Home About us Contact
|
Home About us Contact | ||
|
|
||
Free Iron (free + iron)
Selected AbstractsOxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndromeEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2007Hussam Ghoti Abstract Low-risk myelodysplastic syndrome (MDS) is characterized by cytopenia, mainly anemia, because of ineffective hematopoiesis. Some of the patients with ineffective erythropoiesis, with or without ring sideroblasts in their bone marrow, develop severe anemia requiring frequent blood transfusions and consequently develop iron overload. Excess free iron in cells catalyses the generation of reactive oxygen species (ROS) that cause cell and tissue damage. Using flow cytometry techniques, we compared the oxidative status of red blood cells (RBC), platelets and neutrophils in 14 MDS patients with those of normal donors. The results show that ROS were higher while reduced glutathione (GSH) was lower in their RBC and platelets compared with normal cells. In neutrophils, no difference was found in ROS, while the GSH levels were lower. A correlation (r = 0.6) was found between serum ferritin levels of the patients and the ROS in their RBC and platelets. The oxidative stress was ameliorated by a short incubation with the iron-chelators, the deferrioxamine and deferiprone or with antioxidants such as N -acetylcysteine, suggesting that MDS patients might benefit from treatment with iron-chelators and antioxidants. [source] Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivityGLIA, Issue 10 2008Kryslaine O. Lopes Abstract Degeneration of microglial cells may be important for understanding the pathogenesis of aging-related neurodegeneration and neurodegenerative diseases. In this study, we analyzed the morphological characteristics of microglial cells in the nondemented and Alzheimer's disease (AD) human brain using ferritin immunohistochemistry. The central hypothesis was that expression of the iron storage protein ferritin increases the susceptibility of microglia to degeneration, particularly in the aged brain since senescent microglia might become less efficient in maintaining iron homeostasis and free iron can promote oxidative damage. In a primary set of 24 subjects (age range 34,97 years) examined, microglial cells immunoreactive for ferritin were found to constitute a subpopulation of the larger microglial pool labeled with an antibody for HLA-DR antigens. The majority of these ferritin-positive microglia exhibited aberrant morphological (dystrophic) changes in the aged and particularly in the AD brain. No spatial correlation was found between ferritin-positive dystrophic microglia and senile plaques in AD tissues. Analysis of a secondary set of human postmortem brain tissues with a wide range of postmortem intervals (PMI, average 10.94 ± 5.69 h) showed that the occurrence of microglial dystrophy was independent of PMI and consequently not a product of tissue autolysis. Collectively, these results suggest that microglial involvement in iron storage and metabolism contributes to their degeneration, possibly through increased exposure of the cells to oxidative stress. We conclude that ferritin immunohistochemistry may be a useful method for detecting degenerating microglia in the human brain. © 2008 Wiley-Liss, Inc. [source] Lactoferrin decreases pollen antigen-induced allergic airway inflammation in a murine model of asthmaIMMUNOLOGY, Issue 2 2006Marian L. Kruzel Summary Pollen grains contain reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidases and in contact with mucosal surfaces generate superoxide anion (O2,,). In the presence of iron, O2,, may be converted to more reactive oxygen radicals, such as to H2O2 and/or ,OH, which may augment antigen-induced airway inflammation. The aim of the study was to examine the impact of lactoferrin (LF), an iron-binding protein, on ragweed (Ambrosia artemisiifolia) pollen extract (RWE)-induced cellular oxidative stress levels in cultured bronchial epithelial cells and accumulation of inflammatory and mucin-producing cells in airways in a mouse model of allergic airway inflammation. Results show that LF lowered RWE-induced increase in cellular reactive oxygen species (ROS) levels in bronchial epithelial cells. Most importantly, LF significantly decreased accumulation of eosinophils into airways and subepithelium of intranasally challenged, sensitized mice. LF also prevented development of mucin-producing cells. Amb a 1, the major allergenic ragweed pollen antigen lacking NAD(P)H oxidase activity, induced low-grade airway inflammation. When administered along with glucose oxidase (G-ox), a superoxide-generating enzyme, Amb a 1 induced robust airway inflammation, which was significantly lowered by LF. Surprisingly, LF decreased also inflammation caused by Amb a 1 alone. Iron-saturated hololactoferrin had only a marginal effect on RWE-induced cellular ROS levels and RWE- or Amb a 1 plus G-ox-induced inflammation. We postulate that free iron in the airways chemically reduces O2,, to more reactive species which augment antigen-induced inflammation in a mouse model of asthma. Our results suggest the utility of LF in human allergic inflammatory disorders. [source] Activation of phosphoinositide-3 kinase/Akt pathway by FeSO4 in rat cerebral cortex synaptic endingsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2007Romina M. Uranga Abstract The aim of this work was to study the involvement of the phosphoinositide-3-kinase (PI3K)/Akt pathway in synaptic endings incubated under oxidative stress conditions. Synaptosomes purified from rat cerebral cortex were exposed to FeSO4 (50 ,M) for different periods of time. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction and lactate dehydrogenate (LDH) leakage were significantly affected after 5 min of incubation in the presence of FeSO4, with respect to control conditions. In whole synaptosomes incubated in the presence of [,- 32P]ATP, phosphoinositide (PPI) labeling was increased after 5 min of Fe2+ exposure. This effect was prevented by the specific PI3K inhibitor LY294002. Anti-p85 immunoprecipitates (IPs) obtained from synaptosomes preincubated with Fe2+ (5 min) showed a PI3K activity two-fold higher than the activity recovered under control conditions. Additionally, Akt activation was temporally coincident with PI3K activation. LY294002 was not able to prevent the LDH leakage and diminution of MTT reduction induced by Fe2+. Our results demonstrate that free iron provokes the early activation of PI3K/Akt pathway, but this activation is not sufficient for protecting synaptic endings from oxidative damage. © 2007 Wiley-Liss, Inc. [source] Staphylococcus aureus haem oxygenases are differentially regulated by iron and haemMOLECULAR MICROBIOLOGY, Issue 5 2008Michelle L. Reniere Summary Iron acquisition is a vital process for most pathogenic bacteria, as iron is a limiting nutrient during infection. Staphylococcus aureus, an increasingly important pathogen, acquires iron from host haem via elaboration of the iron-regulated surface determinant system (Isd). IsdG and IsdI are haem oxygenases that have been proposed to degrade exogenous haem in the bacterial cytoplasm as a mechanism to liberate free iron for use as a nutrient source. Herein, we report that IsdG and IsdI are both important for S. aureus growth on haemin as a sole iron source and are necessary for full S. aureus pathogenesis. Investigations into the regulation of these enzymes revealed that IsdG and IsdI are differentially regulated by iron and haem through both transcriptional and post-transcriptional mechanisms. Additionally, IsdI was found to be expressed in infected tissues at the sites of abscess formation, suggesting that abscesses are iron-starved microenvironments inside the host. These findings suggest that S. aureus differentially regulates IsdG and IsdI in response to alterations in iron and haem availability during infection. [source] Submicromolar hydrogen peroxide disrupts the ability of Fur protein to control free-iron levels in Escherichia coliMOLECULAR MICROBIOLOGY, Issue 3 2007Shery Varghese Summary In aerobic environments, mutants of Escherichia coli that lack peroxidase and catalase activities (Hpx,) accumulate submicromolar concentrations of intracellular H2O2. We observed that in defined medium these strains constitutively expressed members of the Fur regulon. Iron-import proteins, which Fur normally represses, were fully induced. H2O2 may antagonize Fur function by oxidizing the Fur:Fe2+ complex and inactivating its repressor function. This is a potential problem, as in iron-rich environments excessive iron uptake would endanger H2O2 -stressed cells by accelerating hydroxyl-radical production through the Fenton reaction. However, the OxyR H2O2 -response system restored Fur repression in iron-replete Luria,Bertani medium by upregulating the synthesis of Fur protein. Indeed, when the OxyR binding site upstream of fur was disrupted, Hpx, mutants failed to repress transporter synthesis, and they exhibited high levels of intracellular free iron. Mutagenesis and bacteriostasis resulted. These defects were eliminated by mutations or chelators that slowed iron import, confirming that dysregulation of iron uptake was the root problem. Thus, aerobic organisms must grapple with a conundrum: how to monitor iron levels in oxidizing environments that might perturb the valence of the analyte. The induction of Fur synthesis by the OxyR response comprises one evolutionary solution to that problem. [source] Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disordersMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 2 2006Silvia Mandel Abstract Neurodegeneration in Parkinson's, Alzheimer's, or other neurodegenerative diseases appears to be multifactorial, where a complex set of toxic reactions, including oxidative stress (OS), inflammation, reduced expression of trophic factors, and accumulation of protein aggregates, lead to the demise of neurons. One of the prominent pathological features is the abnormal accumulation of iron on top of the dying neurons and in the surrounding microglia. The capacity of free iron to enhance and promote the generation of toxic reactive oxygen radicals has been discussed numerous times. The observations that iron induces aggregation of inert ,-synuclein and beta-amyloid peptides to toxic aggregates have reinforced the critical role of iron in OS-induced pathogenesis of neurodegeneration, supporting the notion that a combination of iron chelation and antioxidant therapy may be one significant approach for neuroprotection. Tea flavonoids (catechins) have been reported to possess divalent metal chelating, antioxidant, and anti-inflammatory activities, to penetrate the brain barrier and to protect neuronal death in a wide array of cellular and animal models of neurological diseases. This review aims to shed light on the multipharmacological neuroprotective activities of green tea catechins with special emphasis on their brain-permeable, nontoxic, transitional metal (iron and copper)-chelatable/radical scavenger properties. [source] Control of Oxidative Reactions of Hemoglobin in the Design of Blood Substitutes: Role of the Ascorbate,Glutathione Antioxidant SystemARTIFICIAL ORGANS, Issue 2 2009Jan Simoni Abstract Uncontrolled oxidative reactions of hemoglobin (Hb) are still the main unresolved problem for Hb-based blood substitute developers. Spontaneous oxidation of acellular ferrous Hb into a nonfunctional ferric Hb generates superoxide anion. Hydrogen peroxide, formed after superoxide anion dismutation, may react with ferrous/ferric Hb to produce toxic ferryl Hb, fluorescent heme degradation products, and/or protein-based free radicals. In the presence of free iron released from heme, superoxide anion and hydrogen peroxide might react via the Haber,Weiss and Fenton reactions to generate the hydroxyl radical. These highly reactive oxygen and heme species may not only be involved in shifting the cellular redox balance to the oxidized state that facilitates signal transduction and pro-inflammatory gene expression, but could also be involved in cellular and organ injury, and generation of vasoactive compounds such as isoprostanes and angiotensins. It is believed that these toxic species may be formed after administration of Hb-based blood substitutes, particularly in ischemic patients with a diminished ability to control oxidative reactions. Although varieties of antioxidant strategies have been suggested, this in vitro study examined the ability of the ascorbate,glutathione antioxidant system in preventing Hb oxidation and formation of its ferryl intermediate. The results suggest that although ascorbate is effective in reducing the formation of ferryl Hb, glutathione protects heme against excessive oxidation. Ascorbate without glutathione failed to protect the red blood cell membranes against Hb/hydrogen peroxide-mediated peroxidation. This study provides evidence that the ascorbate,glutathione antioxidant system is essential in attenuation of the pro-oxidant potential of redox active acellular Hbs, and superior to either ascorbate or glutathione alone. [source] Iron elevations in the aging Parkinsonian brain: a consequence of impaired iron homeostasis?JOURNAL OF NEUROCHEMISTRY, Issue 2 2010Donna W. Lee Abstract The contribution of iron dysregulation to the etiology of a variety of neuronal diseases comes as no surprise given its necessity in numerous general cellular and neuron-specific functions, its abundance, and its highly reactive nature. Homeostatic mechanisms such as the iron regulatory protein and hypoxia-inducible factor pathways are firmly evolutionarily set in place to prevent ,free' iron from participating in chemical Fenton and Haber-Weiss reactions which can result in subsequent generation of toxic hydroxyl radicals. However, given the multiple layers of complexity in cellular iron regulation, disruption of any number of genetic and environmental components can disturb the delicate balance between the various molecular players involved in maintaining an appropriate metabolic iron homeostasis. In this review, we will primarily focus on: (i) the impact of aging and gender on iron dysfunction as these are important criteria in the determination of iron-related disorders such as Parkinson's disease (PD), (ii) how iron mismanagement via disruption of cellular entry and exit pathways may contribute to these disorders, and (iii) how the availability of non-invasive measurement of brain iron may aid in PD diagnosis. [source] | |||||||||||||