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Down syndrome (DS, trisomy 21) is the leading cause of chromosomal-related intellectual disability. At an early age, adults with DS develop with the neuropathological hallmarks of Alzheimer's disease, associated with a chronic oxidative stress. To investigate if non-protein bound iron (NPBI) can contribute to building up a pro-oxidative microenvironment, we evaluated NPBI in both plasma and erythrocytes from DS and age-matched controls, together with in vivo markers of lipid peroxidation (F-isoprostanes, F-dihomo-isoprostanes, F-neuroprostanes) and in vitro reactive oxygen species (ROS) formation in erythrocytes. The serum iron panel and uric acid were also measured. Second, we explored possible correlation between NPBI, lipid peroxidation and cognitive performance. Here, we report NPBI increase in DS, which correlates with increased serum ferritin and uric acid. High levels of lipid peroxidation markers and intraerythrocyte ROS formations were also reported. Furthermore, the scores of Raven's Colored Progressive Matrices (RCPM) test, performed as a measure of current cognitive function, are inversely related to NPBI, serum uric acid, and ferritin. Likewise, ROS production, F-isoprostanes, and F-neuroprostanes were also inversely related to cognitive performance, whereas serum transferrin positively correlated to RCPM scores. Our data reveal that increased availability of free redox-active iron, associated with enhanced lipid peroxidation, may be involved in neurodegeneration and cognitive decline in DS. In this respect, we propose chelation therapy as a potential preventive/therapeutic tool in DS.

Background/Aims: The antimycobacterial riminophenazine clofazimine has previously been shown to up-regulate cellular phospholipase A₂ and to induce apoptosis. In erythrocytes phospholipase A₂ stimulates eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Phospholipase A₂ is in part effective by fostering formation of prostaglandin E₂, which triggers Ca²⁺ entry. Stimulators of Ca²⁺ entry and eryptosis further include oxidative stress and energy depletion. The present study tested, whether and how clofazimine induces eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, hemolysis from hemoglobin release, cytosolic Ca²⁺ activity ([Ca²⁺]_i) from Fluo3-fluorescence, reactive oxygen species (ROS) from 2′, 7′-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, and cytosolic ATP level utilizing a luciferin-luciferase assay kit. Results: A 24-48 hours exposure of human erythrocytes to clofazimine (≥1.5 µg/ml) significantly increased the percentage of annexin-V-binding cells without appreciably modifying forward scatter. Clofazimine significantly increased [Ca²⁺]_i, significantly decreased cytosolic ATP, but did not significantly modify ROS. The effect of clofazimine on annexin-V-binding was significantly blunted, but not fully abolished by removal of extracellular Ca²⁺, and by phospholipase A₂ inhibitor quinacrine (25 µM). Clofazimine further augmented the effect of Ca²⁺ ionophore ionomycin (0.1 µM) on eryptosis. The clofazimine induced annexin-V-binding was, however, completely abrogated by combined Ca²⁺ removal and addition of quinacrine. Conclusion: Clofazimine stimulates phospholipid scrambling of the erythrocyte cell membrane, an effect in part dependent on entry of extracellular Ca²⁺, paralleled by cellular energy depletion and sensitive to phospholipase A₂ inhibitor quinacrine.

Oxidative stress is one of the underlying mechanisms of the toxic effects exerted by mercury (Hg) on human health. Several antioxidant compounds, including the olive oil phenol hydroxytyrosol (HT), were investigated for their protective action. Recently, we have reported that 5-S-lipoylhydroxytyrosol (Lipo-HT) has shown increased antioxidant activities compared to HT and exerted potent protective effects against reactive oxygen species (ROS) generation and oxidative damage in human hepatocellular carcinoma HepG2 cell lines. In this study, the effects of Lipo-HT and HT on oxidative alterations of human erythrocytes induced by exposure to 40 μM HgCl2 were comparatively evaluated. When administered to the cells, Lipo-HT (5–20 μM) proved nontoxic and it decreased the Hg-induced generation of ROS, the hemolysis, and the depletion of intracellular GSH levels. At all tested concentrations, Lipo-HT exhibited higher ability to counteract Hg-induced cytotoxicity compared to HT. Model studies indicated the formation of a mercury complex at the SH group of Lipo-HT followed by a redox reaction that would spare intracellular GSH. Thus, the enhanced erythrocyte protective action of Lipo-HT from Hg-induced damage with respect to HT is likely due to an effective chelating and reducing ability toward mercury ions. These findings encourage the use of Lipo-HT in nutraceutical strategies to contrast heavy metal toxicity in humans.

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Fat redistribution occurred in most HIV-infected children undergoing PI therapy. Because serum resistin levels reflect the amount of visceral fat, they could be considered a sensitive marker of fat redistribution in HIV-infected children.