin F Chua; Mark P Mattson; Deborah L Croteau; Vilhelm A Bohr Journal: Nat Rev Mol Cell Biol Date: 2016-03-09 Impact factor: 94.444
Authors: Shih-Chin Cheng; Brendon P Scicluna; Rob J W Arts; Mark S Gresnigt; Ekta Lachmandas; Evangelos J Giamarellos-Bourboulis; Matthijs Kox; Ganesh R Manjeri; Jori A L Wagenaars; Olaf L Cremer; Jenneke Leentjens; Anne J van der Meer; Frank L van de Veerdonk; Marc J Bonten; Marcus J Schultz; Peter H G M Willems; Peter Pickkers; Leo A B Joosten; Tom van der Poll; Mihai G Netea Journal: Nat Immunol Date: 2016-03-07 Impact factor: 25.606