Duality of Nrf2 in iron-overload cardiomyopathy.

Cardiomyopathy deeply affects quality of life and mortality of patients with b-thalassemia or with transfusion-dependent myelodysplastic syndromes. Recently, a link between Nrf2 activity and iron metabolism has been reported in liver ironoverload murine models. Here, we studied C57B6 mice as healthy control and nuclear erythroid factor-2 knockout (Nrf2-/-) male mice aged 4 and 12 months. Eleven-month-old wild-type and Nrf2-/- mice were fed with either standard diet or a diet containing 2.5% carbonyl-iron (iron overload [IO]) for 4 weeks. We show that Nrf2-/- mice develop an age-dependent cardiomyopathy, characterized by severe oxidation, degradation of SERCA2A and iron accumulation. This was associated with local hepcidin expression and increased serum non-transferrin-bound iron, which promotes maladaptive cardiac remodeling and interstitial fibrosis related to overactivation of the TGF-b pathway. When mice were exposed to IO diet, the absence of Nrf2 was paradoxically protective against further heart iron accumulation. Indeed, the combination of prolonged oxidation and the burst induced by IO diet resulted in activation of the unfolded protein response (UPR) system, which in turn promotes hepcidin expression independently from heart iron accumulation. In the heart of Hbbth3/+ mice, a model of b-thalassemia intermedia, despite the activation of Nrf2 pathway, we found severe protein oxidation, activation of UPR system and cardiac fibrosis independently from heart iron content. We describe the dual role of Nrf2 when aging is combined with IO and its novel interrelation with UPR system to ensure cell survival. We open a new perspective for early and intense treatment of cardiomyopathy in patients with b-thalassemia before the appearance of heart iron accumulation.

Anthoxanthin Polyphenols Attenuate Aß Oligomer-induced Neuronal Responses Associated with Alzheimer's Disease.

AIMS: Epidemiological evidence implicates polyphenols as potential natural therapeutics for Alzheimer's disease (AD). To investigate this prospect, five anthoxanthin polyphenols were characterized for their ability to reduce amyloid-ß (Aß) oligomer-induced neuronal responses by two mechanisms of action, modulation of oligomerization and antioxidant activity, as well as the synergy between these two mechanisms. METHODS: Anthoxanthin oligomerization modulation and antioxidant capabilities were evaluated and correlated with anthoxanthin attenuation of oligomer-induced intracellular reactive oxygen species (ROS) and caspase activation using human neuroblastoma cell treatments designed to isolate these mechanisms of action and to achieve dual-action. RESULTS: While modulation of oligomerization resulted in only minor reductions to neuronal responses, anthoxanthin antioxidant action significantly attenuated oligomer-induced intracellular ROS and caspase activation. Kaempferol uniquely exhibited synergism when the two mechanisms functioned in concert, leading to a pronounced reduction in both ROS and caspase activation. CONCLUSIONS: Together, these findings identify the dominant mechanism by which these anthoxanthins attenuate Aß oligomer-induced neuronal responses, elucidate their prospective synergy, and demonstrate the potential of anthoxanthin polyphenols as natural AD therapeutics.