title: NRF2 activation is involved in ozonated human serum upregulation of HO-1 in endothelial cells.
abstract: During the last decade, it has been shown that the activation of NRF2 and the binding to electrophile-responsive element (EpREs), stimulates the expression of a great number of genes responsible for the synthesis of phase I and phase II proteins, including antioxidants enzymes and heme oxygenase-1 (HO-1). This critical cell response occurs in cardiovascular, degenerative and chronic infective diseases aggravated by a chronic oxidative stress. In our previous reports we have shown that ozonated plasma is able to up-regulate HO-1 expression in endothelial cells. In the present work we investigated a candidate mechanism involved in this process. After treatment with increasing doses of ozonated serum (20, 40 and 80 μg/mL O(3) per mL of serum), a clear dose dependent activation of NRF2 and the subsequent induction of HO-1 and NAD(P)H quinone oxidoreductase 1(NQO1) was observed. This effect was also present when cells were treated with serum and hydrogen peroxide (H(2)O(2)) or serum and 4-hydroxynonenal (4HNE). Moreover, the treatment with ozonated serum was associated with a dose-dependent activation of extracellular-signal-regulated kinases (ERK1/2) and p38 MAP kinases (p38), not directly involved in NRF2 activation. These data, provide a new insight on the mechanism responsible for the induction of HO-1 expression by ozonated serum in the endothelium, and have a practical importance as an expedient approach to the treatment of patients with both effective orthodox drugs and ozonated autohemotherapy, targeted to the restoration of redox homeostasis.
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pecorelli
authors.forename: Velio
authors.initials: V
authors.lastname: Bocci
authors.forename: Alessandra
authors.initials: A
authors.lastname: Acquaviva
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Belmonte
authors.forename: Concetta
authors.initials: C
authors.lastname: Gardi
authors.forename: Fabio
authors.initials: F
authors.lastname: Virgili
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciccoli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Valacchi
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000097:blood; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000097:blood / Q000502:physiology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010126:Ozone / Q000633:toxicity*; D044967:Serum / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010126:Ozone; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1