title: Resveratrol accelerates erythroid maturation by activation of FoxO3 and ameliorates anemia in beta-thalassemic mice.
abstract: Resveratrol, a polyphenolic-stilbene, has received increased attention in the last decade due to its wide range of biological activities. Beta(β)-thalassemias are inherited red cell disorders, found worldwide, characterized by ineffective erythropoiesis and red cell oxidative damage with reduced survival. We evaluated the effects of low-dose-resveratrol (5 μM) on in vitro human erythroid differentiation of CD34(+) from normal and β-thalassemic subjects. We found that resveratrol induces accelerated erythroid-maturation, resulting in the reduction of colony-forming units of erythroid cells and increased intermediate and late erythroblasts. In sorted colony-forming units of erythroid cells resveratrol activates Forkhead-box-class-O3, decreases Akt activity and up-regulates anti-oxidant enzymes as catalase. In an in vivo murine model for β-thalassemia, resveratrol (2.4 mg/kg) reduces ineffective erythropoiesis, increases hemoglobin levels, reduces reticulocyte count and ameliorates red cell survival. In both wild-type and β-thalassemic mice, resveratrol up-regulates scavenging enzymes such as catalase and peroxiredoxin-2 through Forkhead-box-class-O3 activation. These data indicate that resveratrol inhibits Akt resulting in FoxO3 activation with upregulation of cytoprotective systems enabling the pathological erythroid precursors to resist the oxidative damage and continue to differentiate. Our data suggest that the dual effect of resveratrol on erythropoiesis through activation of FoxO3 transcriptional factor combined with the amelioration of oxidative stress in circulating red cells may be considered as a potential novel therapeutic strategy in treating β-thalassemia.
authors: lucia.defranceschi@univr.it.
authors: Sara Santos
authors: SS
authors: Franco
authors: Luigia
authors: L
authors: De Falco
authors: Saghi
authors: S
authors: Ghaffari
authors: Carlo
authors: C
authors: Brugnara
authors: David A
authors: DA
authors: Sinclair
authors: Alessandro
authors: A
authors: Matte'
authors: Achille
authors: A
authors: Iolascon
authors: Narla
authors: N
authors: Mohandas
authors: Mariarita
authors: M
authors: Bertoldi
authors: Xiuli
authors: X
authors: An
authors: Angela
authors: A
authors: Siciliano
authors: Pauline
authors: P
authors: Rimmelé
authors: Maria Domenica
authors: MD
authors: Cappellini
authors: Shaday
authors: S
authors: Michan
authors: Elisa
authors: E
authors: Zoratti
authors: Janin
authors: J
authors: Anne
authors: Lucia
authors: L
authors: De Franceschi
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D004920:Erythropoiesis / Q000187:drug effects*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D054464:Peroxiredoxins / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D017086:beta-Thalassemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D013267:Stilbenes; C086065:PRDX2 protein, human; D054464:Peroxiredoxins; D002374:Catalase; D000077185:Resveratrol
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