Cellular zinc content is a major determinant of iron chelator–induced apoptosis of thymocytes

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3831-3839 ◽  
Author(s):  
Kirsteen H. Maclean ◽  
John L. Cleveland ◽  
John B. Porter
Keyword(s):  
Zinc Content ◽  
Iron Chelator ◽  
Iron Chelators ◽  
Intracellular Zinc ◽  
Zinc Chelator ◽  
Thymocyte Apoptosis ◽  
Zinc Levels ◽  
Induced Apoptosis ◽  
Cellular Zinc

Abstract Desferrioxamine (DFO) and the hydroxypiridinone (HPO) deferiprone (CP20) chelate iron as well as other metals. These chelators are used clinically to treat iron overload, but they induce apoptosis in thymocytes. Thymocyte apoptosis is potentiated by zinc deficiency, suggesting that these iron chelators may induce apoptosis by depleting stores of zinc. Exposure of murine thymocytes to either DFO or deferiprone resulted in significant reductions in the labile intracellular zinc pool. Moreover, increasing intracellular zinc levels, by chronic zinc dietary supplementation to mice or in vitro loading with zinc, abrogated deferiprone-induced murine thymocyte apoptosis. Bidentate hydroxypyridinones such as deferiprone interact with intracellular zinc pools in a manner distinct from that of DFO, which is a hexadentate iron chelator. Whereas deferiprone acts synergistically with the zinc chelator NNNN-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) to induce apoptosis, DFO does not. This difference is most likely due to the ability of HPOs but not DFO to “shuttle” zinc onto acceptors such as metallothioneins. By nature of its structure, DFO is larger than deferiprone and is thus less able to access some intracellular zinc pools. Additionally, metal complexes of DFO are more stable than those of HPOs and thus are less likely to donate zinc to other acceptors. The ability of deferiprone to preferentially access zinc pools was also demonstrated by inhibition of a zinc-containing enzyme phospholipase C, particularly when combined with TPEN. These findings suggest that bidentate iron chelators access intracellular zinc pools not available to DFO and that zinc chelation is a mechanism of apoptotic induction by such chelators in thymocytes.

H2O2-Induced Apoptosis of Thymocytes Involves Mobilization of Divalent Cations

2002 ◽  
Vol 15 (3) ◽  
pp. 195-200 ◽  
Author(s):  
A. Acharya
Keyword(s):  
Divalent Cations ◽  
Reactive Oxygen ◽  
Time Dependent ◽  
Dependent Manner ◽  
Reactive Oxygen Intermediates ◽  
Oxygen Intermediates ◽  
Thymocyte Apoptosis ◽  
Induced Apoptosis

More than 90% of thymocytes undergo apoptosis while undergoing differentiation in the thymus. Although several factors act in concert to induce thymocyte apoptosis, it remains speculative if reactive oxygen intermediates produced by thymic macrophages may play a role in this process. The present investigation was carried out to determine if H2O2 is capable of inducing apoptosis of thymocytes in vitro. It was observed that H2O2 could induce apoptosis of thymocytes in vitro in a dose and time dependent manner. It was further found that H2O2-induced thymocyte apoptosis was dependent on the mobilization of divalent cations. The result of this study will help further in the understanding of the mechanism of H2O2 - induced apoptosis.

Oxidative Stress in Red Blood Cells, Platelets and Polymorphonuclear Leukocytes from Patients with Myelodysplastic Syndrome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2632-2632
Author(s):  
Eitan Fibach ◽  
Hussam Ghoti ◽  
Johnny Amer ◽  
Asher Winder ◽  
Eliezer Rachmilewitz
Keyword(s):  
Oxidative Stress ◽  
Myelodysplastic Syndrome ◽  
Blood Cells ◽  
Cell Damage ◽  
Iron Chelator ◽  
Oxidative Status ◽  
Iron Chelators ◽  
Ros Generation ◽  
Transfusion Requirements

Abstract Myelodysplastic syndrome (MDS) is characterized by refractory cytopenias due to ineffective hematopoiesis. Some patients with severe anemia require multiple blood transfusions and develop iron overload. Consequently, reactive oxygen species (ROS) are generated concomitant with a decrease in cellular antioxidants such as reduced gluthatione (GSH). The generated oxidative stress contributes to cell damage, apoptosis and ineffective hematopoiesis. Using flow cytometry, we measured the oxidative state of RBC, platelets and PMN in 14 low-risk MDS patients and 25 normal donors. The results indicate that the majority of the patients had higher ROS in RBC (2.79-fold) and platelets (2.91-fold) and lower GSH in their RBC (3.4-fold) and platelets (2.1-fold) than normal (p<0.005). As for PMN, there were no significant differences in ROS, although GSH was significantly (p<0.1) lower in MDS compared with normal donors. The oxidative stress in MDS cells could be ameliorated by a short in vitro treatment with the iron-chelators deferrioxamine and deferiprone, or with the anti-oxidant N-acetylcysteine. These results suggest that the decrease in transfusion requirements with increase in platelet and PMN counts in MDS patients treated with deferrioxamine may be due to indirect antioxidant effect of the iron chelator and suggest that treatment with a combination of iron-chelators and anti-oxidants might be more effective. ROS generation and GSH content in MDS blood cells ROS generation and GSH content in MDS blood cells Effect of iron chelations and an antioxidant on the oxidative status of MDS cells Effect of iron chelations and an antioxidant on the oxidative status of MDS cells

The Iron Chelator L1 Potentiates Oxidative DNA Damage in Iron-Loaded Liver Cells

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 632-638 ◽  
Author(s):  
Louise Cragg ◽  
Robert P. Hebbel ◽  
Wesley Miller ◽  
Alex Solovey ◽  
Scott Selby ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Iron Overload ◽  
Oxidative Dna Damage ◽  
Iron Chelator ◽  
Liver Cells ◽  
Iron Chelators

Abstract Iron-mediated carcinogenesis is thought to occur through the generation of oxygen radicals. Iron chelators are used in attempts to prevent the long term consequences of iron overload. In particular, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), has shown promise as an effective chelator. Using an established hepatocellular model of iron overload, we studied the generation of iron-catalyzed oxidative DNA damage and the influence of iron chelators, including L1, on such damage. Iron loading of HepG2 cells was found to greatly exacerbate hydrogen peroxide–mediated DNA damage. Desferrithiocin was protective against iron/hydrogen peroxide–induced DNA damage; deferoxamine had no effect. In contrast, L1 exposure markedly potentiated hydrogen peroxide–mediated oxidative DNA damage in iron-loaded liver cells. However, when exposure to L1 was maintained during incubation with hydrogen peroxide, L1 exerted a protective effect. We interpret this as indicating that L1's potential toxicity is highly dependent on the L1:iron ratio. In vitro studies examining iron-mediated ascorbate oxidation in the presence of L1 showed that an L1:iron ratio must be at least 3 to 1 for L1 to inhibit the generation of free radicals; at lower concentrations of L1 increased oxygen radical generation occurs. In the clinical setting, such potentiation of iron-catalyzed oxidative DNA damage at low L1:iron ratios may lead to long-term toxicities that might preclude administration of L1 as an iron chelator. Whether this implication in fact extends to the in vivo situation will have to be verified in animal studies.

The human zinc transporter SLC39A8 (Zip8) is critical in zinc-mediated cytoprotection in lung epithelia

2008 ◽  
Vol 294 (6) ◽  
pp. L1127-L1136 ◽  
Author(s):  
Beth Besecker ◽  
Shengying Bao ◽  
Barbara Bohacova ◽  
Audrey Papp ◽  
Wolfgang Sadee ◽  
...  
Keyword(s):  
Cell Survival ◽  
Zinc Content ◽  
Zinc Transporters ◽  
Rt Pcr ◽  
Intracellular Zinc ◽  
Inflammatory Stress ◽  
Tnf Α ◽  
Zinc Concentrations ◽  
Interfering Rna ◽  
Cellular Zinc

Zinc is an essential micronutrient and cytoprotectant involved in the host response to inflammatory stress. We tested whether zinc transporters, the critical regulators that maintain intracellular zinc concentrations, play a role in cell survival, particularly in lung epithelia, during inflammation. Initially, mRNA transcripts were quantitatively measured by RT-PCR for all known human zinc transporters, including 14 importers (SLC39A1–14) and 10 exporters (SLC30A1–10), in primary human lung epithelia obtained from multiple human donors and BEAS-2B cell cultures under baseline and TNF-α-stimulated conditions. While many zinc transporters were constitutively expressed, only SLC39A8 (Zip8) mRNA was strongly induced by TNF-α. Endogenous Zip8 protein was not routinely detected under baseline conditions. In sharp contrast, TNF-α induced the expression of a glycosylated protein that translocated to the plasma membrane and mitochondria. Increased Zip8 expression resulted in an increase in intracellular zinc content and coincided with cell survival in the presence of TNF-α. Inhibition of Zip8 expression using a short interfering RNA probe reduced cellular zinc content and impaired mitochondrial function in response to TNF-α, resulting in loss of cell viability. These data are the first to characterize human Zip8 and remarkably demonstrate that upregulation of Zip8 is sufficient to protect lung epithelia against TNF-α-induced cytotoxicity. We conclude that Zip8 is unique, relative to other Zip proteins, by functioning as an essential zinc importer at the onset of inflammation, thereby facilitating cytoprotection within the lung.

Abstract 15100: A Decrease in Mitochondrial, but Not Cytosolic, Iron Protects Against Cardiac Ischemia-Reperfusion Damage Through a Reduction in ROS

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Hsiang-Chun Chang ◽  
Rongxue Wu ◽  
Meng Shang ◽  
Hossein Ardehali
Keyword(s):  
Cardiac Function ◽  
Ischemia Reperfusion ◽  
Iron Chelation ◽  
Selective Reduction ◽  
Iron Chelator ◽  
Iron Chelators ◽  
Causative Role ◽  
Novel Approach ◽  
Mitochondrial Iron

Introduction: Iron can catalyze the formation of reactive oxygen species (ROS) and promote tissue damage. While some studies suggested benefits with iron chelation therapy in ischemic heart disease (IHD), several others failed to show any benefits. Mitochondria are a major site of iron utilization and ROS production, and mitochondrial iron accumulation has been associated with increased oxidative stress. We therefore hypothesized that mitochondrial iron plays a causative role in ischemia/reperfusion (I/R) damage, and a decrease in mitochondrial iron (as opposed to cytoplasmic iron) would be sufficient to protect against I/R injury. Results: We observed an increase in cardiac mitochondrial iron in mice after I/R injury. Using two iron chelators with distinct mitochondrial permeability, i.e., 2,2’-bipyridyl (BPD, a mitochondria-accessible iron chelator) and deferoxamine (DFO, an iron chelator that does not modulate mitochondrial iron), we demonstrated that mice pretreated with BPD but not DFO were protected against I/R injury. Similar results were obtained in vitro . Since these two iron chelators also modulate iron in other subcellular compartments, we used transgenic (TG) mice with cardiomyocyte-specific overexpression of the mitochondrial iron export protein ATP-binding cassette (ABC)-B8 to confirm that modulation of mitochondrial iron alone is sufficient to confer protection. ABCB8 TG mice had significantly lower mitochondrial iron (but normal cytosolic iron) in the heart compared to nontransgenic (NTG) littermates at baseline, but exhibited normal cardiac function. After I/R, ABCB8 TG mice displayed significantly less apoptosis and lower levels of markers of ROS and better preserved cardiac function than NTG littermates, suggesting that a reduction in mitochondrial iron protects against I/R injury, most likely through a reduction in ROS. Conclusions: Our findings demonstrate that selective reduction in mitochondrial iron is sufficient to protect against I/R injury. Thus, targeting mitochondrial iron with selective iron chelators may provide a novel approach for the treatment of IHD.

The Iron Chelator L1 Potentiates Oxidative DNA Damage in Iron-Loaded Liver Cells

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 632-638 ◽  
Author(s):  
Louise Cragg ◽  
Robert P. Hebbel ◽  
Wesley Miller ◽  
Alex Solovey ◽  
Scott Selby ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Iron Overload ◽  
Oxidative Dna Damage ◽  
Iron Chelator ◽  
Liver Cells ◽  
Iron Chelators

Iron-mediated carcinogenesis is thought to occur through the generation of oxygen radicals. Iron chelators are used in attempts to prevent the long term consequences of iron overload. In particular, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), has shown promise as an effective chelator. Using an established hepatocellular model of iron overload, we studied the generation of iron-catalyzed oxidative DNA damage and the influence of iron chelators, including L1, on such damage. Iron loading of HepG2 cells was found to greatly exacerbate hydrogen peroxide–mediated DNA damage. Desferrithiocin was protective against iron/hydrogen peroxide–induced DNA damage; deferoxamine had no effect. In contrast, L1 exposure markedly potentiated hydrogen peroxide–mediated oxidative DNA damage in iron-loaded liver cells. However, when exposure to L1 was maintained during incubation with hydrogen peroxide, L1 exerted a protective effect. We interpret this as indicating that L1's potential toxicity is highly dependent on the L1:iron ratio. In vitro studies examining iron-mediated ascorbate oxidation in the presence of L1 showed that an L1:iron ratio must be at least 3 to 1 for L1 to inhibit the generation of free radicals; at lower concentrations of L1 increased oxygen radical generation occurs. In the clinical setting, such potentiation of iron-catalyzed oxidative DNA damage at low L1:iron ratios may lead to long-term toxicities that might preclude administration of L1 as an iron chelator. Whether this implication in fact extends to the in vivo situation will have to be verified in animal studies.

scholarly journals Zinc, metallothioneins and immunosenescence

2010 ◽  
Vol 69 (3) ◽  
pp. 290-299 ◽  
Author(s):  
E. Mocchegiani ◽  
M. Malavolta ◽  
L. Costarelli ◽  
R. Giacconi ◽  
C. Cipriano ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Zinc Supplementation ◽  
Killer Cell ◽  
Zinc Content ◽  
Zinc Homeostasis ◽  
Zinc Transporters ◽  
Intracellular Zinc ◽  
Natural Killer Cell Cytotoxicity ◽  
Zip Family

Ageing is an inevitable biological process with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. The nutritional factor, zinc, may remodel these changes with subsequent healthy ageing, because zinc improves the inflammatory/immune response as shown by in vitro and in vivo studies. The intracellular zinc homeostasis is regulated by buffering metallothioneins (MT) and zinc transporters (ZnT and ZIP families) that mediate the intracellular zinc signalling assigning to zinc a role of ‘second messenger’. In ageing, the intracellular zinc homeostasis is altered, because high MT are unable to release zinc and some zinc transporters deputed to zinc influx (ZIP family) are defective leading to low intracellular zinc content for the immune efficiency. Physiological zinc supplementation in the elderly improves these functions. However, the choice of old subjects for zinc supplementation has to be performed in relation to the specific genetic background of MT and IL-6, because the latter is involved both in MTmRNA and in intracellular zinc homeostasis. Old subjects carrying GG genotypes (C–carriers) in the IL-6–174G/C locus display high IL-6, low intracellular zinc content, impaired innate immunity and enhanced MT. Old subjects carrying GC and CC genotypes (C+carriers) display satisfactory intracellular zinc content, adequate innate immunity and are more prone to reach longevity. Zinc supplementation in old C–carriers restores natural killer cell cytotoxicity and zinc status. The genetic variations of the IL-6−174G/C locus when associated with those of the MT1A+647A/C locus are useful tools for the choice of old people for zinc supplementation.

scholarly journals Low zinc levels at clinical admission associates with poor outcomes in COVID-19

2020 ◽  
Author(s):  
Marina Vogel-González ◽  
Marc Talló-Parra ◽  
Víctor Herrera-Fernández ◽  
Gemma Pérez-Vilaró ◽  
Miguel Chillón ◽  
...  
Keyword(s):  
Zinc Deficiency ◽  
Randomized Clinical Trials ◽  
Serum Zinc ◽  
Zinc Content ◽  
Zinc Concentrations ◽  
Infected Cells ◽  
Poor Outcomes ◽  
Zinc Levels ◽  
Serum Zinc Levels

AbstractBackgroundBiomarkers to predict Coronavirus disease-19 (COVID-19) outcome early at infection are urgently needed to improve prognosis and treatment. Zinc balances immune responses and also has a proven direct antiviral action against some viruses. Importantly, zinc deficiency (ZD) is a common condition in elderly and individuals with chronic diseases, two groups with more severe COVID-19 outcomes. We hypothesize that serum zinc content (SZC) influences COVID-19 disease progression and thus might represent a useful biomarker.MethodsWe run a retrospective observational study with 249 COVID-19 patients admitted in Hospital del Mar. We have studied COVID-19 severity and progression attending to SZC at admission. In parallel we have studied SARS-CoV2 replication in the Vero E6 cell line modifying zinc concentrations.FindingsOur study demonstrates a correlation between serum zinc levels and COVID-19 outcome. Serum zinc levels lower than 50 µg/dl at admission correlated with worse clinical presentation, longer time to reach stability and higher mortality. Our in vitro results indicate that low zinc levels favor viral expansion in SARS-CoV2 infected cells.InterpretationSZC is a novel biomarker to predict COVID-19 outcome. We encourage performing randomized clinical trials to study zinc supplementation as potential prophylaxis and treatment with people at risk of zinc deficiency.FundingSpanish Ministry of Science and Innovation, “Maria de Maeztu” Programme for Units of Excellence in R&D and Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement of the Generalitat de Catalunya. Instituto Carlos III Fondos de Investigaciones Sanitarias (FIS), CIBER on Frailty and Healthy Ageing and FEDER funds

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