title: Role of nutraceutical SIRT1 modulators in AMPK and mTOR pathway: Evidence of a synergistic effect.
abstract: OBJECTIVE
  The aim of this study was to evaluate the effect of different natural substances on SIRT1 expression and on AMPK and mTOR phosphorylation. Moreover, we investigated the presence of a synergistic effect between the substances.
  
  
  METHODS
  Human cervical carcinoma cells were seeded in 12-well plates, then incubated with the nine tested substances (resveratrol, quercetin, berberine, catechin, tyrosol, ferulic acid, niclosamide, curcumin, and malvidin) at different concentrations and left in incubation for 3, 6, and 24 h. The targeting proteins' expression and phosphorylation were evaluated by immunoblotting, and cytotoxicity tests were performed by CellTiter-Blue Cell Viability Assay.
  
  
  RESULTS
  No statistically significant decrease (P > 0.05) in the number of viable cells was found. The expression of SIRT1 was significantly increased in all experimental groups compared with the control group (P < 0.001). Instead, the simultaneous administration involved a significant and synergistic increase in the expression of SIRT1 for some but not all of the tested compounds. Finally, the individual administration of berberine, quercetin, ferulic acid, and tyrosol resulted in a statistically significant increase in AMPK activation and mTOR inhibition, whereas their associated administration did not reveal a synergistic effect.
  
  
  CONCLUSIONS
  Our results provide evidence that all compounds have the potential to stimulate SIRT1 and sustain the stimulating action of resveratrol on SIRT1, already widely reported in the literature. In this regard, we confirm the interaction of these substances also with the pathway of AMPK and mTOR, in support of the studies that highlight the importance of SIRT1/AMPK and mTOR pathway in many diseases.
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, Pharmacology, Medical School, University of Pisa, Pisa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Giovannini
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, Pharmacology, Medical School, University of Pisa, Pisa, Italy. Electronic address: Sara.bianchi1987@hotmail.it.
authors.forename: Sara
authors.initials: S
authors.lastname: Bianchi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000872:Anthocyanins / Q000494:pharmacology; D001599:Berberine / Q000494:pharmacology; D002392:Catechin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003373:Coumaric Acids / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology; D019587:Dietary Supplements; D005786:Gene Expression Regulation; D006801:Humans; D009534:Niclosamide / Q000494:pharmacology; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation; D011794:Quercetin / Q000494:pharmacology; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000872:Anthocyanins; D003373:Coumaric Acids; D013267:Stilbenes; D001599:Berberine; C065861:malvidin; C011867:4-hydroxyphenylethanol; D009534:Niclosamide; D002392:Catechin; D011794:Quercetin; C004999:ferulic acid; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D003474:Curcumin; D010626:Phenylethyl Alcohol; D000077185:Resveratrol
keywords: AMPK; Nutraceutical modulators; SIRT1; Synergistic effect; mTOR