title: Hexapeptide-11 is a novel modulator of the proteostasis network in human diploid fibroblasts.
abstract: Despite the fact that several natural products (e.g. crude extracts or purified compounds) have been found to activate cell antioxidant responses and/or delay cellular senescence the effect(s) of small peptides on cell viability and/or modulation of protective mechanisms (e.g. the proteostasis network) remain largely elusive. We have thus studied a hexapeptide (Hexapeptide-11) of structure Phe-Val-Ala-Pro-Phe-Pro (FVAPFP) originally isolated from yeast extracts and later synthesized by solid state synthesis to high purity. We show herein that Hexapeptide-11 exhibits no significant toxicity in normal human diploid lung or skin fibroblasts. Exposure of fibroblasts to Hexapeptide-11 promoted dose and time-dependent activation of proteasome, autophagy, chaperones and antioxidant responses related genes. Moreover, it promoted increased nuclear accumulation of Nrf2; higher expression levels of proteasomal protein subunits and increased proteasome peptidase activities. In line with these findings we noted that Hexapeptide-11 conferred significant protection in fibroblasts against oxidative-stress-mediated premature cellular senescence, while at in vivo skin deformation assays in human subjects it improved skin elasticity. Finally, Hexapeptide-11 was found to induce the activity of extracellular MMPs and it also suppressed cell migration. Our presented findings indicate that Hexapeptide-11 is a promising anti-ageing agent.
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 15784, Greece.
authors.forename: Aimilia D
authors.initials: AD
authors.lastname: Sklirou
authors.affiliation: Korres S.A. Natural Products, 57th Athens-Lamia National Road, 32011 Inofyta, Greece.
authors.forename: Marianna
authors.initials: M
authors.lastname: Ralli
authors.affiliation: Lonza, 70 Tyler Place, South Plainfield, NJ 07080, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Dominguez
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 15784, Greece.
authors.forename: Issidora
authors.initials: I
authors.lastname: Papassideri
authors.affiliation: Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 15784, Greece.
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Trougakos
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004171:Diploidy; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018832:Molecular Chaperones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009842:Oligopeptides; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D046988:Proteasome Endopeptidase Complex; C581722:Phe-Val-Ala-Pro-Phe-Pro
keywords: Antioxidant responses; Chaperone; Hexapeptide-11; Human fibroblasts; Proteasome; Proteostasis; Senescence