title: Cyanidin-3-O-glucoside counters the response to TNF-alpha of endothelial cells by activating Nrf2 pathway.
abstract: METHODS
  Many dietary phytochemicals have been shown able to prevent a large spectrum of diseases, including cardiovascular disorders, with a mechanism commonly ascribed to an antioxidant effect. However, these in vivo beneficial effects are unlikely to be explained on the base of this mechanism. The discovery of specific genes regulated by the antioxidant responsive element (ARE) affected by antioxidants/electrophiles, led to the hypothesis that some phytochemicals may act as modulators of signal transduction pathways. The aim of the study was to investigate if in vitro pharmacological activation of Nrf2 pathway by cyanidin-3-O-glucoside (C3G) may be involved in its antiatherogenic effects.
  
  
  RESULTS
  Herein, we investigated the in vitro effects of C3G on cell signaling pathways in human umbilical vein endothelial cells (HUVECs) challenged with tumor necrosis factor-α (TNF-α). Pretreatment with C3G prevented oxidative stress, improved antioxidant systems, and activated Nrf2/ARE pathway, at baseline and after TNF-α treatment. Furthermore, we demonstrated the involvement of specific mitogen-activated protein kinases (MAPKs) (ERK1/2) in C3G induction of Nrf2/ARE pathway. Finally, the inactivation of ERK1/2 activity by the inhibitor PD98059 abolished the increase of Nrf2 nuclear accumulation induced by C3G, and also increased NF-κB p65 nuclear translocation in TNF-α challenged cells.
  
  
  CONCLUSIONS
  Our data confirm the hypothesis that natural Nrf2 and HO-1 inducers, such as C3G and other dietary phytochemicals, might be a potential therapeutic strategy to protect vascular system against various stressors preventing several pathological conditions.
authors.affiliation: Department of Drug Sciences and Health Products, University of Messina, Messina, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Speciale
authors.forename: Sirajudheen
authors.initials: S
authors.lastname: Anwar
authors.forename: Raffaella
authors.initials: R
authors.lastname: Canali
authors.forename: Joselita
authors.initials: J
authors.lastname: Chirafisi
authors.forename: Antonella
authors.initials: A
authors.lastname: Saija
authors.forename: Fabio
authors.initials: F
authors.lastname: Virgili
authors.forename: Francesco
authors.initials: F
authors.lastname: Cimino
mesh_terms: D000872:Anthocyanins / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D005960:Glucosides / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000872:Anthocyanins; D000975:Antioxidants; D005960:Glucosides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D014409:Tumor Necrosis Factor-alpha; C462279:cyanidin-3-O-beta-glucopyranoside; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione
keywords: Cellular adaptive response; Cyanidin; Endothelial dysfunction; Nrf2; Oxidative stress