Resveratrol accelerates erythroid maturation by activation of FoxO3 and ameliorates anemia in beta-thalassemic mice

Sara Santos Franco, Luigia De Falco, Saghi Ghaffari, Carlo Brugnara, David A. Sinclair, Alessandro Matte, Achille Iolascon, Narla Mohandas, Mariarita Bertoldi, Xiuli An, Angela Siciliano, Pauline Rimmelé, Maria Domenica Cappellini, Shaday Michan, Elisa Zoratti, Janin Anne, Lucia De Franceschi

Research output: Contribution to journalArticle

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 mM) 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 vivomurine 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.

Original languageEnglish
Pages (from-to)267-275
Number of pages9
JournalHaematologica
Volume99
Issue number2
DOIs
Publication statusPublished - Feb 1 2014

ASJC Scopus subject areas

  • Hematology

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    Franco, S. S., De Falco, L., Ghaffari, S., Brugnara, C., Sinclair, D. A., Matte, A., Iolascon, A., Mohandas, N., Bertoldi, M., An, X., Siciliano, A., Rimmelé, P., Cappellini, M. D., Michan, S., Zoratti, E., Anne, J., & De Franceschi, L. (2014). Resveratrol accelerates erythroid maturation by activation of FoxO3 and ameliorates anemia in beta-thalassemic mice. Haematologica, 99(2), 267-275. https://doi.org/10.3324/haematol.2013.090076