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Sample records for iron metabolism induced

  1. METABOLISM OF IRON STORES

    PubMed Central

    SAITO, HIROSHI

    2014-01-01

    ABSTRACT Remarkable progress was recently achieved in the studies on molecular regulators of iron metabolism. Among the main regulators, storage iron, iron absorption, erythropoiesis and hepcidin interact in keeping iron homeostasis. Diseases with gene-mutations resulting in iron overload, iron deficiency, and local iron deposition have been introduced in relation to the regulators of storage iron metabolism. On the other hand, the research on storage iron metabolism has not advanced since the pioneering research by Shoden in 1953. However, we recently developed a new method for determining ferritin iron and hemosiderin iron by computer-assisted serum ferritin kinetics. Serum ferritin increase or decrease curves were measured in patients with normal storage iron levels (chronic hepatitis C and iron deficiency anemia treated by intravenous iron injection), and iron overload (hereditary hemochromatosis and transfusion dependent anemia). We thereby confirmed the existence of two iron pathways where iron flows followed the numbered order (1) labile iron, (2) ferritin and (3) hemosiderin in iron deposition and mobilization among many previously proposed but mostly unproven routes. We also demonstrated the increasing and decreasing phases of ferritin iron and hemosiderin iron in iron deposition and mobilization. The author first demonstrated here the change in proportion between pre-existing ferritin iron and new ferritin iron synthesized by removing iron from hemosiderin in the course of iron removal. In addition, the author disclosed the cause of underestimation of storage iron turnover rate which had been reported by previous investigators in estimating storage iron turnover rate of normal subjects. PMID:25741033

  2. The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress.

    PubMed

    Koskenkorva-Frank, Taija S; Weiss, Günter; Koppenol, Willem H; Burckhardt, Susanna

    2013-12-01

    Production of minute concentrations of superoxide (O2(*-)) and nitrogen monoxide (nitric oxide, NO*) plays important roles in several aspects of cellular signaling and metabolic regulation. However, in an inflammatory environment, the concentrations of these radicals can drastically increase and the antioxidant defenses may become overwhelmed. Thus, biological damage may occur owing to redox imbalance-a condition called oxidative and/or nitrosative stress. A complex interplay exists between iron metabolism, O2(*-), hydrogen peroxide (H2O2), and NO*. Iron is involved in both the formation and the scavenging of these species. Iron deficiency (anemia) (ID(A)) is associated with oxidative stress, but its role in the induction of nitrosative stress is largely unclear. Moreover, oral as well as intravenous (iv) iron preparations used for the treatment of ID(A) may also induce oxidative and/or nitrosative stress. Oral administration of ferrous salts may lead to high transferrin saturation levels and, thus, formation of non-transferrin-bound iron, a potentially toxic form of iron with a propensity to induce oxidative stress. One of the factors that determine the likelihood of oxidative and nitrosative stress induced upon administration of an iv iron complex is the amount of labile (or weakly-bound) iron present in the complex. Stable dextran-based iron complexes used for iv therapy, although they contain only negligible amounts of labile iron, can induce oxidative and/or nitrosative stress through so far unknown mechanisms. In this review, after summarizing the main features of iron metabolism and its complex interplay with O2(*-), H2O2, NO*, and other more reactive compounds derived from these species, the potential of various iron therapies to induce oxidative and nitrosative stress is discussed and possible underlying mechanisms are proposed. Understanding the mechanisms, by which various iron formulations may induce oxidative and nitrosative stress, will help us

  3. Physiology of Iron Metabolism

    PubMed Central

    Waldvogel-Abramowski, Sophie; Waeber, Gérard; Gassner, Christoph; Buser, Andreas; Frey, Beat M.; Favrat, Bernard; Tissot, Jean-Daniel

    2014-01-01

    Summary A revolution occurred during the last decade in the comprehension of the physiology as well as in the physiopathology of iron metabolism. The purpose of this review is to summarize the recent knowledge that has accumulated, allowing a better comprehension of the mechanisms implicated in iron homeostasis. Iron metabolism is very fine tuned. The free molecule is very toxic; therefore, complex regulatory mechanisms have been developed in mammalian to insure adequate intestinal absorption, transportation, utilization, and elimination. ‘Ironomics’ certainly will be the future of the understanding of genes as well as of the protein-protein interactions involved in iron metabolism. PMID:25053935

  4. Macrophages and Iron Metabolism.

    PubMed

    Soares, Miguel P; Hamza, Iqbal

    2016-03-15

    Iron is a transition metal that due to its inherent ability to exchange electrons with a variety of molecules is essential to support life. In mammals, iron exists mostly in the form of heme, enclosed within an organic protoporphyrin ring and functioning primarily as a prosthetic group in proteins. Paradoxically, free iron also has the potential to become cytotoxic when electron exchange with oxygen is unrestricted and catalyzes the production of reactive oxygen species. These biological properties demand that iron metabolism is tightly regulated such that iron is available for core biological functions while preventing its cytotoxic effects. Macrophages play a central role in establishing this delicate balance. Here, we review the impact of macrophages on heme-iron metabolism and, reciprocally, how heme-iron modulates macrophage function.

  5. Cellular iron metabolism.

    PubMed

    Ponka, P

    1999-03-01

    Iron is essential for oxidation-reduction catalysis and bioenergetics, but unless appropriately shielded, iron plays a key role in the formation of toxic oxygen radicals that can attack all biological molecules. Hence, specialized molecules for the acquisition, transport (transferrin), and storage (ferritin) of iron in a soluble nontoxic form have evolved. Delivery of iron to most cells, probably including those of the kidney, occurs following the binding of transferrin to transferrin receptors on the cell membrane. The transferrin-receptor complexes are then internalized by endocytosis, and iron is released from transferrin by a process involving endosomal acidification. Cellular iron storage and uptake are coordinately regulated post-transcriptionally by cytoplasmic factors, iron-regulatory proteins 1 and 2 (IRP-1 and IRP-2). Under conditions of limited iron supply, IRP binding to iron-responsive elements (present in 5' untranslated region of ferritin mRNA and 3' untranslated region of transferrin receptor mRNA) blocks ferritin mRNA translation and stabilizes transferrin receptor mRNA. The opposite scenario develops when iron in the transit pool is plentiful. Moreover, IRP activities/levels can be affected by various forms of "oxidative stress" and nitric oxide. The kidney also requires iron for metabolic processes, and it is likely that iron deficiency or excess can cause disturbed function of kidney cells. Transferrin receptors are not evenly distributed throughout the kidney, and there is a cortical-to-medullary gradient in heme biosynthesis, with greatest activity in the cortex and least in the medulla. This suggests that there are unique iron/heme metabolism features in some kidney cells, but the specific aspects of iron and heme metabolism in the kidney are yet to be explained.

  6. Iron-induced changes in pyruvate metabolism of Tritrichomonas foetus and involvement of iron in expression of hydrogenosomal proteins.

    PubMed

    Vanácová, S; Rasoloson, D; Rázga, J; Hrdý, I; Kulda, J; Tachezy, J

    2001-01-01

    The main function of the hydrogenosome, a typical organelle of trichomonads, is to convert malate or pyruvate to H(2), CO(2) and acetate by a pathway associated with ATP synthesis. This pathway relies on activity of iron-sulfur proteins such as pyruvate:ferredoxin oxidoreductase (PFOR), hydrogenase and ferredoxin. To examine the effect of iron availability on proper hydrogenosomal function, the metabolic activity of the hydrogenosome and expression of hydrogenosomal enzymes were compared in Tritrichomonas foetus maintained under iron-rich (150 microM iron nitrilotriacetate) or iron-restricted (180 microM 2,2-dipyridyl) conditions in vitro. The activities of PFOR and hydrogenase, and also production of acetate and H(2), were markedly decreased or absent in iron-restricted trichomonads. Moreover, a decrease in activity of the hydrogenosomal malic enzyme, which is a non-Fe-S protein, was also observed. Impaired function of hydrogenosomes under iron-restricted conditions was compensated for by activation of the cytosolic pathway, mediating conversion of pyruvate to ethanol via acetaldehyde. This metabolic switch was fully reversible. Production of hydrogen by iron-restricted trichomonads was restored to the level of organisms grown under iron-rich conditions within 3 h after addition of 150 microM iron nitrilotriacetate. Protein analysis of purified hydrogenosomes from iron-restricted cells showed decreased levels of proteins corresponding to PFOR, malic enzyme and ferredoxin. Accordingly, these cells displayed decreased steady-state level and synthesis of mRNAs encoding PFOR and hydrogenosomal malic enzyme. These data demonstrate that iron is essential for function of the hydrogenosome, show its involvement in the expression of hydrogenosomal proteins and indicate the presence of iron-dependent control of gene transcription in Tt. foetus. PMID:11160800

  7. Discovering the role of mitochondria in the iron deficiency-induced metabolic responses of plants.

    PubMed

    Vigani, Gianpiero

    2012-01-01

    In plants, iron (Fe) deficiency-induced chlorosis is a major problem, affecting both yield and quality of crops. Plants have evolved multifaceted strategies, such as reductase activity, proton extrusion, and specialised storage proteins, to mobilise Fe from the environment and distribute it within the plant. Because of its fundamental role in plant productivity, several issues concerning Fe homeostasis in plants are currently intensively studied. The activation of Fe uptake reactions requires an overall adaptation of the primary metabolism because these activities need the constant supply of energetic substrates (i.e., NADPH and ATP). Several studies concerning the metabolism of Fe-deficient plants have been conducted, but research focused on mitochondrial implications in adaptive responses to nutritional stress has only begun in recent years. Mitochondria are the energetic centre of the root cell, and they are strongly affected by Fe deficiency. Nevertheless, they display a high level of functional flexibility, which allows them to maintain the viability of the cell. Mitochondria represent a crucial target of studies on plant homeostasis, and it might be of interest to concentrate future research on understanding how mitochondria orchestrate the reprogramming of root cell metabolism under Fe deficiency. In this review, I summarise what it is known about the effect of Fe deficiency on mitochondrial metabolism and morphology. Moreover, I present a detailed view of the possible roles of mitochondria in the development of plant responses to Fe deficiency, integrating old findings with new and discussing new hypotheses for future investigations.

  8. The role of ceruloplasmin in iron metabolism.

    PubMed

    Roeser, H P; Lee, G R; Nacht, S; Cartwright, G E

    1970-12-01

    The importance of ceruloplasmin in iron metabolism was studied in swine made hypoceruloplasminemic by copper deprivation. When the plasma ceruloplasmin level fell below 1% of normal, cell-to-plasma iron flow became sufficiently impaired to cause hypoferremia, even though total body iron stores were normal. When ceruloplasmin was administered to such animals, plasma iron increased immediately and continued to rise at a rate proportional to the logarithm of the ceruloplasmin dose. The administration of inorganic copper induced increases in plasma iron only after ceruloplasmin appeared in the circulation. Thus, ceruloplasmin appeared to be essential to the normal movement of iron from cells to plasma. Studies designed to define the mechanism of action of ceruloplasmin were based on the in vitro observation that ceruloplasmin behaves as an enzyme (ferroxidase) that catalyzes oxidation of ferrous iron. Retention of injected ferrous iron in the plasma of ceruloplasmin-deficient swine was significantly less than that of ferric iron, reflecting impaired transferrin iron binding. Rat ceruloplasmin, which has little ferroxidase activity, was much less effective than porcine or human ceruloplasmin in inducing increases in plasma iron. These observations suggest that ceruloplasmin acts by virtue of its ferroxidase activity. Eight patients with Wilson's disease were evaluated in order to investigate iron metabolism in a disorder characterized by reduced ceruloplasmin levels. Evidence of iron deficiency was found in six of these, and in five of the six, plasma ceruloplasmin was less than 5% of normal. In comparison, the two patients without evidence of iron deficiency had ceruloplasmin levels of 11 and 18% of normal. It is suggested that iron deficiency tends to occur in those patients with Wilson's disease who have the severest degrees of hypoceruloplasminemia, possibly because of defective transfer of iron from intestinal mucosal cells to plasma.

  9. Effects of interferon-gamma and lipopolysaccharide on macrophage iron metabolism are mediated by nitric oxide-induced degradation of iron regulatory protein 2.

    PubMed

    Kim, S; Ponka, P

    2000-03-01

    Iron regulatory proteins (IRP-1 and IRP-2) control the synthesis of transferrin receptors (TfR) and ferritin by binding to iron-responsive elements, which are located in the 3'-untranslated region and the 5'-untranslated region of their respective mRNAs. Cellular iron levels affect binding of IRPs to iron-responsive elements and consequently expression of TfR and ferritin. Moreover, NO(*), a redox species of nitric oxide that interacts primarily with iron, can activate IRP-1 RNA binding activity resulting in an increase in TfR mRNA levels. Recently we found that treatment of RAW 264.7 cells (a murine macrophage cell line) with NO(+) (nitrosonium ion, which causes S-nitrosylation of thiol groups) resulted in a rapid decrease in RNA binding of IRP-2 followed by IRP-2 degradation, and these changes were associated with a decrease in TfR mRNA levels (Kim, S., and Ponka, P. (1999) J. Biol. Chem. 274, 33035-33042). In this study, we demonstrated that stimulation of RAW 264.7 cells with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) increased IRP-1 binding activity, whereas RNA binding of IRP-2 decreased and was followed by a degradation of this protein. Moreover, the decrease of IRP-2 binding/protein levels was associated with a decrease in TfR mRNA levels in LPS/IFN-gamma-treated cells, and these changes were prevented by inhibitors of inducible nitric oxide synthase. Furthermore, LPS/IFN-gamma-stimulated RAW 264.7 cells showed increased rates of ferritin synthesis. These results suggest that NO(+)-mediated degradation of IRP-2 plays a major role in iron metabolism during inflammation.

  10. Iron Metabolism in Hodgkin's Disease

    PubMed Central

    Beamish, M. R.; Jones, P. Ashley; Trevett, D.; Evans, I. Howell; Jacobs, A.

    1972-01-01

    An evaluation of iron metabolism has been carried out in 23 untreated patients with Hodgkin's disease and 6 patients with other lymphomata. The reduction in red cell life span is related to the stage of the disease. There is an almost universal impairment of iron release from the reticuloendothelial system with a consequent sideropenia and failure of iron delivery to the bone marrow for erythropoiesis. This defect is found in all stages of the disease and is not related to systemic symptoms. PMID:4567182

  11. [Bone and Nutrition. The relationship between iron and phosphate metabolism].

    PubMed

    Takashi, Yuichi; Fukumoto, Seiji

    2015-07-01

    Fibroblast growth factor 23 (FGF23) is an essential hormone for phosphate metabolism. It has been shown that intravenous administration of some iron formulations including saccharated ferric oxide induces hypophosphatemic osteomalacia with high FGF23 levels. On the other hand, iron deficiency promotes FGF23 and induces hypophosphatemia in patients with autosomal dominant hypophosphatemic rickets (ADHR). While iron and phosphate metabolism is connected, the detailed mechanism of this connection remains to be clarified.

  12. A Systems Biology Approach to Iron Metabolism

    PubMed Central

    Chifman, J.; Laubenbacher, R.; Torti, S.V.

    2015-01-01

    Iron is critical to the survival of almost all living organisms. However, inappropriately low or high levels of iron are detrimental and contribute to a wide range of diseases. Recent advances in the study of iron metabolism have revealed multiple intricate pathways that are essential to the maintenance of iron homeostasis. Further, iron regulation involves processes at several scales, ranging from the subcellular to the organismal. This complexity makes a systems biology approach crucial, with its enabling technology of computational models based on a mathematical description of regulatory systems. Systems biology may represent a new strategy for understanding imbalances in iron metabolism and their underlying causes. PMID:25480643

  13. Melatonin exerts a more potent effect than S-adenosyl-l-methionine against iron metabolism disturbances, oxidative stress and tissue injury induced by obstructive jaundice in rats.

    PubMed

    Muñoz-Castañeda, Juan R; Túnez, Isaac; Herencia, Carmen; Ranchal, Isidora; González, Raúl; Ramírez, Luz M; Arjona, Alvaro; Barcos, Montserrat; Espejo, Isabel; Cruz, Adolfo; Montilla, Pedro; Padillo, Francisco J; Muntané, Jordi

    2008-07-30

    Melatonin and S-adenosyl-l-methionine (SAMe) prevent oxidative stress and tissue dysfunction in obstructive jaundice (OJ). Lipid peroxidation is exacerbated in the presence of trace amounts of iron (Fe). The study investigated the regulation by melatonin and SAMe the induction of oxidative stress, iron metabolism disturbances and tissue injury in an experimental model of OJ. Different parameters of lipid peroxidation, antioxidant status, tissue injury and Fe metabolism were determined in liver and blood. OJ induced Fe accumulation in liver, and increased transferrin (Tf) saturation and loosely bound Fe content in blood. Melatonin, and SAMe at lesser extent, enhanced protein Tf content in liver and blood, that reduced loosely bound Fe content in blood. Melatonin and SAMe did not affect ferritin (FT) and Tf mRNA expression, but reduced Tf receptor (TfR) mRNA expression in liver. In conclusion, the effect of melatonin and SAMe on Fe metabolism may be included in the beneficial properties of these agents on lipid peroxidation and tissue injury induced by OJ.

  14. Mammalian iron metabolism and its control by iron regulatory proteins☆

    PubMed Central

    Anderson, Cole P.; Shen, Lacy; Eisenstein, Richard S.; Leibold, Elizabeth A.

    2013-01-01

    Cellular iron homeostasis is maintained by iron regulatory proteins 1 and 2 (IRP1 and IRP2). IRPs bind to iron-responsive elements (IREs) located in the untranslated regions of mRNAs encoding protein involved in iron uptake, storage, utilization and export. Over the past decade, significant progress has been made in understanding how IRPs are regulated by iron-dependent and iron-independent mechanisms and the pathological consequences of IRP2 deficiency in mice. The identification of novel IREs involved in diverse cellular pathways has revealed that the IRP–IRE network extends to processes other than iron homeostasis. A mechanistic understanding of IRP regulation will likely yield important insights into the basis of disorders of iron metabolism. This article is part of a Special Issue entitled: Cell Biology of Metals. PMID:22610083

  15. Metabolic Remodeling in Iron-deficient Fungi

    PubMed Central

    Philpott, Caroline C.; Leidgens, Sebastien; Frey, Avery G.

    2012-01-01

    Eukaryotic cells contain dozens, perhaps hundreds, of iron-dependent proteins, which perform critical functions in nearly every major cellular process. Nutritional iron is frequently available to cells in only limited amounts; thus, unicellular and higher eukaryotes have evolved mechanisms to cope with iron scarcity. These mechanisms have been studied at the molecular level in the model eukaryotes Saccharomyces cerevisiae and Schizosaccharomyces pombe, as well as in some pathogenic fungi. Each of these fungal species exhibits metabolic adaptations to iron deficiency that serve to reduce the cell’s reliance on iron. However, the regulatory mechanisms that accomplish these adaptations differ greatly between fungal species. PMID:22306284

  16. [Phosphate metabolism and iron deficiency].

    PubMed

    Yokoyama, Keitaro

    2016-02-01

    Autosomal dominant hypophosphatemic rickets(ADHR)is caused by gain-of-function mutations in FGF23 that prevent its proteolytic cleavage. Fibroblast growth factor 23(FGF23)is a hormone that inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D biosynthesis. Low iron status plays a role in the pathophysiology of ADHR. Iron deficiency is an environmental trigger that stimulates FGF23 expression and hypophosphatemia in ADHR. It was reported that FGF23 elevation in patients with CKD, who are often iron deficient. In patients with nondialysis-dependent CKD, treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and FGF23.

  17. Diversity and Evolutionary History of Iron Metabolism Genes in Diatoms.

    PubMed

    Groussman, Ryan D; Parker, Micaela S; Armbrust, E Virginia

    2015-01-01

    Ferroproteins arose early in Earth's history, prior to the emergence of oxygenic photosynthesis and the subsequent reduction of bioavailable iron. Today, iron availability limits primary productivity in about 30% of the world's oceans. Diatoms, responsible for nearly half of oceanic primary production, have evolved molecular strategies for coping with variable iron concentrations. Our understanding of the evolutionary breadth of these strategies has been restricted by the limited number of species for which molecular sequence data is available. To uncover the diversity of strategies marine diatoms employ to meet cellular iron demands, we analyzed 367 newly released marine microbial eukaryotic transcriptomes, which include 47 diatom species. We focused on genes encoding proteins previously identified as having a role in iron management: iron uptake (high-affinity ferric reductase, multi-copper oxidase, and Fe(III) permease); iron storage (ferritin); iron-induced protein substitutions (flavodoxin/ferredoxin, and plastocyanin/cytochrome c6) and defense against reactive oxygen species (superoxide dismutases). Homologs encoding the high-affinity iron uptake system components were detected across the four diatom Classes suggesting an ancient origin for this pathway. Ferritin transcripts were also detected in all Classes, revealing a more widespread utilization of ferritin throughout diatoms than previously recognized. Flavodoxin and plastocyanin transcripts indicate possible alternative redox metal strategies. Predicted localization signals for ferredoxin identify multiple examples of gene transfer from the plastid to the nuclear genome. Transcripts encoding four superoxide dismutase metalloforms were detected, including a putative nickel-coordinating isozyme. Taken together, our results suggest that the majority of iron metabolism genes in diatoms appear to be vertically inherited with functional diversity achieved via possible neofunctionalization of paralogs. This

  18. Diversity and Evolutionary History of Iron Metabolism Genes in Diatoms

    PubMed Central

    Groussman, Ryan D.; Parker, Micaela S.; Armbrust, E. Virginia

    2015-01-01

    Ferroproteins arose early in Earth’s history, prior to the emergence of oxygenic photosynthesis and the subsequent reduction of bioavailable iron. Today, iron availability limits primary productivity in about 30% of the world’s oceans. Diatoms, responsible for nearly half of oceanic primary production, have evolved molecular strategies for coping with variable iron concentrations. Our understanding of the evolutionary breadth of these strategies has been restricted by the limited number of species for which molecular sequence data is available. To uncover the diversity of strategies marine diatoms employ to meet cellular iron demands, we analyzed 367 newly released marine microbial eukaryotic transcriptomes, which include 47 diatom species. We focused on genes encoding proteins previously identified as having a role in iron management: iron uptake (high-affinity ferric reductase, multi-copper oxidase, and Fe(III) permease); iron storage (ferritin); iron-induced protein substitutions (flavodoxin/ferredoxin, and plastocyanin/cytochrome c6) and defense against reactive oxygen species (superoxide dismutases). Homologs encoding the high-affinity iron uptake system components were detected across the four diatom Classes suggesting an ancient origin for this pathway. Ferritin transcripts were also detected in all Classes, revealing a more widespread utilization of ferritin throughout diatoms than previously recognized. Flavodoxin and plastocyanin transcripts indicate possible alternative redox metal strategies. Predicted localization signals for ferredoxin identify multiple examples of gene transfer from the plastid to the nuclear genome. Transcripts encoding four superoxide dismutase metalloforms were detected, including a putative nickel-coordinating isozyme. Taken together, our results suggest that the majority of iron metabolism genes in diatoms appear to be vertically inherited with functional diversity achieved via possible neofunctionalization of paralogs. This

  19. Nitric oxide induces hypoxia ischemic injury in the neonatal brain via the disruption of neuronal iron metabolism.

    PubMed

    Lu, Qing; Harris, Valerie A; Rafikov, Ruslan; Sun, Xutong; Kumar, Sanjiv; Black, Stephen M

    2015-12-01

    We have recently shown that increased hydrogen peroxide (H2O2) generation is involved in hypoxia-ischemia (HI)-mediated neonatal brain injury. H2O2 can react with free iron to form the hydroxyl radical, through Fenton Chemistry. Thus, the objective of this study was to determine if there was a role for the hydroxyl radical in neonatal HI brain injury and to elucidate the underlying mechanisms. Our data demonstrate that HI increases the deposition of free iron and hydroxyl radical formation, in both P7 hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD), and the neonatal rat exposed to HI. Both these processes were found to be nitric oxide (NO) dependent. Further analysis demonstrated that the NO-dependent increase in iron deposition was mediated through increased transferrin receptor expression and a decrease in ferritin expression. This was correlated with a reduction in aconitase activity. Both NO inhibition and iron scavenging, using deferoxamine administration, reduced hydroxyl radical levels and neuronal cell death. In conclusion, our results suggest that increased NO generation leads to neuronal cell death during neonatal HI, at least in part, by altering iron homeostasis and hydroxyl radical generation.

  20. [Iron metabolism: pathophysiology and biomarkers in elderly population].

    PubMed

    Gavazzi, Gaëtan

    2014-06-01

    Iron deficiency is frequent in elderly population and is responsable for numerous clinical situations. Because of the frequent association of inflammatory diseases, chronic diseases associated with iron loss, diagnosis of iron deficiency is often difficult in elderly population. For the last ten years, new biomarkers of iron physiology lead to better understand physiology and pathophysiology of iron metabolism particularly in iron deficiency. This overview aims to show modifications of iron metabolism with ageing, pathophysiological mecanisms associated with iron deficiency and give a stratification of the use of biomarkers as diagnostic tools differentiating absolute deficiency or functional deficeincy. PMID:25031216

  1. Iron metabolism: a promising target for antibacterial strategies.

    PubMed

    Ballouche, Mathieu; Cornelis, Pierre; Baysse, Christine

    2009-11-01

    In the fight against pathogenic and opportunistic bacteria, development and spreading of resistance to antibiotics is an increasing public health problem. The available antibacterial treatments are becoming less and less effective, making urgent the discovery of new active molecules. One strategy that has been explored to bypass the bacterial adaptation to drugs is to target the iron metabolism of bacteria, since iron is critical for all bacteria to grow. To date, three major ways have been assessed to exploit weaknesses in the bacterial iron metabolism: the "Trojan Horse strategy" which takes advantages of natural iron-uptake systems to deliver antimicrobial compounds inside the cells; the use of iron-antagonists and iron-chelators in order to reduce iron availability and the inhibition of enzymatic steps of iron metabolism via chemical compounds. This review discusses these antibacterial strategies interfering with several levels of the bacterial iron metabolism, with a special emphasis on recently published and/or patented discoveries.

  2. Update on iron metabolism and molecular perspective of common genetic and acquired disorder, hemochromatosis.

    PubMed

    Yun, Seongseok; Vincelette, Nicole D

    2015-07-01

    Iron is an essential component of erythropoiesis and its metabolism is tightly regulated by a variety of internal and external cues including iron storage, tissue hypoxia, inflammation and degree of erythropoiesis. There has been remarkable improvement in our understanding of the molecular mechanisms of iron metabolism past decades. The classical model of iron metabolism with iron response element/iron response protein (IRE/IRP) is now extended to include hepcidin model. Endogenous and exogenous signals funnel down to hepcidin via wide range of signaling pathways including Janus Kinase/Signal Transducer and Activator of Transcription 3 (JAK/STAT3), Bone Morphogenetic Protein/Hemojuvelin/Mothers Against Decapentaplegic Homolog (BMP/HJV/SMAD), and Von Hippel Lindau/Hypoxia-inducible factor/Erythropoietin (VHL/HIF/EPO), then relay to ferroportin, which directly regulates intra- and extracellular iron levels. The successful molecular delineation of iron metabolism further enhanced our understanding of common genetic and acquired disorder, hemochromatosis. The majority of the hereditary hemochromatosis (HH) patients are now shown to have mutations in the genes coding either upstream or downstream proteins of hepcidin, resulting in iron overload. The update on hepcidin centered mechanisms of iron metabolism and their clinical perspective in hemochromatosis will be discussed in this review.

  3. Effects of Pregnancy and Lactation on Iron Metabolism in Rats

    PubMed Central

    Gao, Guofen; Liu, Shang-Yuan; Wang, Hui-Jie; Zhang, Tian-Wei; Yu, Peng; Duan, Xiang-Lin; Zhao, Shu-E; Chang, Yan-Zhong

    2015-01-01

    In female, inadequate iron supply is a highly prevalent problem that often leads to iron-deficiency anemia. This study aimed to understand the effects of pregnancy and lactation on iron metabolism. Rats with different days of gestation and lactation were used to determine the variations in iron stores and serum iron level and the changes in expression of iron metabolism-related proteins, including ferritin, ferroportin 1 (FPN1), ceruloplasmin (Cp), divalent metal transporter 1 (DMT1), transferrin receptor 1 (TfR1), and the major iron-regulatory molecule—hepcidin. We found that iron stores decline dramatically at late-pregnancy period, and the low iron store status persists throughout the lactation period. The significantly increased FPN1 level in small intestine facilitates digestive iron absorption, which maintains the serum iron concentration at a near-normal level to meet the increase of iron requirements. Moreover, a significant decrease of hepcidin expression is observed during late-pregnancy and early-lactation stages, suggesting the important regulatory role that hepcidin plays in iron metabolism during pregnancy and lactation. These results are fundamental to the understanding of iron homeostasis during pregnancy and lactation and may provide experimental bases for future studies to identify key molecules expressed during these special periods that regulate the expression of hepcidin, to eventually improve the iron-deficiency status. PMID:26788496

  4. Iron metabolism and iron supplementation in cancer patients.

    PubMed

    Ludwig, Heinz; Evstatiev, Rayko; Kornek, Gabriela; Aapro, Matti; Bauernhofer, Thomas; Buxhofer-Ausch, Veronika; Fridrik, Michael; Geissler, Dietmar; Geissler, Klaus; Gisslinger, Heinz; Koller, Elisabeth; Kopetzky, Gerhard; Lang, Alois; Rumpold, Holger; Steurer, Michael; Kamali, Houman; Link, Hartmut

    2015-12-01

    Iron deficiency and iron deficiency-associated anemia are common complications in cancer patients. Most iron deficient cancer patients present with functional iron deficiency (FID), a status with adequate storage iron, but insufficient iron supply for erythroblasts and other iron dependent tissues. FID is the consequence of the cancer-associated cytokine release, while in absolute iron deficiency iron stores are depleted resulting in similar but often more severe symptoms of insufficient iron supply. Here we present a short review on the epidemiology, pathophysiology, diagnosis, clinical symptoms, and treatment of iron deficiency in cancer patients. Special emphasis is given to intravenous iron supplementation and on the benefits and limitations of different formulations. Based on these considerations and recommendations from current international guidelines we developed recommendations for clinical practice and classified the level of evidence and grade of recommendation according to the principles of evidence-based medicine.

  5. METABOLIC CAPACITY REGULATES IRON HOMEOSTATIS IN ENDOTHELIAL CELLS

    EPA Science Inventory

    The sensitivity of endothelial cells to oxidative stress and the high concentrations of iron in mitochondria led us to test the hypotheses that (1) changes in respiratory capacity alter iron homeostasis, and (2) lack of aerobic metabolism decreases labile iron stores and attenuat...

  6. Alginate-Iron Speciation and Its Effect on In Vitro Cellular Iron Metabolism

    PubMed Central

    Horniblow, Richard D.; Dowle, Miriam; Iqbal, Tariq H.; Latunde-Dada, Gladys O.; Palmer, Richard E.

    2015-01-01

    Alginates are a class of biopolymers with known iron binding properties which are routinely used in the fabrication of iron-oxide nanoparticles. In addition, alginates have been implicated in influencing human iron absorption. However, the synthesis of iron oxide nanoparticles employs non-physiological pH conditions and whether nanoparticle formation in vivo is responsible for influencing cellular iron metabolism is unclear. Thus the aims of this study were to determine how alginate and iron interact at gastric-comparable pH conditions and how this influences iron metabolism. Employing a range of spectroscopic techniques under physiological conditions alginate-iron complexation was confirmed and, in conjunction with aberration corrected scanning transmission electron microscopy, nanoparticles were observed. The results infer a nucleation-type model of iron binding whereby alginate is templating the condensation of iron-hydroxide complexes to form iron oxide centred nanoparticles. The interaction of alginate and iron at a cellular level was found to decrease cellular iron acquisition by 37% (p < 0.05) and in combination with confocal microscopy the alginate inhibits cellular iron transport through extracellular iron chelation with the resulting complexes not internalised. These results infer alginate as being useful in the chelation of excess iron, especially in the context of inflammatory bowel disease and colorectal cancer where excess unabsorbed luminal iron is thought to be a driver of disease. PMID:26378798

  7. Mammalian target of rapamycin coordinates iron metabolism with iron-sulfur cluster assembly enzyme and tristetraprolin.

    PubMed

    Guan, Peng; Wang, Na

    2014-09-01

    Both iron deficiency and excess are relatively common health concerns. Maintaining the body's levels of iron within precise boundaries is critical for cell functions. However, the difference between iron deficiency and overload is often a question of a scant few milligrams of iron. The mammalian target of rapamycin (mTOR), an atypical Ser/Thr protein kinase, is attracting significant amounts of interest due to its recently described role in iron homeostasis. Despite extensive study, a complete understanding of mTOR function has remained elusive. mTOR can form two multiprotein complexes that consist of mTOR complex 1 (mTORC1) and mTOR complex 2. Recent advances clearly demonstrate that mTORC1 can phosphorylate iron-sulfur cluster assembly enzyme ISCU and affect iron-sulfur clusters assembly. Moreover, mTOR is reported to control iron metabolism through modulation of tristetraprolin expression. It is now well appreciated that the hormonal hepcidin-ferroportin system and the cellular iron-responsive element/iron-regulatory protein regulatory network play important regulatory roles for systemic iron metabolism. Sustained ISCU protein levels enhanced by mTORC1 can inhibit iron-responsive element and iron-regulatory protein binding activities. In this study, hepcidin gene and protein expression in the livers of tristetraprolin knockout mice were dramatically reduced. Here, we highlight and summarize the current understanding of how mTOR pathways serve to modulate iron metabolism and homeostasis as the third iron-regulatory system.

  8. Disorders of Iron Metabolism and Anemia in Chronic Kidney Disease.

    PubMed

    Panwar, Bhupesh; Gutiérrez, Orlando M

    2016-07-01

    Dysregulated iron homeostasis plays a central role in the development of anemia of chronic kidney disease (CKD) and is a major contributor toward resistance to treatment with erythropoiesis-stimulating agents. Understanding the underlying pathophysiology requires an in-depth understanding of normal iron physiology and regulation. Recent discoveries in the field of iron biology have greatly improved our understanding of the hormonal regulation of iron trafficking in human beings and how its alterations lead to the development of anemia of CKD. In addition, emerging evidence has suggested that iron homeostasis interacts with bone and mineral metabolism on multiple levels, opening up new avenues of investigation into the genesis of disordered iron metabolism in CKD. Building on recent advances in our understanding of normal iron physiology and abnormalities in iron homeostasis in CKD, this review characterizes how anemia related to disordered iron metabolism develops in the setting of CKD. In addition, this review explores our emerging recognition of the connections between iron homeostasis and mineral metabolism and their implications for the management of altered iron status and anemia of CKD.

  9. Disorders of Iron Metabolism and Anemia in Chronic Kidney Disease.

    PubMed

    Panwar, Bhupesh; Gutiérrez, Orlando M

    2016-07-01

    Dysregulated iron homeostasis plays a central role in the development of anemia of chronic kidney disease (CKD) and is a major contributor toward resistance to treatment with erythropoiesis-stimulating agents. Understanding the underlying pathophysiology requires an in-depth understanding of normal iron physiology and regulation. Recent discoveries in the field of iron biology have greatly improved our understanding of the hormonal regulation of iron trafficking in human beings and how its alterations lead to the development of anemia of CKD. In addition, emerging evidence has suggested that iron homeostasis interacts with bone and mineral metabolism on multiple levels, opening up new avenues of investigation into the genesis of disordered iron metabolism in CKD. Building on recent advances in our understanding of normal iron physiology and abnormalities in iron homeostasis in CKD, this review characterizes how anemia related to disordered iron metabolism develops in the setting of CKD. In addition, this review explores our emerging recognition of the connections between iron homeostasis and mineral metabolism and their implications for the management of altered iron status and anemia of CKD. PMID:27475656

  10. Drug-Induced Metabolic Acidosis

    PubMed Central

    Pham, Amy Quynh Trang; Xu, Li Hao Richie; Moe, Orson W.

    2015-01-01

    Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs’ characteristics. PMID:26918138

  11. Drug-Induced Metabolic Acidosis.

    PubMed

    Pham, Amy Quynh Trang; Xu, Li Hao Richie; Moe, Orson W

    2015-01-01

    Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs' characteristics. PMID:26918138

  12. SIRT3 regulates cellular iron metabolism and cancer growth by repressing iron regulatory protein 1.

    PubMed

    Jeong, S M; Lee, J; Finley, L W S; Schmidt, P J; Fleming, M D; Haigis, M C

    2015-04-16

    Iron metabolism is essential for many cellular processes, including oxygen transport, respiration and DNA synthesis, and many cancer cells exhibit dysregulation in iron metabolism. Maintenance of cellular iron homeostasis is regulated by iron regulatory proteins (IRPs), which control the expression of iron-related genes by binding iron-responsive elements (IREs) of target mRNAs. Here, we report that mitochondrial SIRT3 regulates cellular iron metabolism by modulating IRP1 activity. SIRT3 loss increases reactive oxygen species production, leading to elevated IRP1 binding to IREs. As a consequence, IRP1 target genes, such as the transferrin receptor (TfR1), a membrane-associated glycoprotein critical for iron uptake and cell proliferation, are controlled by SIRT3. Importantly, SIRT3 deficiency results in a defect in cellular iron homeostasis. SIRT3 null cells contain high levels of iron and lose iron-dependent TfR1 regulation. Moreover, SIRT3 null mice exhibit higher levels of iron and TfR1 expression in the pancreas. We found that the regulation of iron uptake and TfR1 expression contribute to the tumor-suppressive activity of SIRT3. Indeed, SIRT3 expression is negatively correlated with TfR1 expression in human pancreatic cancers. SIRT3 overexpression decreases TfR1 expression by inhibiting IRP1 and represses proliferation in pancreatic cancer cells. Our data uncover a novel role of SIRT3 in cellular iron metabolism through IRP1 regulation and suggest that SIRT3 functions as a tumor suppressor, in part, by modulating cellular iron metabolism. PMID:24909164

  13. Changes in Iron Metabolism and Oxidative Status in STZ-Induced Diabetic Rats Treated with Bis(maltolato) Oxovanadium (IV) as an Antidiabetic Agent

    PubMed Central

    Sánchez-González, Cristina; López-Chaves, Carlos; Trenzado, Cristina E.; Aranda, Pilar; López-Jurado, María; Gómez-Aracena, Jorge; Montes-Bayón, María; Sanz-Medel, Alfredo; Llopis, Juan

    2014-01-01

    The role of vanadium as a micronutrient and hypoglycaemic agent has yet to be fully clarified. The present study was undertaken to investigate changes in the metabolism of iron and in antioxidant defences of diabetic STZ rats following treatment with vanadium. Four groups were examined: control; diabetic; diabetic treated with 1 mgV/day; and Diabetic treated with 3 mgV/day. The vanadium was supplied in drinking water as bis(maltolato) oxovanadium (IV) (BMOV). The experiment had a duration of five weeks. Iron was measured in food, faeces, urine, serum, muscle, kidney, liver, spleen, and femur. Superoxide dismutase, catalase, NAD(P)H: quinone-oxidoreductase-1 (NQO1) activity, and protein carbonyl group levels in the liver were determined. In the diabetic rats, higher levels of Fe absorbed, Fe content in kidney, muscle, and femur, and NQO1 activity were recorded, together with decreased catalase activity, in comparison with the control rats. In the rats treated with 3 mgV/day, there was a significant decrease in fasting glycaemia, Fe content in the liver, spleen, and heart, catalase activity, and levels of protein carbonyl groups in comparison with the diabetic group. In conclusion BMOV was a dose-dependent hypoglycaemic agent. Treatment with 3 mgV/day provoked increased Fe deposits in the tissues, which promoted a protein oxidative damage in the liver. PMID:24511298

  14. Role of nitric oxide in cellular iron metabolism.

    PubMed

    Kim, Sangwon; Ponka, Prem

    2003-03-01

    Iron regulatory proteins (IRP1 and IRP2) control the synthesis of transferrin receptors (TfR) and ferritin by binding to iron-responsive elements (IREs) which are located in the 3' untranslated region (UTR) and the 5' UTR of their respective mRNAs. Cellular iron levels affect binding of IRPs to IREs and consequently expression of TfR and ferritin. Moreover, NO*, a redox species of nitric oxide that interacts primarily with iron, can activate IRP1 RNA-binding activity resulting in an increase in TfR mRNA levels. We have shown that treatment of RAW 264.7 cells (a murine macrophage cell line) with NO+ (nitrosonium ion, which causes S-nitrosylation of thiol groups) resulted in a rapid decrease in RNA-binding of IRP2, followed by IRP2 degradation, and these changes were associated with a decrease in TfR mRNA levels. Moreover, we demonstrated that stimulation of RAW 264.7 cells with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) increased IRP1 binding activity, whereas RNA-binding of IRP2 decreased and was followed by a degradation of this protein. Furthermore, the decrease of IRP2 binding/protein levels was associated with a decrease in TfR mRNA levels in LPS/IFN-gamma-treated cells, and these changes were prevented by inhibitors of inducible nitric oxide synthase. These results suggest that NO+-mediated degradation of IRP2 plays a major role in iron metabolism during inflammation.

  15. Molecular and Cellular Bases of Iron Metabolism in Humans.

    PubMed

    Milto, I V; Suhodolo, I V; Prokopieva, V D; Klimenteva, T K

    2016-06-01

    Iron is a microelement with the most completely studied biological functions. Its wide dissemination in nature and involvement in key metabolic pathways determine the great importance of this metal for uni- and multicellular organisms. The biological role of iron is characterized by its indispensability in cell respiration and various biochemical processes providing normal functioning of cells and organs of the human body. Iron also plays an important role in the generation of free radicals, which under different conditions can be useful or damaging to biomolecules and cells. In the literature, there are many reviews devoted to iron metabolism and its regulation in pro- and eukaryotes. Significant progress has been achieved recently in understanding molecular bases of iron metabolism. The purpose of this review is to systematize available data on mechanisms of iron assimilation, distribution, and elimination from the human body, as well as on its biological importance and on the major iron-containing proteins. The review summarizes recent ideas about iron metabolism. Special attention is paid to mechanisms of iron absorption in the small intestine and to interrelationships of cellular and extracellular pools of this metal in the human body.

  16. Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis.

    PubMed

    Muñoz, Manuel; García-Erce, José Antonio; Remacha, Angel Francisco

    2011-04-01

    IRON FUNCTIONS: Iron is an essential micronutrient, as it is required for satisfactory erythropoietic function, oxidative metabolism and cellular immune response. IRON PHYSIOLOGY: Absorption of dietary iron (1-2 mg/day) is tightly regulated and just balanced against iron loss because there are no active iron excretory mechanisms. Dietary iron is found in haem (10%) and non-haem (ionic, 90%) forms, and their absorption occurs at the apical surface of duodenal enterocytes via different mechanisms. Iron is exported by ferroportin 1 (the only putative iron exporter) across the basolateral membrane of the enterocyte into the circulation (absorbed iron), where it binds to transferrin and is transported to sites of use and storage. Transferrin-bound iron enters target cells-mainly erythroid cells, but also immune and hepatic cells-via receptor-mediated endocytosis. Senescent erythrocytes are phagocytosed by reticuloendothelial system macrophages, haem is metabolised by haem oxygenase, and the released iron is stored as ferritin. Iron will be later exported from macrophages to transferrin. This internal turnover of iron is essential to meet the requirements of erythropoiesis (20-30 mg/day). As transferrin becomes saturated in iron-overload states, excess iron is transported to the liver, the other main storage organ for iron, carrying the risk of free radical formation and tissue damage. REGULATION OF IRON HOMOEOSTASIS: Hepcidin, synthesised by hepatocytes in response to iron concentrations, inflammation, hypoxia and erythropoiesis, is the main iron-regulatory hormone. It binds ferroportin on enterocytes, macrophages and hepatocytes triggering its internalisation and lysosomal degradation. Inappropriate hepcidin secretion may lead to either iron deficiency or iron overload.

  17. Myocardial iron metabolism in the regulation of cardiovascular diseases in rats.

    PubMed

    Zhao, Na; Sun, Zhidan; Mao, Yuying; Hang, Pengzhou; Jiang, Xing; Sun, Lihua; Zhao, Jinlong; Du, Zhimin

    2010-01-01

    The iron homeostasis plays an important role in cardiac function. To understand how it acts in diabetic and ischemic myocardial injury, we studied the myocardial iron metabolism in diabetic and myocardial ischemic rats. Diabetic rats were induced by intraperitoneal injection of streptozocin (STZ) after intragastric administration of a high-fat diet while the ischemic rat hearts were subjected to coronary artery ligation for 0.5, 1, 6, 12 or 24 h, respectively. In STZ-induced diabetic rats, the contents of serum and myocardial iron were found elevated obviously accompany with the decrease of hepatic iron determined by the flame emission atomic absorption spectroscopy. The levels of superoxide dismutase (SOD), malonaldehyde (MDA) and serum ferritin were increased in diabetic rats. Moreover, protein level of divalent metal transporter 1 (DMT1) was decreased while that for transferrin receptor (TfR) and metal transporter protein 1 (MTP1) was increased. In contrast, no alteration of iron concentration was observed in the ischemic rats. The expression of DMT1, TfR and MTP1 has not changed after infraction. The findings suggested that diabetes mellitus (DM) induced the iron overload in the myocardium, at least in part by up-regulation of TfR. Meanwhile, down-regulation of DMT1 and up-regulation of MTP1 were induced to alleviate the excessive iron in the myocardium. However, myocardial infraction (MI) has not broken the balance of myocardial iron. In conclusion, the iron homeostasis reacts differently in DM and MI. PMID:20511703

  18. Divergence of iron metabolism in wild Malaysian yeast.

    PubMed

    Lee, Hana N; Mostovoy, Yulia; Hsu, Tiffany Y; Chang, Amanda H; Brem, Rachel B

    2013-12-09

    Comparative genomic studies have reported widespread variation in levels of gene expression within and between species. Using these data to infer organism-level trait divergence has proven to be a key challenge in the field. We have used a wild Malaysian population of S. cerevisiae as a test bed in the search to predict and validate trait differences based on observations of regulatory variation. Malaysian yeast, when cultured in standard medium, activated regulatory programs that protect cells from the toxic effects of high iron. Malaysian yeast also showed a hyperactive regulatory response during culture in the presence of excess iron and had a unique growth defect in conditions of high iron. Molecular validation experiments pinpointed the iron metabolism factors AFT1, CCC1, and YAP5 as contributors to these molecular and cellular phenotypes; in genome-scale sequence analyses, a suite of iron toxicity response genes showed evidence for rapid protein evolution in Malaysian yeast. Our findings support a model in which iron metabolism has diverged in Malaysian yeast as a consequence of a change in selective pressure, with Malaysian alleles shifting the dynamic range of iron response to low-iron concentrations and weakening resistance to extreme iron toxicity. By dissecting the iron scarcity specialist behavior of Malaysian yeast, our work highlights the power of expression divergence as a signpost for biologically and evolutionarily relevant variation at the organismal level. Interpreting the phenotypic relevance of gene expression variation is one of the primary challenges of modern genomics.

  19. New developments and controversies in iron metabolism and iron chelation therapy.

    PubMed

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-03-26

    Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients' therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic

  20. New developments and controversies in iron metabolism and iron chelation therapy

    PubMed Central

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-01-01

    Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients’ therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic

  1. New developments and controversies in iron metabolism and iron chelation therapy.

    PubMed

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-03-26

    Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients' therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic

  2. Oxidative Stress and the Homeodynamics of Iron Metabolism

    PubMed Central

    Bresgen, Nikolaus; Eckl, Peter M.

    2015-01-01

    Iron and oxygen share a delicate partnership since both are indispensable for survival, but if the partnership becomes inadequate, this may rapidly terminate life. Virtually all cell components are directly or indirectly affected by cellular iron metabolism, which represents a complex, redox-based machinery that is controlled by, and essential to, metabolic requirements. Under conditions of increased oxidative stress—i.e., enhanced formation of reactive oxygen species (ROS)—however, this machinery may turn into a potential threat, the continued requirement for iron promoting adverse reactions such as the iron/H2O2-based formation of hydroxyl radicals, which exacerbate the initial pro-oxidant condition. This review will discuss the multifaceted homeodynamics of cellular iron management under normal conditions as well as in the context of oxidative stress. PMID:25970586

  3. Vitamin A deficiency modulates iron metabolism via ineffective erythropoiesis.

    PubMed

    da Cunha, Marcela S B; Siqueira, Egle M A; Trindade, Luciano S; Arruda, Sandra F

    2014-10-01

    Vitamin A modulates inflammatory status, iron metabolism and erythropoiesis. Given that these factors modulate the expression of the hormone hepcidin (Hamp), we investigated the effect of vitamin A deficiency on molecular biomarkers of iron metabolism, the inflammatory response and the erythropoietic system. Five groups of male Wistar rats were treated: control (AIN-93G), the vitamin A-deficient (VAD) diet, the iron-deficient (FeD) diet, the vitamin A- and iron-deficient (VAFeD) diet or the diet with 12 mg atRA/kg diet replacing all-trans-retinyl palmitate by all-trans retinoic acid (atRA). Vitamin A deficiency reduced serum iron and transferrin saturation levels, increased spleen iron concentrations, reduced hepatic Hamp and kidney erythropoietin messenger RNA (mRNA) levels and up-regulated hepatic and spleen heme oxygenase-1 gene expression while reducing the liver HO-1 specific activity compared with the control. The FeD and VAFeD rats exhibited lower levels of serum iron and transferrin saturation, lower iron concentrations in tissues and lower hepatic Hamp mRNA levels compared with the control. The treatment with atRA resulted in lower serum iron and transferrin concentrations, an increased iron concentration in the liver, a decreased iron concentration in the spleen and in the gut, and decreased hepatic Hamp mRNA levels. In summary, these findings suggest that vitamin A deficiency leads to ineffective erythropoiesis by the down-regulation of renal erythropoietin expression in the kidney, resulting in erythrocyte malformation and the consequent accumulation of the heme group in the spleen. Vitamin A deficiency indirectly modulates systemic iron homeostasis by enhancing erythrophagocytosis of undifferentiated erythrocytes. PMID:24998947

  4. Vitamin A deficiency modulates iron metabolism via ineffective erythropoiesis.

    PubMed

    da Cunha, Marcela S B; Siqueira, Egle M A; Trindade, Luciano S; Arruda, Sandra F

    2014-10-01

    Vitamin A modulates inflammatory status, iron metabolism and erythropoiesis. Given that these factors modulate the expression of the hormone hepcidin (Hamp), we investigated the effect of vitamin A deficiency on molecular biomarkers of iron metabolism, the inflammatory response and the erythropoietic system. Five groups of male Wistar rats were treated: control (AIN-93G), the vitamin A-deficient (VAD) diet, the iron-deficient (FeD) diet, the vitamin A- and iron-deficient (VAFeD) diet or the diet with 12 mg atRA/kg diet replacing all-trans-retinyl palmitate by all-trans retinoic acid (atRA). Vitamin A deficiency reduced serum iron and transferrin saturation levels, increased spleen iron concentrations, reduced hepatic Hamp and kidney erythropoietin messenger RNA (mRNA) levels and up-regulated hepatic and spleen heme oxygenase-1 gene expression while reducing the liver HO-1 specific activity compared with the control. The FeD and VAFeD rats exhibited lower levels of serum iron and transferrin saturation, lower iron concentrations in tissues and lower hepatic Hamp mRNA levels compared with the control. The treatment with atRA resulted in lower serum iron and transferrin concentrations, an increased iron concentration in the liver, a decreased iron concentration in the spleen and in the gut, and decreased hepatic Hamp mRNA levels. In summary, these findings suggest that vitamin A deficiency leads to ineffective erythropoiesis by the down-regulation of renal erythropoietin expression in the kidney, resulting in erythrocyte malformation and the consequent accumulation of the heme group in the spleen. Vitamin A deficiency indirectly modulates systemic iron homeostasis by enhancing erythrophagocytosis of undifferentiated erythrocytes.

  5. Neonatal iron deficiency causes abnormal phosphate metabolism by elevating FGF23 in normal and ADHR mice.

    PubMed

    Clinkenbeard, Erica L; Farrow, Emily G; Summers, Lelia J; Cass, Taryn A; Roberts, Jessica L; Bayt, Christine A; Lahm, Tim; Albrecht, Marjorie; Allen, Matthew R; Peacock, Munro; White, Kenneth E

    2014-02-01

    Fibroblast growth factor 23 (FGF23) gain of function mutations can lead to autosomal dominant hypophosphatemic rickets (ADHR) disease onset at birth, or delayed onset following puberty or pregnancy. We previously demonstrated that the combination of iron deficiency and a knock-in R176Q FGF23 mutation in mature mice induced FGF23 expression and hypophosphatemia that paralleled the late-onset ADHR phenotype. Because anemia in pregnancy and in premature infants is common, the goal of this study was to test whether iron deficiency alters phosphate handling in neonatal life. Wild-type (WT) and ADHR female breeder mice were provided control or iron-deficient diets during pregnancy and nursing. Iron-deficient breeders were also made iron replete. Iron-deficient WT and ADHR pups were hypophosphatemic, with ADHR pups having significantly lower serum phosphate (p < 0.01) and widened growth plates. Both genotypes increased bone FGF23 mRNA (>50 fold; p < 0.01). WT and ADHR pups receiving low iron had elevated intact serum FGF23; ADHR mice were affected to a greater degree (p < 0.01). Iron-deficient mice also showed increased Cyp24a1 and reduced Cyp27b1, and low serum 1,25-dihydroxyvitamin D (1,25D). Iron repletion normalized most abnormalities. Because iron deficiency can induce tissue hypoxia, oxygen deprivation was tested as a regulator of FGF23, and was shown to stimulate FGF23 mRNA in vitro and serum C-terminal FGF23 in normal rats in vivo. These studies demonstrate that FGF23 is modulated by iron status in young WT and ADHR mice and that hypoxia independently controls FGF23 expression in situations of normal iron. Therefore, disturbed iron and oxygen metabolism in neonatal life may have important effects on skeletal function and structure through FGF23 activity on phosphate regulation.

  6. Iron uptake and metabolism in pseudomonads.

    PubMed

    Cornelis, Pierre

    2010-05-01

    Pseudomonads are ubiquitous Gram-negative gamma proteobacteria known for their extreme versatility and adaptability. Some are plant pathogens (Pseudomonas syringae) which have to survive on the surface of leaves while others can colonize the rhizosphere or survive in soil (Pseudomonas fluorescens, Pseudomonas putida), and one species, Pseudomonas entomophila, is an insect pathogen. The most investigated species, Pseudomonas aeruginosa, is known to be an opportunistic pathogen able to infect plants, nematodes, insects, and mammals, including humans. Like for other bacteria, iron is a key nutrient for pseudomonads. The fluorescent pseudomonads produce siderophores, the best known being the fluorescent high-affinity peptidic pyoverdines. Often diverse secondary siderophores of lower affinity are produced as well (pyochelin, pseudomonin, corrugatins and ornicorrugatins, yersiniabactin, and thioquinolobactin). Reflecting their large capacity of adaptation to changing environment and niche colonization, pseudomonads are able to obtain their iron from heme or from siderophores produced by other microorganisms (xenosiderophores) via the expression of outer membrane TonB-dependent receptors. As expected, iron uptake is exquisitely and hierarchically regulated in these bacteria. In this short review, the diversity of siderophores produced, receptors, and finally the way iron homeostasis is regulated in P. aeruginosa, P. syringae, P. putida, and P. fluorescens, will be presented and, when possible, put in relation with the lifestyle and the ecological niche. PMID:20352420

  7. Orphan nuclear receptor SHP regulates iron metabolism through inhibition of BMP6-mediated hepcidin expression

    PubMed Central

    Kim, Don-Kyu; Kim, Yong-Hoon; Jung, Yoon Seok; Kim, Ki-Sun; Jeong, Jae-Ho; Lee, Yong-Soo; Yuk, Jae-Min; Oh, Byung-Chul; Choy, Hyon E.; Dooley, Steven; Muckenthaler, Martina U.; Lee, Chul-Ho; Choi, Hueng-Sik

    2016-01-01

    Small heterodimer partner (SHP) is a transcriptional corepressor regulating diverse metabolic processes. Here, we show that SHP acts as an intrinsic negative regulator of iron homeostasis. SHP-deficient mice maintained on a high-iron diet showed increased serum hepcidin levels, decreased expression of the iron exporter ferroportin as well as iron accumulation compared to WT mice. Conversely, overexpression of either SHP or AMP-activated protein kinase (AMPK), a metabolic sensor inducing SHP expression, suppressed BMP6-induced hepcidin expression. In addition, an inhibitory effect of AMPK activators metformin and AICAR on BMP6-mediated hepcidin gene expression was significantly attenuated by ablation of SHP expression. Interestingly, SHP physically interacted with SMAD1 and suppressed BMP6-mediated recruitment of the SMAD complex to the hepcidin gene promoter by inhibiting the formation of SMAD1 and SMAD4 complex. Finally, overexpression of SHP and metformin treatment of BMP6 stimulated mice substantially restored hepcidin expression and serum iron to baseline levels. These results reveal a previously unrecognized role for SHP in the transcriptional control of iron homeostasis. PMID:27688041

  8. Diet-induced metabolic acidosis.

    PubMed

    Adeva, María M; Souto, Gema

    2011-08-01

    The modern Western-type diet is deficient in fruits and vegetables and contains excessive animal products, generating the accumulation of non-metabolizable anions and a lifespan state of overlooked metabolic acidosis, whose magnitude increases progressively with aging due to the physiological decline in kidney function. In response to this state of diet-derived metabolic acidosis, the kidney implements compensating mechanisms aimed to restore the acid-base balance, such as the removal of the non-metabolizable anions, the conservation of citrate, and the enhancement of kidney ammoniagenesis and urinary excretion of ammonium ions. These adaptive processes lower the urine pH and induce an extensive change in urine composition, including hypocitraturia, hypercalciuria, and nitrogen and phosphate wasting. Low urine pH predisposes to uric acid stone formation. Hypocitraturia and hypercalciuria are risk factors for calcium stone disease. Even a very mild degree of metabolic acidosis induces skeletal muscle resistance to the insulin action and dietary acid load may be an important variable in predicting the metabolic abnormalities and the cardiovascular risk of the general population, the overweight and obese persons, and other patient populations including diabetes and chronic kidney failure. High dietary acid load is more likely to result in diabetes and systemic hypertension and may increase the cardiovascular risk. Results of recent observational studies confirm an association between insulin resistance and metabolic acidosis markers, including low serum bicarbonate, high serum anion gap, hypocitraturia, and low urine pH.

  9. A high-fat diet modulates iron metabolism but does not promote liver fibrosis in hemochromatotic Hjv⁻/⁻ mice.

    PubMed

    Padda, Ranjit Singh; Gkouvatsos, Konstantinos; Guido, Maria; Mui, Jeannie; Vali, Hojatollah; Pantopoulos, Kostas

    2015-02-15

    Hemojuvelin (Hjv) is a membrane protein that controls body iron metabolism by enhancing signaling to hepcidin. Hjv mutations cause juvenile hemochromatosis, a disease of systemic iron overload. Excessive iron accumulation in the liver progressively leads to inflammation and disease, such as fibrosis, cirrhosis, or hepatocellular cancer. Fatty liver (steatosis) may also progress to inflammation (steatohepatitis) and liver disease, and iron is considered as pathogenic cofactor. The aim of this study was to investigate the pathological implications of parenchymal iron overload due to Hjv ablation in the fatty liver. Wild-type (WT) and Hjv(-/-) mice on C57BL/6 background were fed a standard chow, a high-fat diet (HFD), or a HFD supplemented with 2% carbonyl iron (HFD+Fe) for 12 wk. The animals were analyzed for iron and lipid metabolism. As expected, all Hjv(-/-) mice manifested higher serum and hepatic iron and diminished hepcidin levels compared with WT controls. The HFD reduced iron indexes and promoted liver steatosis in both WT and Hjv(-/-) mice. Notably, steatosis was attenuated in Hjv(-/-) mice on the HFD+Fe regimen. Hjv(-/-) animals gained less body weight and exhibited reduced serum glucose and cholesterol levels. Histological and ultrastructural analysis revealed absence of iron-induced inflammation or liver fibrosis despite early signs of liver injury (expression of α-smooth muscle actin). We conclude that parenchymal hepatic iron overload does not suffice to trigger progression of liver steatosis to steatohepatitis or fibrosis in C57BL/6 mice.

  10. A high-fat diet modulates iron metabolism but does not promote liver fibrosis in hemochromatotic Hjv⁻/⁻ mice.

    PubMed

    Padda, Ranjit Singh; Gkouvatsos, Konstantinos; Guido, Maria; Mui, Jeannie; Vali, Hojatollah; Pantopoulos, Kostas

    2015-02-15

    Hemojuvelin (Hjv) is a membrane protein that controls body iron metabolism by enhancing signaling to hepcidin. Hjv mutations cause juvenile hemochromatosis, a disease of systemic iron overload. Excessive iron accumulation in the liver progressively leads to inflammation and disease, such as fibrosis, cirrhosis, or hepatocellular cancer. Fatty liver (steatosis) may also progress to inflammation (steatohepatitis) and liver disease, and iron is considered as pathogenic cofactor. The aim of this study was to investigate the pathological implications of parenchymal iron overload due to Hjv ablation in the fatty liver. Wild-type (WT) and Hjv(-/-) mice on C57BL/6 background were fed a standard chow, a high-fat diet (HFD), or a HFD supplemented with 2% carbonyl iron (HFD+Fe) for 12 wk. The animals were analyzed for iron and lipid metabolism. As expected, all Hjv(-/-) mice manifested higher serum and hepatic iron and diminished hepcidin levels compared with WT controls. The HFD reduced iron indexes and promoted liver steatosis in both WT and Hjv(-/-) mice. Notably, steatosis was attenuated in Hjv(-/-) mice on the HFD+Fe regimen. Hjv(-/-) animals gained less body weight and exhibited reduced serum glucose and cholesterol levels. Histological and ultrastructural analysis revealed absence of iron-induced inflammation or liver fibrosis despite early signs of liver injury (expression of α-smooth muscle actin). We conclude that parenchymal hepatic iron overload does not suffice to trigger progression of liver steatosis to steatohepatitis or fibrosis in C57BL/6 mice. PMID:25501544

  11. Dietary iron controls circadian hepatic glucose metabolism through heme synthesis.

    PubMed

    Simcox, Judith A; Mitchell, Thomas Creighton; Gao, Yan; Just, Steven F; Cooksey, Robert; Cox, James; Ajioka, Richard; Jones, Deborah; Lee, Soh-Hyun; King, Daniel; Huang, Jingyu; McClain, Donald A

    2015-04-01

    The circadian rhythm of the liver maintains glucose homeostasis, and disruption of this rhythm is associated with type 2 diabetes. Feeding is one factor that sets the circadian clock in peripheral tissues, but relatively little is known about the role of specific dietary components in that regard. We assessed the effects of dietary iron on circadian gluconeogenesis. Dietary iron affects circadian glucose metabolism through heme-mediated regulation of the interaction of nuclear receptor subfamily 1 group d member 1 (Rev-Erbα) with its cosuppressor nuclear receptor corepressor 1 (NCOR). Loss of regulated heme synthesis was achieved by aminolevulinic acid (ALA) treatment of mice or cultured cells to bypass the rate-limiting enzyme in hepatic heme synthesis, ALA synthase 1 (ALAS1). ALA treatment abolishes differences in hepatic glucose production and in the expression of gluconeogenic enzymes seen with variation of dietary iron. The differences among diets are also lost with inhibition of heme synthesis with isonicotinylhydrazine. Dietary iron modulates levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional activator of ALAS1, to affect hepatic heme. Treatment of mice with the antioxidant N-acetylcysteine diminishes PGC-1α variation observed among the iron diets, suggesting that iron is acting through reactive oxygen species signaling.

  12. Iron-induced nickel deficiency in pecan

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Economic loss due to nickel (Ni) deficiency can occur in horticultural and agronomic crops. This study assesses impact of excessive iron (Fe) on expression of Ni deficiency in pecan [Carya illinoinensis (Wangenh.) K. Koch]. Field and greenhouse experiments found Ni deficiency to be inducible by ei...

  13. Human macrophage hemoglobin-iron metabolism in vitro

    SciTech Connect

    Custer, G.; Balcerzak, S.; Rinehart, J.

    1982-01-01

    An entirely in vitro technique was employed to characterize hemoglobin-iron metabolism by human macrophages obtained by culture of blood monocytes and pulmonary alveolar macrophages. Macrophages phagocytized about three times as many erythrocytes as monocytes and six times as many erythrocytes as pulmonary alveolar macrophages. The rate of subsequent release of /sup 59/Fe to the extracellular transferrin pool was two- to fourfold greater for macrophages as compared to the other two cell types. The kinetics of /sup 59/Fe-transferrin release were characterized by a relatively rapid early phase (hours 1-4) followed by a slow phase (hours 4-72) for all three cell types. Intracellular movement of iron was characterized by a rapid shift from hemoglobin to ferritin that was complete with the onset of the slow phase of extracellular release. A transient increase in /sup 59/Fe associated with an intracellular protein eluting with transferrin was also observed within 1 hour after phagocytosis. The process of hemoglobin-iron release to extracellular transferrin was inhibited at 4 degrees C but was unaffected by inhibitory of protein synthesis, glycolysis, microtubule function, and microfilament function. These data emphasize the rapidity of macrophage hemoglobin iron metabolism, provide a model for characterization of this process in vitro, and in general confirm data obtained utilizing in vivo animal models.

  14. Iron metabolism in aerobes: managing ferric iron hydrolysis and ferrous iron autoxidation.

    PubMed

    Kosman, Daniel J

    2013-01-01

    Aerobes and anaerobes alike express a plethora of essential iron enzymes; in the resting state, the iron atom(s) in these proteins are in the ferrous state. For aerobes, ferric iron is the predominant environmental valence form which, given ferric iron's aqueous chemistry, occurs as 'rust', insoluble, bio-inert polymeric ferric oxide that results from the hydrolysis of [Fe(H(2)O)(6)](3+). Mobilizing this iron requires bio-ferrireduction which in turn requires managing the rapid autoxidation of the resulting Fe(II) which occurs at pH > 6. This review examines the aqueous redox chemistry of iron and the mechanisms evolved in aerobes to suppress the 'rusting out' of Fe(III) and the ROS-generating autoxidation of Fe(II) so as to make this metal ion available as the most ubiquitous prosthetic group in metallobiology. PMID:23264695

  15. Estrogen contributes to regulating iron metabolism through governing ferroportin signaling via an estrogen response element.

    PubMed

    Qian, Yi; Yin, Chunyang; Chen, Yue; Zhang, Shuping; Jiang, Li; Wang, Fudi; Zhao, Meirong; Liu, Sijin

    2015-05-01

    Ferroportin (FPN) is the only known iron exporter in mammalian cells, and is universally expressed in most types of cells. FPN signaling plays a crucial role in maintaining iron homeostasis through governing the level of intracellular iron. Serum iron storage is conversely related with the estrogen level in the female bodies, and women in post-menopause are possibly subjected to iron retention. However, the potential effects of estrogen on iron metabolism are not clearly understood. Here, FPN mRNA transcription in all selected estrogen receptor positive (ER+) cells was significantly reduced upon 17β-estradiol (E2) treatment; and this inhibitory effect could be attenuated by ER antagonist tamoxifen. Likewise, in murine bone marrow-derived macrophages (BMDMs), FPN reduction with elevated intracellular iron (reflected by increased ferritin) was observed in response to E2; however, ferritin level barely responded to E2 in FPN-null BMDMs. The observation of inhibition of FPN mRNA expression was not replicated in ER(-) cells upon E2. A functional estrogen response element (ERE) was identified within the promoter of FPN, and this ERE was responsible for the suppressive effect of E2 on FPN expression. Moreover, ovariectomized (OVX) and sham-operated (SHAM) mice were used to further confirm the in vitro finding. The expression of hepatic FPN was induced in OVX mice, compared to that in the SHAM mice. Taken together, our results demonstrated that estrogen is involved in regulating FPN expression through a functional ERE on its promoter, providing additional insights into a vital role of estrogen in iron metabolism.

  16. [Effect of hepcidin on iron metabolism in athletes].

    PubMed

    Domínguez, Raúl; Garnacho-Castaño, Manuel Vicente; Maté-Muñoz, José Luis

    2014-12-01

    The role of iron in the human body is essential, and athletes must always try to keep an adequate iron status. Hepcidin is proposed as the main hormone responsible for the control of iron reserves in the body, given its ability to induce degradation of ferroportin. The action of hepcidin on ferroportin leads to a decreased dietary iron absorption, as well as to a decrease in macrophages. Several factors such as the iron status, the amount of dietary iron, the inflammation, the hypoxia, the testosterone and the physical exercise have been pointed out as affecting the synthesis of hepcidin. This study has aimed at analysing the researches on hepcidin response to exercise, as well as designing a specific strategy to prevent a potential ferropenic status in athletes. The main findings are an association between exercise at an intensity over 65% VO2max and transient increases in the synthesis of hepcidin, and a possible regulatory effect of intermittent hypoxic stimuli in the early post-exercise recovery. Other factors such as the training volume, sex, kind of exercise or the type of surface where the training takes place do not seem to affect the response of hepcidin to exercise.

  17. Oral iron treatment has a positive effect on iron metabolism in elite soccer players.

    PubMed

    Villanueva, Jesús; Soria, Marisol; González-Haro, Carlos; Ezquerra, Laura; Nieto, José L; Escanero, Jesús F

    2011-09-01

    The purpose of this study was to assess the effects of oral iron supplementation on hematological and iron metabolism in elite soccer players. Thirty-five members of the Real Zaragoza SAD soccer team took part in this study: group A (GA, n = 24; Spanish Premier League) took an oral iron supplement of 80 mg day(-1) for 3 weeks, and group B (GB, n = 11; Spanish Third Division League) did not receive any supplementation. In GA, the parameters were measured before and after giving the iron supplements, while in GB, measurements were only made at the time of collecting the second set of data from GA. After supplementation, GA showed an increase in serum iron (SI) (P < 0.05), serum ferritin (Ftn) (P < 0.01), and transferrin saturation (Sat) (P < 0.01) with respect to the basal values. In addition, GA showed higher values of hematocrit (P < 0.01), mean corpuscular volume (P < 0.01), Ftn (P < 0.01), and Sat (P < 0.01) than GB. No significant differences were found in any other parameters. More specifically, a higher percentage of players had Ftn levels above upper limits in GA vs. GB (P < 0.05), and GB had a higher incidence of Ftn below lower limits with respect to subjects in GA (P < 0.01). Further, after treatment, 58.3% of GA had >800 mg of SI, while all players in GB presented levels below the lower limits. In conclusion, iron supplementation with 80 mg·day(-1) for 3 weeks, before the start of the soccer season, can be recommended for elite soccer players.

  18. Oral iron treatment has a positive effect on iron metabolism in elite soccer players.

    PubMed

    Villanueva, Jesús; Soria, Marisol; González-Haro, Carlos; Ezquerra, Laura; Nieto, José L; Escanero, Jesús F

    2011-09-01

    The purpose of this study was to assess the effects of oral iron supplementation on hematological and iron metabolism in elite soccer players. Thirty-five members of the Real Zaragoza SAD soccer team took part in this study: group A (GA, n = 24; Spanish Premier League) took an oral iron supplement of 80 mg day(-1) for 3 weeks, and group B (GB, n = 11; Spanish Third Division League) did not receive any supplementation. In GA, the parameters were measured before and after giving the iron supplements, while in GB, measurements were only made at the time of collecting the second set of data from GA. After supplementation, GA showed an increase in serum iron (SI) (P < 0.05), serum ferritin (Ftn) (P < 0.01), and transferrin saturation (Sat) (P < 0.01) with respect to the basal values. In addition, GA showed higher values of hematocrit (P < 0.01), mean corpuscular volume (P < 0.01), Ftn (P < 0.01), and Sat (P < 0.01) than GB. No significant differences were found in any other parameters. More specifically, a higher percentage of players had Ftn levels above upper limits in GA vs. GB (P < 0.05), and GB had a higher incidence of Ftn below lower limits with respect to subjects in GA (P < 0.01). Further, after treatment, 58.3% of GA had >800 mg of SI, while all players in GB presented levels below the lower limits. In conclusion, iron supplementation with 80 mg·day(-1) for 3 weeks, before the start of the soccer season, can be recommended for elite soccer players. PMID:20798998

  19. Mitochondrial mayhem: the mitochondrion as a modulator of iron metabolism and its role in disease.

    PubMed

    Huang, Michael Li-Hsuan; Lane, Darius J R; Richardson, Des R

    2011-12-15

    The mitochondrion plays vital roles in various aspects of cellular metabolism, ranging from energy transduction and apoptosis to the synthesis of important molecules such as heme. Mitochondria are also centrally involved in iron metabolism, as exemplified by disruptions in mitochondrial proteins that lead to perturbations in whole-cell iron processing. Recent investigations have identified a host of mitochondrial proteins (e.g., mitochondrial ferritin; mitoferrins 1 and 2; ABCBs 6, 7, and 10; and frataxin) that may play roles in the homeostasis of mitochondrial iron. These mitochondrial proteins appear to participate in one or more processes of iron storage, iron uptake, and heme and iron-sulfur cluster synthesis. In this review, we present and critically discuss the evidence suggesting that the mitochondrion may contribute to the regulation of whole-cell iron metabolism. Further, human diseases that arise from a dysregulation of these mitochondrial molecules reveal the ability of the mitochondrion to communicate with cytosolic iron metabolism to coordinate whole-cell iron processing and to fulfill the high demands of this organelle for iron. This review highlights new advances in understanding iron metabolism in terms of novel molecular players and diseases associated with its dysregulation.

  20. Insights into the Structure and Metabolic Function of Microbes That Shape Pelagic Iron-Rich Aggregates (“Iron Snow”)

    PubMed Central

    Lu, Shipeng; Chourey, Karuna; Reiche, Marco; Nietzsche, Sandor; Shah, Manesh B.; Neu, Thomas R.; Hettich, Robert L.

    2013-01-01

    Microbial ferrous iron [Fe(II)] oxidation leads to the formation of iron-rich macroscopic aggregates (“iron snow”) at the redoxcline in a stratified lignite mine lake in east-central Germany. We aimed to identify the abundant Fe-oxidizing and Fe-reducing microorganisms likely to be involved in the formation and transformation of iron snow present in the redoxcline in two basins of the lake that differ in their pH values. Nucleic acid- and lipid-stained microbial cells of various morphologies detected by confocal laser scanning microscopy were homogeneously distributed in all iron snow samples. The dominant iron mineral appeared to be schwertmannite, with shorter needles in the northern than in the central basin samples. Total bacterial 16S rRNA gene copies ranged from 5.0 × 108 copies g (dry weight)−1 in the acidic central lake basin (pH 3.3) to 4.0 × 1010 copies g (dry weight)−1 in the less acidic (pH 5.9) northern basin. Total RNA-based quantitative PCR assigned up to 61% of metabolically active microbial communities to Fe-oxidizing- and Fe-reducing-related bacteria, indicating that iron metabolism was an important metabolic strategy. Molecular identification of abundant groups suggested that iron snow surfaces were formed by chemoautotrophic iron oxidizers, such as Acidimicrobium, Ferrovum, Acidithiobacillus, Thiobacillus, and Chlorobium, in the redoxcline and were rapidly colonized by heterotrophic iron reducers, such as Acidiphilium, Albidiferax-like, and Geobacter-like groups. Metaproteomics yielded 283 different proteins from northern basin iron snow samples, and protein identification provided a glimpse into some of their in situ metabolic processes, such as primary production (CO2 fixation), respiration, motility, and survival strategies. PMID:23645202

  1. Insights into the structure and metabolic function of microbes that shape pelagic iron-rich aggregates ("iron snow").

    PubMed

    Lu, Shipeng; Chourey, Karuna; Reiche, Marco; Nietzsche, Sandor; Shah, Manesh B; Neu, Thomas R; Hettich, Robert L; Küsel, Kirsten

    2013-07-01

    Microbial ferrous iron [Fe(II)] oxidation leads to the formation of iron-rich macroscopic aggregates ("iron snow") at the redoxcline in a stratified lignite mine lake in east-central Germany. We aimed to identify the abundant Fe-oxidizing and Fe-reducing microorganisms likely to be involved in the formation and transformation of iron snow present in the redoxcline in two basins of the lake that differ in their pH values. Nucleic acid- and lipid-stained microbial cells of various morphologies detected by confocal laser scanning microscopy were homogeneously distributed in all iron snow samples. The dominant iron mineral appeared to be schwertmannite, with shorter needles in the northern than in the central basin samples. Total bacterial 16S rRNA gene copies ranged from 5.0 × 10(8) copies g (dry weight)(-1) in the acidic central lake basin (pH 3.3) to 4.0 × 10(10) copies g (dry weight)(-1) in the less acidic (pH 5.9) northern basin. Total RNA-based quantitative PCR assigned up to 61% of metabolically active microbial communities to Fe-oxidizing- and Fe-reducing-related bacteria, indicating that iron metabolism was an important metabolic strategy. Molecular identification of abundant groups suggested that iron snow surfaces were formed by chemoautotrophic iron oxidizers, such as Acidimicrobium, Ferrovum, Acidithiobacillus, Thiobacillus, and Chlorobium, in the redoxcline and were rapidly colonized by heterotrophic iron reducers, such as Acidiphilium, Albidiferax-like, and Geobacter-like groups. Metaproteomics yielded 283 different proteins from northern basin iron snow samples, and protein identification provided a glimpse into some of their in situ metabolic processes, such as primary production (CO2 fixation), respiration, motility, and survival strategies.

  2. Sleep disorders: A review of the interface between restless legs syndrome and iron metabolism.

    PubMed

    Daubian-Nosé, Paulo; Frank, Miriam K; Esteves, Andrea Maculano

    2014-12-01

    Restless legs syndrome (RLS) is characterized by unpleasant sensations mainly in the legs. 43% of RLS-associated conditions have also been associated with systemic iron deficiency. The objective of this study was to review in the literature the relationship between iron metabolism and RLS. With an initial search using the keywords combination "Iron Metabolism OR Iron Deficiency AND Restless Legs Syndrome," 145 articles were screened, and 20 articles were selected. Few studies were found for this review in the period of 2001-2014, however, the correlation between RLS and iron was evident. PMID:26483934

  3. Sleep disorders: A review of the interface between restless legs syndrome and iron metabolism

    PubMed Central

    Daubian-Nosé, Paulo; Frank, Miriam K.; Esteves, Andrea Maculano

    2014-01-01

    Restless legs syndrome (RLS) is characterized by unpleasant sensations mainly in the legs. 43% of RLS-associated conditions have also been associated with systemic iron deficiency. The objective of this study was to review in the literature the relationship between iron metabolism and RLS. With an initial search using the keywords combination “Iron Metabolism OR Iron Deficiency AND Restless Legs Syndrome,” 145 articles were screened, and 20 articles were selected. Few studies were found for this review in the period of 2001–2014, however, the correlation between RLS and iron was evident. PMID:26483934

  4. Chromosomal intrachanges induced by swift iron ions

    NASA Astrophysics Data System (ADS)

    Horstmann, M.; Durante, M.; Johannes, C.; Obe, G.

    We measured the induction of structural aberrations in human chromosome 5 induced by iron ions using the novel technique of multicolor banding in situ hybridization (mBAND). Human lymphocytes isolated from whole blood were exposed in vitro to 500 MeV/n (LET = 200 keV/μm, doses 1 or 4 Gy) Fe nuclei at the HIMAC accelerator in Chiba (Japan). Chromosomes were prematurely condensed by calyculin A after 48 h in culture and slides were painted by mBAND. We found a frequency of 0.11 and 0.57 residual breakpoints per chromosome 5 after 1 and 4 Gy Fe-ions, respectively. Inter-chromosomal exchanges were the prevalent aberration type measured at both doses, followed by terminal deletions, and by intra-chromosomal exchanges. Among intra-chromosomal exchanges, intra-arm events were more frequent than inter-arm, but a significant number of intra-changes was associated to inter-changes involving the same chromosome after 4 Gy of iron ions. These events show that the complexity of chromosomal exchanges induced by heavy ions can be higher than expected by previous FISH studies.

  5. Like iron in the blood of the people: the requirement for heme trafficking in iron metabolism

    PubMed Central

    Korolnek, Tamara; Hamza, Iqbal

    2014-01-01

    Heme is an iron-containing porphyrin ring that serves as a prosthetic group in proteins that function in diverse metabolic pathways. Heme is also a major source of bioavailable iron in the human diet. While the synthesis of heme has been well-characterized, the pathways for heme trafficking remain poorly understood. It is likely that heme transport across membranes is highly regulated, as free heme is toxic to cells. This review outlines the requirement for heme delivery to various subcellular compartments as well as possible mechanisms for the mobilization of heme to these compartments. We also discuss how these trafficking pathways might function during physiological events involving inter- and intra-cellular mobilization of heme, including erythropoiesis, erythrophagocytosis, heme absorption in the gut, as well as heme transport pathways supporting embryonic development. Lastly, we aim to question the current dogma that heme, in toto, is not mobilized from one cell or tissue to another, outlining the evidence for these pathways and drawing parallels to other well-accepted paradigms for copper, iron, and cholesterol homeostasis. PMID:24926267

  6. New strategies to target iron metabolism for the treatment of beta thalassemia.

    PubMed

    Oikonomidou, Paraskevi Rea; Casu, Carla; Rivella, Stefano

    2016-03-01

    Iron is one of the most abundant elements in the Earth and a fundamental component of enzymes and other proteins that participate in a wide range of biological processes. As the human body has no mechanisms to eliminate the excess of iron, its metabolism needs to be tightly controlled in order to avoid all the sequelae associated with high iron levels. Iron overload is the main cause of morbidity and mortality in beta thalassemia. The master regulator of iron homeostasis, hepcidin, is chronically repressed in this disorder, leading to increased intestinal iron absorption and consequent iron overload. Many groups have focused on obtaining a better understanding of the pathways involved in iron regulation. New molecules have recently been synthesized and used in animal models of dysregulated iron metabolism, demonstrating their ability to target and reduce iron load. Antisense oligonucleotides, as well as lipid nanoparticle-formulated small interfering RNAs and minihepcidins peptides, are novel agents that have already proved to be efficient in modulating iron metabolism in mouse models and are therefore promising candidates for the treatment of patients affected by iron disorders. PMID:26919168

  7. Oxidation inhibits iron-induced blood coagulation.

    PubMed

    Pretorius, Etheresia; Bester, Janette; Vermeulen, Natasha; Lipinski, Boguslaw

    2013-01-01

    Blood coagulation under physiological conditions is activated by thrombin, which converts soluble plasma fibrinogen (FBG) into an insoluble clot. The structure of the enzymatically-generated clot is very characteristic being composed of thick fibrin fibers susceptible to the fibrinolytic degradation. However, in chronic degenerative diseases, such as atherosclerosis, diabetes mellitus, cancer, and neurological disorders, fibrin clots are very different forming dense matted deposits (DMD) that are not effectively removed and thus create a condition known as thrombosis. We have recently shown that trivalent iron (ferric ions) generates hydroxyl radicals, which subsequently convert FBG into abnormal fibrin clots in the form of DMDs. A characteristic feature of DMDs is their remarkable and permanent resistance to the enzymatic degradation. Therefore, in order to prevent thrombotic incidences in the degenerative diseases it is essential to inhibit the iron-induced generation of hydroxyl radicals. This can be achieved by the pretreatment with a direct free radical scavenger (e.g. salicylate), and as shown in this paper by the treatment with oxidizing agents such as hydrogen peroxide, methylene blue, and sodium selenite. Although the actual mechanism of this phenomenon is not yet known, it is possible that hydroxyl radicals are neutralized by their conversion to the molecular oxygen and water, thus inhibiting the formation of dense matted fibrin deposits in human blood.

  8. Multiple-shocks induced nanocrystallization in iron

    SciTech Connect

    Matsuda, Tomoki; Hirose, Akio; Sano, Tomokazu; Arakawa, Kazuto

    2014-07-14

    We found that multiple shots of femtosecond laser-driven shock pulses changed coarse crystalline iron grains with a size of 140 μm into nanocrystals with a high density of dislocations, which had never been observed in conventional shock processes. We performed metallurgical microstructure observations using transmission electron microscopy (TEM) and hardness measurements using nanoindentation on cross-sections of shocked iron. TEM images showed that grains with sizes from 10 nm through 1 μm exist within 2 μm of the surface, where the dislocation density reached 2 × 10{sup 15 }m{sup −2}. Results of the hardness measurements showed a significant increase in hardness in the nanocrystallized region. We suggest that the formation of a high density of dislocations, which is produced by a single shock, induces local three-dimensional pile-up by the multiple-shocks, which causes grain refinement at the nanoscale.

  9. Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli.

    PubMed

    Seo, Sang Woo; Kim, Donghyuk; Latif, Haythem; O'Brien, Edward J; Szubin, Richard; Palsson, Bernhard O

    2014-09-15

    The ferric uptake regulator (Fur) plays a critical role in the transcriptional regulation of iron metabolism. However, the full regulatory potential of Fur remains undefined. Here we comprehensively reconstruct the Fur transcriptional regulatory network in Escherichia coli K-12 MG1655 in response to iron availability using genome-wide measurements. Integrative data analysis reveals that a total of 81 genes in 42 transcription units are directly regulated by three different modes of Fur regulation, including apo- and holo-Fur activation and holo-Fur repression. We show that Fur connects iron transport and utilization enzymes with negative-feedback loop pairs for iron homeostasis. In addition, direct involvement of Fur in the regulation of DNA synthesis, energy metabolism and biofilm development is found. These results show how Fur exhibits a comprehensive regulatory role affecting many fundamental cellular processes linked to iron metabolism in order to coordinate the overall response of E. coli to iron availability.

  10. Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli.

    PubMed

    Seo, Sang Woo; Kim, Donghyuk; Latif, Haythem; O'Brien, Edward J; Szubin, Richard; Palsson, Bernhard O

    2014-01-01

    The ferric uptake regulator (Fur) plays a critical role in the transcriptional regulation of iron metabolism. However, the full regulatory potential of Fur remains undefined. Here we comprehensively reconstruct the Fur transcriptional regulatory network in Escherichia coli K-12 MG1655 in response to iron availability using genome-wide measurements. Integrative data analysis reveals that a total of 81 genes in 42 transcription units are directly regulated by three different modes of Fur regulation, including apo- and holo-Fur activation and holo-Fur repression. We show that Fur connects iron transport and utilization enzymes with negative-feedback loop pairs for iron homeostasis. In addition, direct involvement of Fur in the regulation of DNA synthesis, energy metabolism and biofilm development is found. These results show how Fur exhibits a comprehensive regulatory role affecting many fundamental cellular processes linked to iron metabolism in order to coordinate the overall response of E. coli to iron availability. PMID:25222563

  11. Fixing frataxin: ‘ironing out’ the metabolic defect in Friedreich's ataxia

    PubMed Central

    Anzovino, A; Lane, D J R; Huang, M L-H; Richardson, D R

    2014-01-01

    The metabolically active and redox-active mitochondrion appears to play a major role in the cellular metabolism of the transition metal, iron. Frataxin, a mitochondrial matrix protein, has been identified as playing a key role in the iron metabolism of this organelle due to its iron-binding properties and is known to be essential for iron–sulphur cluster formation. However, the precise function of frataxin remains elusive. The decrease in frataxin expression, as seen in the inherited disorder Friedreich's ataxia, markedly alters cellular and mitochondrial iron metabolism in both the mitochondrion and the cell. The resulting dysregulation of iron trafficking damages affects tissues leading to neuro-and cardiodegeneration. This disease underscores the importance of iron homeostasis in the redox-active environment of the mitochondrion and the molecular players involved. Unravelling the mechanisms of altered iron metabolism in Friedreich's ataxia will help elucidate a biochemical function for frataxin. Consequently, this will enable the development of more effective and rationally designed treatments. This review will focus on the emerging function of frataxin in relation to the observed alterations in mitochondrial iron metabolism in Friedreich's ataxia. Tissue-specific alterations due to frataxin loss will also be discussed, as well as current and emerging therapeutic strategies. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8 PMID:24138602

  12. Searching iron sensors in plants by exploring the link among 2′-OG-dependent dioxygenases, the iron deficiency response and metabolic adjustments occurring under iron deficiency

    PubMed Central

    Vigani, Gianpiero; Morandini, Piero; Murgia, Irene

    2013-01-01

    Knowledge accumulated on the regulation of iron (Fe) homeostasis, its intracellular trafficking and transport across various cellular compartments and organs in plants; storage proteins, transporters and transcription factors involved in Fe metabolism have been analyzed in detail in recent years. However, the key sensor(s) of cellular plant “Fe status” triggering the long-distance shoot–root signaling and leading to the root Fe deficiency responses is (are) still unknown. Local Fe sensing is also a major task for roots, for adjusting the internal Fe requirements to external Fe availability: how such sensing is achieved and how it leads to metabolic adjustments in case of nutrient shortage, is mostly unknown. Two proteins belonging to the 2′-OG-dependent dioxygenases family accumulate several folds in Fe-deficient Arabidopsis roots. Such proteins require Fe(II) as enzymatic cofactor; one of their subgroups, the HIF-P4H (hypoxia-inducible factor-prolyl 4-hydroxylase), is an effective oxygen sensor in animal cells. We envisage here the possibility that some members of the 2′-OG dioxygenase family may be involved in the Fe deficiency response and in the metabolic adjustments to Fe deficiency or even in sensing Fe, in plant cells. PMID:23755060

  13. Candida albicans Hap43 Is a Repressor Induced under Low-Iron Conditions and Is Essential for Iron-Responsive Transcriptional Regulation and Virulence ▿

    PubMed Central

    Hsu, Po-Chen; Yang, Cheng-Yao; Lan, Chung-Yu

    2011-01-01

    Candida albicans is an opportunistic fungal pathogen that exists as normal flora in healthy human bodies but causes life-threatening infections in immunocompromised patients. In addition to innate and adaptive immunities, hosts also resist microbial infections by developing a mechanism of “natural resistance” that maintains a low level of free iron to restrict the growth of invading pathogens. C. albicans must overcome this iron-deprived environment to cause infections. There are three types of iron-responsive transcriptional regulators in fungi; Aft1/Aft2 activators in yeast, GATA-type repressors in many fungi, and HapX/Php4 in Schizosaccharomyces pombe and Aspergillus species. In this study, we characterized the iron-responsive regulator Hap43, which is the C. albicans homolog of HapX/Php4 and is repressed by the GATA-type repressor Sfu1 under iron-sufficient conditions. We provide evidence that Hap43 is essential for the growth of C. albicans under low-iron conditions and for C. albicans virulence in a mouse model of infection. Hap43 was not required for iron acquisition under low-iron conditions. Instead, it was responsible for repression of genes that encode iron-dependent proteins involved in mitochondrial respiration and iron-sulfur cluster assembly. We also demonstrated that Hap43 executes its function by becoming a transcriptional repressor and accumulating in the nucleus in response to iron deprivation. Finally, we found a connection between Hap43 and the global corepressor Tup1 in low-iron-induced flavinogenesis. Taken together, our data suggest a complex interplay among Hap43, Sfu1, and Tup1 to coordinately regulate iron acquisition, iron utilization, and other iron-responsive metabolic activities. PMID:21131439

  14. Advantages and disadvantages of the animal models v. in vitro studies in iron metabolism: a review.

    PubMed

    García, Y; Díaz-Castro, J

    2013-10-01

    Iron deficiency is the most common nutritional deficiency in the world. Special molecules have evolved for iron acquisition, transport and storage in soluble, nontoxic forms. Studies about the effects of iron on health are focused on iron metabolism or nutrition to prevent or treat iron deficiency and anemia. These studies are focused in two main aspects: (1) basic studies to elucidate iron metabolism and (2) nutritional studies to evaluate the efficacy of iron supplementation to prevent or treat iron deficiency and anemia. This paper reviews the advantages and disadvantages of the experimental models commonly used as well as the methods that are more used in studies related to iron. In vitro studies have used different parts of the gut. In vivo studies are done in humans and animals such as mice, rats, pigs and monkeys. Iron metabolism is a complex process that includes interactions at the systemic level. In vitro studies, despite physiological differences to humans, are useful to increase knowledge related to this essential micronutrient. Isotopic techniques are the most recommended in studies related to iron, but their high cost and required logistic, making them difficult to use. The depletion-repletion of hemoglobin is a method commonly used in animal studies. Three depletion-repletion techniques are mostly used: hemoglobin regeneration efficiency, relative biological values (RBV) and metabolic balance, which are official methods of the association of official analytical chemists. These techniques are well-validated to be used as studies related to iron and their results can be extrapolated to humans. Knowledge about the main advantages and disadvantages of the in vitro and animal models, and methods used in these studies, could increase confidence of researchers in the experimental results with less costs.

  15. Mitochondrial Iron Metabolism and Its Role in Neurodegeneration

    PubMed Central

    Horowitz, Maxx P.; Greenamyre, J. Timothy

    2011-01-01

    In addition to their well-established role in providing the cell with ATP, mitochondria are the source of iron-sulfur clusters (ISCs) and heme – prosthetic groups that are utilized by proteins throughout the cell in various critical processes. The post-transcriptional system that mammalian cells use to regulate intracellular iron homeostasis depends, in part, upon the synthesis of ISCs in mitochondria. Thus, proper mitochondrial function is crucial to cellular iron homeostasis. Many neurodegenerative diseases are marked by mitochondrial impairment, brain iron accumulation, and oxidative stress – pathologies that are inter-related. This review discusses the physiological role that mitochondria play in cellular iron homeostasis and, in so doing, attempts to clarify how mitochondrial dysfunction may initiate and/or contribute to iron dysregulation in the context of neurodegenerative disease. We review what is currently known about the entry of iron into mitochondria, the ways in which iron is utilized therein, and how mitochondria are integrated into the system of iron homeostasis in mammalian cells. Lastly, we turn to recent advances in our understanding of iron dysregulation in two neurodegenerative diseases (Alzheimer’s disease and Parkinson’s disease), and discuss the use of iron chelation as a potential therapeutic approach to neurodegenerative disease. PMID:20463401

  16. Chromosomal intrachanges induced by swift iron ions

    NASA Astrophysics Data System (ADS)

    Horstmann, M.; Durante, M.; Johannes, C.; Obe, G.

    We measured the induction of aberrations in human chromosome 5 by iron ions using the novel technique of multicolor banding in situ hybridization (mBAND). Human lymphocytes isolated from whole blood were exposed in vitro to 500 MeV/n (LET=200 keV/μ m, doses 1 or 4 Gy) 56Fe nuclei at the HIMAC accelerator in Chiba (Japan). Chromosomes were prematurely condensed by calyculin A after 48 h in culture, and slides were painted by mBAND (MetaSystems). We found a frequency of 0.11 and 0.57 residual breakpoints per chromosome 5 after 1 Gy and 4 Gy Fe-ions, respectively. The distribution per unit length were similar in the p- and q-arm of chromosome 5, and >50% of the observed fragments measured <30% of the whole chromosome length. Only small fragments (<40% of the chromosome size) were involved in intra-chromosomal exchanges (interstitial deletions or inversions), whereas fragments up to 75% of the whole chromosome 5 were found in inter-chromosomal exchanges. We measured more inter-changes than intra-changes, and more intra-arm than inter-arm exchanges at both doses. No significant differences in the ratios of these aberrations were detected with respect to X-rays. On the other hand, Fe-ions induced a significantly higher fraction of complex-type exchanges when compared to sparsely ionizing radiation. Work supported by DLR, BMBF, INTAS and NIRS-HIMAC.

  17. Protective effects of naringenin on iron-overload-induced cerebral cortex neurotoxicity correlated with oxidative stress.

    PubMed

    Chtourou, Yassine; Fetoui, Hamadi; Gdoura, Radhouane

    2014-06-01

    Iron is a component of several metalloproteins involved in crucial metabolic processes such as oxygen sensing and transport, energy metabolism, and DNA synthesis. This metal progressively accumulates in the pathogenesis of Alzheimer's (AD) and Parkinson's (PD) diseases. Naringenin (NGEN), a natural flavonoid compound, has been reported to possess neuroprotective effect against PD-related pathology, however, the mechanisms underlying its beneficial effects are poorly defined. Thus, the aim of this study is to investigate the potential mechanism involved in the cytoprotection of NGEN against iron-induced neurotoxicity in the cerebral cortex of Wistar rats. Animals that were given repetitive injections of iron dextran for a total of 4 weeks showed a significant increase in lipid and protein markers such as thiobarbituric reactive acid substances, protein carbonyl product content levels, and DNA apoptosis in the cerebral cortex. These changes were accompanied by a decrease of enzymatic antioxidants like superoxide dismutase and catalase and in the levels of nonenzymatic antioxidants like total thiols and ascorbic acid. The activity of glutathione peroxidase remained unchanged in rats. A significant decrease in acetylcholinesterase and Na(+)/K(+)-ATPase activities was also shown, with a substantial rise in the nitric oxide levels. Coadministration of NGEN to iron-treated rats significantly improved antioxidant enzyme activities and attenuated oxidative damages observed in the cerebral cortex. The potential effect of NGEN to prevent iron-induced neurotoxicity was also reflected by the microscopic study, indicative of its neuroprotective effects. PMID:24682942

  18. Iron metabolism in Pseudomonas: salicylic acid, a siderophore of Pseudomonas fluorescens CHAO.

    PubMed

    Meyer, J M; Azelvandre, P; Georges, C

    1992-12-01

    Under iron-starvation conditions of growth, Pseudomonas fluorescens CHA0, a soil isolate involved in phytopathogenic fungi antagonisms, produced, together with pyoverdine, a second iron-chelating compound which was purified and identified by spectroscopy, HPLC and 1H-NMR to be salicylic acid. Mutants unable to synthesize pyoverdine overproduced this compound by a factor of 9-14. The biosynthesis of salicylic acid was under iron control; it was fully inhibited by 5 microM added iron in the growth medium. In contrast, salicylic acid of either bacterial or commercial origin facilitated labeled iron incorporation in iron-starved cells. Based on these two relationships observed with bacterial iron metabolism it is concluded that salicylic acid has a siderophore function for this strain. PMID:1292472

  19. The Metabolic Status Drives Acclimation of Iron Deficiency Responses in Chlamydomonas reinhardtii as Revealed by Proteomics Based Hierarchical Clustering and Reverse Genetics*

    PubMed Central

    Höhner, Ricarda; Barth, Johannes; Magneschi, Leonardo; Jaeger, Daniel; Niehues, Anna; Bald, Till; Grossman, Arthur; Fufezan, Christian; Hippler, Michael

    2013-01-01

    Iron is a crucial cofactor in numerous redox-active proteins operating in bioenergetic pathways including respiration and photosynthesis. Cellular iron management is essential to sustain sufficient energy production and minimize oxidative stress. To produce energy for cell growth, the green alga Chlamydomonas reinhardtii possesses the metabolic flexibility to use light and/or carbon sources such as acetate. To investigate the interplay between the iron-deficiency response and growth requirements under distinct trophic conditions, we took a quantitative proteomics approach coupled to innovative hierarchical clustering using different “distance-linkage combinations” and random noise injection. Protein co-expression analyses of the combined data sets revealed insights into cellular responses governing acclimation to iron deprivation and regulation associated with photosynthesis dependent growth. Photoautotrophic growth requirements as well as the iron deficiency induced specific metabolic enzymes and stress related proteins, and yet differences in the set of induced enzymes, proteases, and redox-related polypeptides were evident, implying the establishment of distinct response networks under the different conditions. Moreover, our data clearly support the notion that the iron deficiency response includes a hierarchy for iron allocation within organelles in C. reinhardtii. Importantly, deletion of a bifunctional alcohol and acetaldehyde dehydrogenase (ADH1), which is induced under low iron based on the proteomic data, attenuates the remodeling of the photosynthetic machinery in response to iron deficiency, and at the same time stimulates expression of stress-related proteins such as NDA2, LHCSR3, and PGRL1. This finding provides evidence that the coordinated regulation of bioenergetics pathways and iron deficiency response is sensitive to the cellular and chloroplast metabolic and/or redox status, consistent with systems approach data. PMID:23820728

  20. Gene Expression Profiling in Entamoeba histolytica Identifies Key Components in Iron Uptake and Metabolism

    PubMed Central

    Hernández-Cuevas, Nora Adriana; Weber, Christian; Hon, Chung-Chau; Guillen, Nancy

    2014-01-01

    Entamoeba histolytica is an ameboid parasite that causes colonic dysentery and liver abscesses in humans. The parasite encounters dramatic changes in iron concentration during its invasion of the host, with relatively low levels in the intestinal lumen and then relatively high levels in the blood and liver. The liver notably contains sources of iron; therefore, the parasite's ability to use these sources might be relevant to its survival in the liver and thus the pathogenesis of liver abscesses. The objective of the present study was to identify factors involved in iron uptake, use and storage in E. histolytica. We compared the respective transcriptomes of E. histolytica trophozoites grown in normal medium (containing around 169 µM iron), low-iron medium (around 123 µM iron), iron-deficient medium (around 91 µM iron), and iron-deficient medium replenished with hemoglobin. The differentially expressed genes included those coding for the ATP-binding cassette transporters and major facilitator transporters (which share homology with bacterial siderophores and heme transporters) and genes involved in heme biosynthesis and degradation. Iron deficiency was associated with increased transcription of genes encoding a subset of cell signaling molecules, some of which have previously been linked to adaptation to the intestinal environment and virulence. The present study is the first to have assessed the transcriptome of E. histolytica grown under various iron concentrations. Our results provide insights into the pathways involved in iron uptake and metabolism in this parasite. PMID:25210888

  1. Gene expression profiling in Entamoeba histolytica identifies key components in iron uptake and metabolism.

    PubMed

    Hernández-Cuevas, Nora Adriana; Weber, Christian; Hon, Chung-Chau; Guillen, Nancy

    2014-01-01

    Entamoeba histolytica is an ameboid parasite that causes colonic dysentery and liver abscesses in humans. The parasite encounters dramatic changes in iron concentration during its invasion of the host, with relatively low levels in the intestinal lumen and then relatively high levels in the blood and liver. The liver notably contains sources of iron; therefore, the parasite's ability to use these sources might be relevant to its survival in the liver and thus the pathogenesis of liver abscesses. The objective of the present study was to identify factors involved in iron uptake, use and storage in E. histolytica. We compared the respective transcriptomes of E. histolytica trophozoites grown in normal medium (containing around 169 µM iron), low-iron medium (around 123 µM iron), iron-deficient medium (around 91 µM iron), and iron-deficient medium replenished with hemoglobin. The differentially expressed genes included those coding for the ATP-binding cassette transporters and major facilitator transporters (which share homology with bacterial siderophores and heme transporters) and genes involved in heme biosynthesis and degradation. Iron deficiency was associated with increased transcription of genes encoding a subset of cell signaling molecules, some of which have previously been linked to adaptation to the intestinal environment and virulence. The present study is the first to have assessed the transcriptome of E. histolytica grown under various iron concentrations. Our results provide insights into the pathways involved in iron uptake and metabolism in this parasite.

  2. Iron-induced hydroxyl radical generation from basaltic volcanic ash

    NASA Astrophysics Data System (ADS)

    Horwell, C. J.; Fenoglio, I.; Fubini, B.

    2007-09-01

    Iron-induced hydroxyl radical generation from the surface of volcanic ash particles is a possible mechanism of respiratory toxicity in addition to crystalline silica induced pathogenicity. Here we show that volcanic ash generates hydroxyl radicals, with greater reactivity in iron-rich, silica-poor samples, such as basaltic ash. Basaltic particles expose at the surface high levels of poorly-coordinated iron ions in both Fe(II) and Fe(III) oxidation states which are likely to be the cause of such reactivity. Hitherto, basaltic ash has been disregarded as a hazard due to the lack of crystalline silica particulate but future hazard assessment should consider its toxic potential.

  3. The Crossroads of Iron with Hypoxia and Cellular Metabolism. Implications in the Pathobiology of Pulmonary Hypertension

    PubMed Central

    Graham, Brian B.; Rouault, Tracey C.; Tuder, Rubin M.

    2014-01-01

    The pathologic hallmark of pulmonary arterial hypertension (PAH) is pulmonary vascular remodeling, characterized by endothelial cell proliferation, smooth muscle hypertrophy, and perivascular inflammation, ultimately contributing to increased pulmonary arterial pressures. Several recent studies have observed that iron deficiency in patients with various forms of PAH is associated with worsened clinical outcome. Iron plays a key role in many cellular processes regulating the response to hypoxia, oxidative stress, cellular proliferation, and cell metabolism. Given the potential importance of iron supplementation in patients with the disease and the broad cellular functions of iron, we review its role in processes that pertain to PAH. PMID:24988529

  4. MBD5 regulates iron metabolism via methylation-independent genomic targeting of Fth1 through KAT2A in mice.

    PubMed

    Tao, Yunlong; Wu, Qian; Guo, Xin; Zhang, Zhuzhen; Shen, Yuanyuan; Wang, Fudi

    2014-07-01

    Ferritin plays important roles in iron metabolism and controls iron absorption in the intestine. The ferritin subunits ferritin heavy chain (Fth1) and ferritin light chain (Ftl1) are tightly regulated at both the transcriptional and post-transcriptional levels. However, mechanisms of maintaining stable, basal expression of Fth1 are poorly understood. Here, we show that global deletion of Mbd5 in mice induces an iron overload phenotype. Liver and serum iron levels in Mbd5(-/-) mice were 3·2-fold and 1·5-fold higher respectively, than wild-type littermates; moreover, serum ferritin was increased >5-fold in the Mbd5(-/-) mice. Mbd5 encodes a member of the methyl-CpG binding domain family; however, the precise function of this gene is poorly understood. Here, we found that intestinal Fth1 mRNA levels were decreased in Mbd5(-/-) mice. Loss of Fth1 expression in the intestine could lead to iron over-absorption. Furthermore, deleting Mbd5 specifically in the intestine resulted in a phenotype similar to that of conditional deletion of Fth1 mice. An Fth1 promoter-report luciferase assay indicated that overexpression of Mbd5 enhanced Fth1 transcription in a dose-dependent manner. Histone H4 acetylation of the Fth1 promoter was reduced in the intestine of Mbd5(-/-) mice and further analysis showed that histone acetyltransferase KAT2A was essential for MBD5-induced Fth1 transcription.

  5. Neuroprotective effects of ginkgetin against neuroinjury in Parkinson's disease model induced by MPTP via chelating iron.

    PubMed

    Wang, Y-Q; Wang, M-Y; Fu, X-R; Peng-Yu; Gao, G-F; Fan, Y-M; Duan, X-L; Zhao, B-L; Chang, Y-Z; Shi, Z-H

    2015-01-01

    Disruption of neuronal iron homeostasis and oxidative stress are closely related to the pathogenesis of Parkinson's disease (PD). Ginkgetin, a natural biflavonoid isolated from leaves of Ginkgo biloba L, has many known effects, including anti-inflammatory, anti-influenza virus, and anti-fungal activities, but its underlying mechanism of the neuroprotective effects in PD remains unclear. The present study utilized PD models induced by 1-methyl-4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to explore the neuroprotective ability of ginkgetin in vivo and in vitro. Our results showed that ginkgetin could provide significant protection from MPP(+)-induced cell damage in vitro by decreasing the levels of intracellular reactive oxygen species and maintaining mitochondrial membrane potential. Meanwhile, ginkgetin dramatically inhibited cell apoptosis induced by MPP+ through the caspase-3 and Bcl2/Bax pathway. Moreover, ginkgetin significantly improved sensorimotor coordination in a mouse PD model induced by MPTP by dramatically inhibiting the decrease of tyrosine hydroxylase expression in the substantia nigra and superoxide dismutase activity in the striatum. Interestingly, ginkgetin could strongly chelate ferrous ion and thereby inhibit the increase of the intracellular labile iron pool through downregulating L-ferritin and upregulating transferrin receptor 1. These results indicate that the neuroprotective mechanism of ginkgetin against neurological injury induced by MPTP occurs via regulating iron homeostasis. Therefore, ginkgetin may provide neuroprotective therapy for PD and iron metabolism disorder related diseases. PMID:25968939

  6. Transferrin Receptor 2 Dependent Alterations of Brain Iron Metabolism Affect Anxiety Circuits in the Mouse

    PubMed Central

    Pellegrino, Rosa Maria; Boda, Enrica; Montarolo, Francesca; Boero, Martina; Mezzanotte, Mariarosa; Saglio, Giuseppe; Buffo, Annalisa; Roetto, Antonella

    2016-01-01

    The Transferrin Receptor 2 (Tfr2) modulates systemic iron metabolism through the regulation of iron regulator Hepcidin (Hepc) and Tfr2 inactivation causes systemic iron overload. Based on data demonstrating Tfr2 expression in brain, we analysed Tfr2-KO mice in order to examine the molecular, histological and behavioural consequences of Tfr2 silencing in this tissue. Tfr2 abrogation caused an accumulation of iron in specific districts in the nervous tissue that was not accompanied by a brain Hepc response. Moreover, Tfr2-KO mice presented a selective overactivation of neurons in the limbic circuit and the emergence of an anxious-like behaviour. Furthermore, microglial cells showed a particular sensitivity to iron perturbation. We conclude that Tfr2 is a key regulator of brain iron homeostasis and propose a role for Tfr2 alpha in the regulation of anxiety circuits. PMID:27477597

  7. Transferrin Receptor 2 Dependent Alterations of Brain Iron Metabolism Affect Anxiety Circuits in the Mouse.

    PubMed

    Pellegrino, Rosa Maria; Boda, Enrica; Montarolo, Francesca; Boero, Martina; Mezzanotte, Mariarosa; Saglio, Giuseppe; Buffo, Annalisa; Roetto, Antonella

    2016-01-01

    The Transferrin Receptor 2 (Tfr2) modulates systemic iron metabolism through the regulation of iron regulator Hepcidin (Hepc) and Tfr2 inactivation causes systemic iron overload. Based on data demonstrating Tfr2 expression in brain, we analysed Tfr2-KO mice in order to examine the molecular, histological and behavioural consequences of Tfr2 silencing in this tissue. Tfr2 abrogation caused an accumulation of iron in specific districts in the nervous tissue that was not accompanied by a brain Hepc response. Moreover, Tfr2-KO mice presented a selective overactivation of neurons in the limbic circuit and the emergence of an anxious-like behaviour. Furthermore, microglial cells showed a particular sensitivity to iron perturbation. We conclude that Tfr2 is a key regulator of brain iron homeostasis and propose a role for Tfr2 alpha in the regulation of anxiety circuits. PMID:27477597

  8. Insights into the Structure and Metabolic Function of Microbes That Shape Pelagic Iron-Rich Aggregates ( Iron Snow )

    SciTech Connect

    Lu, S; Chourey, Karuna; REICHE, M; Nietzsche, S; Shah, Manesh B; Hettich, Robert {Bob} L; Kusel, K

    2013-01-01

    Metaproteomics combined with total nucleic acid-based methods aided in deciphering the roles of microorganisms in the formation and transformation of iron-rich macroscopic aggregates (iron snow) formed in the redoxcline of an acidic lignite mine lake. Iron snow had high total bacterial 16S rRNA gene copies, with 2 x 109 copies g (dry wt)-1 in the acidic (pH 3.5) central lake basin and 4 x 1010 copies g (dry wt)-1 in the less acidic (pH 5.5) northern lake basin. Active microbial communities in the central basin were dominated by Alphaproteobacteria (36.6%) and Actinobacteria (21.4%), and by Betaproteobacteria (36.2%) in the northern basin. Microbial Fe-cycling appeared to be the dominant metabolism in the schwertmannite-rich iron snow, because cloning and qPCR assigned up to 61% of active bacteria as Fe-cycling bacteria (FeB). Metaproteomics revealed 70 unique proteins from central basin iron snow and 283 unique proteins from 43 genera from northern basin. Protein identification provided a glimpse into in situ processes, such as primary production, motility, metabolism of acidophilic FeB, and survival strategies of neutrophilic FeB. Expression of carboxysome shell proteins and RubisCO indicated active CO2 fixation by Fe(II) oxidizers. Flagellar proteins from heterotrophs indicated their activity to reach and attach surfaces. Gas vesicle proteins related to CO2-fixing Chlorobium suggested that microbes could influence iron snow sinking. We suggest that iron snow formed by autotrophs in the redoxcline acts as a microbial parachute, since it is colonized by motile heterotrophs during sinking which start to dissolve schwertmannite.

  9. Hepcidin and iron metabolism in non-diabetic obese and type 2 diabetic rats.

    PubMed

    Chen, Yue; Yin, Hui-qing; Liu, Hao-ling; Xiu, Lei; Peng, Xiao-yu

    2015-12-01

    The aim of this study was to investigate the changes of iron levels and hepatic regulatory molecules expression involved in iron metabolism in non-diabetic obese/type 2 diabetic rat models. Male Wistar rats were divided into 3 groups: control group, non-diabetic obese group and type 2 diabetic group (n=20 each). The rats were evaluated physiologically and biochemically. The hepatic histopathological changes were observed using haematoxylin and eosin (HE) staining. The mRNA expression patterns of hepcidin, interleukin-6 (IL-6), hypoxia-inducible factor (HIF) and ferroportin (Fpn) in the rat liver in control group, non-diabetic obese group and type 2 diabetic group were analyzed by real-time RT-PCR. The protein expression patterns of hepcidin in liver of each group were further analyzed by immunohistochemistry and Western blotting. As compared with control group, the ferritin in non-diabetic obese group and type 2 diabetic group was increased significantly (P<0.001). However, there was no significant difference in soluble transferring receptor (sTfR):ferritin ratio among the three groups (P>0.05). The real-time RT-PCR, immunohistochemistry and Western blotting results all revealed that the expression levels of hepcidin in non-diabetic obese group and type 2 diabetic group were elevated significantly as compared with those in control group (P<0.001). The expression levels of hepcidin mRNA between non-diabetic obese group and type 2 diabetic group showed no significant difference (P>0.05). However, the protein expression levels of hepcidin in type 2 diabetic group were significantly higher than those in non-diabetic obese group (P<0.05). Compared to control group, the expression levels of IL-6 mRNA in non-diabetic obese group and type 2 diabetic group were increased significantly and the expression levels of Fpn mRNA decreased (P<0.05). However, the expression levels of HIF mRNA had no significant difference among three groups. It is suggested that iron metabolism is

  10. Iron metabolism and the IRE/IRP regulatory system: an update.

    PubMed

    Pantopoulos, Kostas

    2004-03-01

    Cellular iron homeostasis is accomplished by the coordinated regulated expression of the transferrin receptor and ferritin, which mediate iron uptake and storage, respectively. The mechanism is posttranscriptional and involves two cytoplasmic iron regulatory proteins, IRP1 and IRP2. Under conditions of iron starvation, IRPs stabilize the transferrin receptor and inhibit the translation of ferritin mRNAs by binding to "iron responsive elements" (IREs) within their untranslated regions. The IRE/IRP system also controls the expression of additional IRE-containing mRNAs, encoding proteins of iron and energy metabolism. The activities of IRP1 and IRP2 are regulated by distinct posttranslational mechanisms in response to cellular iron levels. Thus, in iron-replete cells, IRP1 assembles a cubane iron-sulfur cluster, which prevents IRE binding, while IRP2 undergoes proteasomal degradation. IRP1 and IRP2 also respond, albeit differentially, to iron-independent signals, such as hydrogen peroxide, hypoxia, or nitric oxide. Basic principles of the IRE/IRP system and recent advances in understanding the regulation and the function of IRP1 and IRP2 are discussed.

  11. Red blood cell and iron metabolism during space flight

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.

    2002-01-01

    Space flight anemia is a widely recognized phenomenon in astronauts. Reduction in circulating red blood cells and plasma volume results in a 10% to 15% decrement in circulatory volume. This effect appears to be a normal physiologic adaptation to weightlessness and results from the removal of newly released blood cells from the circulation. Iron availability increases, and (in the few subjects studied) iron stores increase during long-duration space flight. The consequences of these changes are not fully understood.

  12. Disturbance of aerobic metabolism accompanies neurobehavioral changes induced by nickel in mice.

    PubMed

    He, Min-Di; Xu, Shang-Cheng; Zhang, Xin; Wang, Yan; Xiong, Jia-Chuan; Zhang, Xiao; Lu, Yong-Hui; Zhang, Lei; Yu, Zheng-Ping; Zhou, Zhou

    2013-09-01

    The oral ingestion of soluble nickel compounds leads to neurological symptoms in humans. Deficiencies in aerobic metabolism induced by neurotoxic stimulus can cause an energy crisis in the brain that results in a variety of neurotoxic effects. In the present study, we focused on the aerobic metabolic states to investigate whether disturbance of aerobic metabolism was involved in nickel-induced neurological effects in mice. Mice were orally administered nickel chloride, and neurobehavioral performance was evaluated using the Morris water maze and open field tests at different time points. Aerobic metabolic states in the cerebral cortex were analyzed at the same time points at which neurobehavioral changes were evident. We found that nickel exposure caused deficits in both spatial memory and exploring activity in mice and that nickel was deposited in their cerebral cortex. Deficient aerobic metabolism manifested as decreased O2 consumption and ATP concentrations, lactate and NADH accumulation, and oxidative stress. Meanwhile, the activity of prototypical iron-sulfur clusters (ISCs) containing enzymes that are known to control aerobic metabolism, including complex I and aconitase, and the expression of ISC assembly scaffold protein (ISCU) were inhibited following nickel deposition. Overall, these data suggest that aerobic metabolic disturbances, which accompanied the neurobehavioral changes, may participate in nickel-induced neurologic effects. The inactivation of ISC containing metabolic enzymes may result in the disturbance of aerobic metabolism. A better understanding of how nickel impacts the energy metabolic processes may provide insight into the prevention of nickel neurotoxicity.

  13. Analysis of hypoxia-induced metabolic reprogramming.

    PubMed

    Yang, Chendong; Jiang, Lei; Zhang, Huafeng; Shimoda, Larissa A; DeBerardinis, Ralph J; Semenza, Gregg L

    2014-01-01

    Hypoxia is a common finding in advanced human tumors and is often associated with metastatic dissemination and poor prognosis. Cancer cells adapt to hypoxia by utilizing physiological adaptation pathways that promote a switch from oxidative to glycolytic metabolism. This promotes the conversion of glucose into lactate while limiting its transformation into acetyl coenzyme A (acetyl-CoA). The uptake of glucose and the glycolytic flux are increased under hypoxic conditions, mostly owing to the upregulation of genes encoding glucose transporters and glycolytic enzymes, a process that depends on hypoxia-inducible factor 1 (HIF-1). The reduced delivery of acetyl-CoA to the tricarboxylic acid cycle leads to a switch from glucose to glutamine as the major substrate for fatty acid synthesis in hypoxic cells. In addition, hypoxia induces (1) the HIF-1-dependent expression of BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L), which trigger mitochondrial autophagy, thereby decreasing the oxidative metabolism of both fatty acids and glucose, and (2) the expression of the sodium-hydrogen exchanger NHE1, which maintains an alkaline intracellular pH. Here, we present a compendium of methods to study hypoxia-induced metabolic alterations.

  14. Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism.

    PubMed

    Brittenham, Gary M.; Weiss, Günter; Brissot, Pierre; Lainé, Fabrice; Guillygomarc'h, Anne; Guyader, Dominique; Moirand, Romain; Deugnier, Yves

    2000-01-01

    This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage-transferrin, transferrin receptor, and ferritin-have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the "Stimulator of Fe Transport" (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on

  15. [Ceruloplasmin, hephaestin and zyklopen: the three multicopper oxidases important for human iron metabolism].

    PubMed

    Wierzbicka, Diana; Gromadzka, Grazyna

    2014-01-01

    Multi-copper oxidases are a group of proteins which demonstrate enzymatic activity and are capable of oxidizing their substrates with the concomitant reduction of dioxygen to two water molecules. For some multi-copper oxidases there has been demonstrated ferroxidase activity which is related to their specific structure characterized by the presence of copper centres and iron-binding sites. Three multi-copper oxidases have been included in this group: ceruloplasmin, hephaestin and zyklopen. Multi-copper oxidases which are expressed in different tissues are capable of oxidizing a wide spectrum of substrates. Multi-copper oxidases are capable of oxidizing a wide spectrum of substrates. Ceruloplasmin exhibits antioxidant activity as well as being involved in many other biological processes. The observations of phenotypic effects of absence or low expression of multi-copper ferroxidase-coding genes suggest that the main role of these proteins is taking part in iron metabolism. The main role of ceruloplasmin in iron turnover is oxidizing Fe2+ into Fe3+, a process which is essential for iron binding to transferrin (the main iron-transporting protein), as well as to ferritin (the main iron-storage protein). The function of hephaestin as ferroxidase is essential for iron binding to apotransferrin in the lamina propria of the intestinal mucosa, a process that is important for further transport of iron to the liver by the portal vein. Available data indicate that zyklopen is responsible for the placental iron transport. The presence of three multi-copper oxidases with ferroxidase activity emphasizes the significance of oxidation for iron metabolism. The distribution of multi-copper ferroxidases in many tissues ensures the proper iron turnover in the body as well as preventing toxic effects related to the presence of Fe2+ ions. These ions contribute to generation of free radicals, including the highly reactive hydroxyl radical, through the Fenton and Haber-Weiss reactions

  16. [Peculiarities of iron metabolism in patients with Beta - thalassemia at different periods after splenectomy].

    PubMed

    Kadimova, E

    2007-11-01

    Often thalassaemia patients have significant iron stores. The present research has been conducted to estimate a level of the overall store and degree of an iron overload in patients suffering from beta-thalassemia in pre- and post-surgery periods (pre-surgery, and to the second, seventh, fifteenth, and thirtieth days) after splenectomy. Observation was conducted once a year. The observation period was eight years. The analysis of parameters of iron metabolism in patients with beta-thalassemia in the distant period of time after splenectomy showed that the decrease of serum iron level and index of transferrin saturation was unchanged during the first year. The index of serum ferittin was unchanged during two years. SFT value remained reduced within a year; two years after splenectomy this parameter reached a preoperative level. The index of total serum coupling capacity remaind unchanged during the whole period of observation. The research revealed, that splenectomy has a positive effect on iron balance.

  17. The effects of iron limitation and cell density on prokaryotic metabolism and gene expression: Excerpts from Fusobacterium necrophorum strain 774 (sheep isolate).

    PubMed

    Antiabong, John F; Ball, Andrew S; Brown, Melissa H

    2015-05-25

    Fusobacterium necrophorum is a Gram-negative obligate anaerobe associated with several diseases in humans and animals. Despite its increasing clinical significance, there is little or no data on the relationship between its metabolism and virulence. Previous studies have shown that bacteria grown under iron-limitation express immunogenic antigens similar to those generated in vivo. Thus, this paper describes the relationship between F. necrophorum subsp. necrophorum (Fnn) metabolism and the expression of the encoded putative virulence factors under iron-restricted conditions. At the midlog phase, iron limitation reduced Fnn growth but the cell density was dependent on the size of the inoculum. Preferential utilization of glucose-1-phosphate, d-mannitol and l-phenylalanine; production of 2-hydroxycaproic acid and termination of dimethyl sulphide production were major Fnn response-factors to iron limitation. Ultimately, iron restriction resulted in an increased ability of Fnn to metabolize diverse carbon sources and in the expression of stress-specific virulence factors. Iron starvation in low Fnn cell density was associated with the up-regulation of haemagglutinin (HA) and leukotoxin (lktA) genes (2.49 and 3.72 fold change respectively). However, Fnn encoded Haemolysin (Hly), yebN homologue (febN) and tonB homologue, were down-regulated (0.15, 0.79 and 0.33, fold changes respectively). Interestingly, cell density appeared to play a regulatory role in the final bacteria cell biomass, induction of a metabolic gene expression and the expression pattern virulence factors in Fnn suggesting the role of a cell density-associated regulatory factor. This report suggest that future studies on differential expression of bacterial genes under altered environmental condition(s) should consider testing the effect of cell concentrations as this is often neglected in such studies. In conclusion, iron restriction induces preferential utilization of carbon sources and altered

  18. Effects of dietary manganese and iron on manganese and iron metabolism during infancy

    SciTech Connect

    Kiehl, H.; Loennerdal, B. )

    1991-03-15

    To derive a better understanding of the metabolism of Mn during infancy, infant formulas with different levels of Mn and Fe were labeled with {sup 54}Mn and {sup 59}Fe and administered orally to suckling rats: control low-Fe formula; control with 100-times Mn; and control with 100-times Fe. Another group received 200 {mu}g MnCl{sub 2} daily during infancy. 12 hr post-dosing, the pattern of {sup 54}Mn distribution in the tissues paralleled that of {sup 59}Fe. An excess of either mineral decreased overall retention but led to higher recoveries of both elements in the proximal intestine and liver. Conversely, these recoveries in pups given Mn from birth were lower than in controls. Analysis of the cytosolic fractions from intestine and liver using FPLC gel filtration demonstrated the impact of the mineral loads on protein profiles. In all cases except the high-Mn dose, dietary manipulations resulted in greater relative levels of a high molecular weight protein with MW similar to ferritin. The high-Mn formula seemed to induce in the hepatocyte a lower MW protein with which most of the {sup 54}Mn and {sup 59}Fe was associated. These results suggest a possible role of Mn as a regulator in the synthesis of cytosolic proteins of the enterocyte and hepatocyte in infants.

  19. Insights into the pathophysiology of iron metabolism in Pythium insidiosum infections.

    PubMed

    Zanette, R A; Bitencourt, P E R; Alves, S H; Fighera, R A; Flores, M M; Wolkmer, P; Hecktheuer, P A; Thomas, L R; Pereira, P L; Loreto, E S; Santurio, J M

    2013-03-23

    Pythium insidiosum causes life-threatening disease in mammals. Animals with pythiosis usually develop anemia, and most human patients are reported to have thalassemia and the major consequence of thalassemia, iron overload. Therefore, this study evaluated the iron metabolism in rabbits experimentally infected with P. insidiosum. Ten infected rabbits were divided into two groups: one groups received a placebo, and the other was treated with immunotherapy. Five rabbits were used as negative controls. The hematological and biochemical parameters, including the iron profile, were evaluated. Microcytic hypochromic anemia was observed in the infected animals, and this condition was more accentuated in the untreated group. The serum iron level was decreased, whereas the transferrin level was increased, resulting in low saturation. The level of stainable iron in hepatocytes was markedly decreased in the untreated group. A high correlation was observed between the total iron binding capacity and the lesion size, and this correlation likely confirms the affinity of P. insidiosum for iron. The data from this study corroborate the previous implications of iron in the pathogenesis of pythiosis in humans and animals. PMID:23182911

  20. Measurement of Microbially Induced Transformation of Magnetic Iron Minerals in Soils Allows Localization of Hydrocarbon Contamination

    NASA Astrophysics Data System (ADS)

    Kappler, A.; Porsch, K.; Rijal, M.; Appel, E.

    2007-12-01

    Soil contamination by crude oil and other hydrocarbons represents a severe environmental problem, but often the location and extent of contamination is not known. Hydrocarbons, or their degradation products, can stimulate iron-metabolizing microorganisms, leading to the formation or dissolution of (magnetic) iron minerals and an associated change of soil magnetic properties. Therefore, the screening of soil magnetic properties has the potential to serve as an efficient and inexpensive tool to localize such contaminations. In order to identify the influence of different biogeochemical factors on the microbially influenced changes of magnetic iron minerals after hydrocarbon contamination, oil spills were simulated in laboratory batch experiments. The parameters tested in these experiments included soils with different bedrocks, type and amount of added hydrocarbon, and microbiological parameters (sterile and autochthonous microorganisms). In order to follow the changes of the soil magnetic properties, the magnetic susceptibility of the samples was measured weekly. First results show that changes in the magnetic mineralogy are caused by microbial activity, as sterile samples showed no changes. In the microbially active set-ups, the magnetic susceptibility increased or decreased up to 10% in comparison to the initial magnetic susceptibility within a few weeks. In one iron-rich soil even a decrease of the magnetic susceptibility of ~40% was observed. Although the amount and type of hydrocarbons did not effect the changes in magnetic susceptibility, DGGE fingerprints revealed that they influenced microbial communities. These results show that the magnetic susceptibility changes in the presence of hydrocarbons and that this change is microbially induced. This suggests that the screening of soil magnetic properties can be applied to localize and assess hydrocarbon contamination. In order to understand the biogeochemical processes better, the change of the iron mineralogy

  1. Microbially Induced Iron Oxidation: What, Where, How

    SciTech Connect

    SCHIERMEYER,ELISA M.; PROVENCIO,PAULA P.; NORTHUP,DIANA E.

    2000-08-15

    From the results of the different bacterial cells seen, it is fairly certain that Gallionella is present because of the bean-shaped cells and twisted stalks found with the TEM. The authors cannot confirm, though, what other iron-oxidizing genera exist in the tubes, since the media was only preferential and not one that isolated a specific genus of bacteria. Based on the environment in which they live and the source of the water, they believe their cultures contain Gallionella, Leptothrix, and possibly Crenothrix and Sphaerotilus. They believe the genus Leptothrix rather than Sphaerotilus exist in the tubes because the water source was fresh, unlike the polluted water in which Sphaerotilus are usually found. The TEM preparations worked well. The cryogenic method rapidly froze the cells in place and allowed them to view their morphology. The FAA method, as stated previously, was the best of the three methods because it gave the best contrast. The gluteraldehyde samples did not come out as well. It is possible that the gluteraldehyde the authors prepared was still too concentrated and did not mix well. Although these bacteria were collected from springs and then cultured in an environment containing a presumably pure iron-bearing metal, it seems the tube already containing Manganese Gradient Medium could be used with a piece of metal containing these bacteria. A small piece of corroding metal could then be inserted into the test tube and cultured to study the bacteria.

  2. Proteomic Analysis Reveals That Iron Availability Alters the Metabolic Status of the Pathogenic Fungus Paracoccidioides brasiliensis

    PubMed Central

    Parente, Ana F. A.; Bailão, Alexandre M.; Borges, Clayton L.; Parente, Juliana A.; Magalhães, Adriana D.; Ricart, Carlos A. O.; Soares, Célia M. A.

    2011-01-01

    Paracoccidioides brasiliensis is a thermodimorphic fungus and the causative agent of paracoccidioidomycosis (PCM). The ability of P. brasiliensis to uptake nutrients is fundamental for growth, but a reduction in the availability of iron and other nutrients is a host defense mechanism many pathogenic fungi must overcome. Thus, fungal mechanisms that scavenge iron from host may contribute to P. brasiliensis virulence. In order to better understand how P. brasiliensis adapts to iron starvation in the host we compared the two-dimensional (2D) gel protein profile of yeast cells during iron starvation to that of iron rich condition. Protein spots were selected for comparative analysis based on the protein staining intensity as determined by image analysis. A total of 1752 protein spots were selected for comparison, and a total of 274 out of the 1752 protein spots were determined to have changed significantly in abundance due to iron depletion. Ninety six of the 274 proteins were grouped into the following functional categories; energy, metabolism, cell rescue, virulence, cell cycle, protein synthesis, protein fate, transcription, cellular communication, and cell fate. A correlation between protein and transcript levels was also discovered using quantitative RT-PCR analysis from RNA obtained from P. brasiliensis under iron restricting conditions and from yeast cells isolated from infected mouse spleens. In addition, western blot analysis and enzyme activity assays validated the differential regulation of proteins identified by 2-D gel analysis. We observed an increase in glycolytic pathway protein regulation while tricarboxylic acid cycle, glyoxylate and methylcitrate cycles, and electron transport chain proteins decreased in abundance under iron limiting conditions. These data suggest a remodeling of P. brasiliensis metabolism by prioritizing iron independent pathways. PMID:21829521

  3. Influence of lead on repetitive behavior and dopamine metabolism in a mouse model of iron overload.

    PubMed

    Chang, JuOae; Kueon, Chojin; Kim, Jonghan

    2014-12-01

    Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that

  4. Oxidation-Induced Degradable Nanogels for Iron Chelation

    PubMed Central

    Liu, Zhi; Wang, Yan; Purro, Max; Xiong, May P.

    2016-01-01

    Iron overload can increase cellular oxidative stress levels due to formation of reactive oxygen species (ROS); untreated, it can be extremely destructive to organs and fatal to patients. Since elevated oxidative stress levels are inherent to the condition in such patients, oxidation-induced degradable nanogels for iron chelation were rationally designed by simultaneously polymerizing oxidation-sensitive host-guest crosslinkers between β-cyclodextrin (β-CD) and ferrocene (Fc) and iron chelating moieties composed of deferoxamine (DFO) into the final gel scaffold in reverse emulsion reaction chambers. UV-Vis absorption and atomic absorption spectroscopy (AAS) was used to verify iron chelating capability of nanogels. These materials can degrade into smaller chelating fragments at rates proportional to the level of oxidative stress present. Conjugating DFO reduces the cytotoxicity of the chelator in the macrophage cells. Importantly, the nanogel can effectively reduce cellular ferritin expression in iron overloaded cells and regulate intracellular iron levels at the same time, which is important for maintaining a homeostatic level of this critical metal in cells. PMID:26868174

  5. Iron Metabolism in Field Hockey Players During an Annual Training Cycle

    PubMed Central

    Podgórski, Tomasz; Kryściak, Jakub; Konarski, Jan; Domaszewska, Katarzyna; Durkalec-Michalski, Krzysztof; Strzelczyk, Ryszard; Pawlak, Maciej

    2015-01-01

    Post-physical training changes in iron metabolism in the human body often occur. To fully describe these processes, fifteen male Polish National Team field hockey players (age 27.7 ± 5.2 years, body mass 72.8 ± 7.6 kg and body height 177.1 ± 5.7 cm) were examined in three phases of an annual training cycle: preparatory (T1), competitive (T2) and transition (T3). To assess aerobic fitness, maximal oxygen uptake (VO2max) was evaluated. Based on the iron concentration, the changes in total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC) and other selected haematological indicators (haemoglobin, erythrocytes, mean corpuscular haemoglobin - MCH) in iron metabolism were estimated. The average values of maximum oxygen uptake increased from 54.97 ± 3.62 ml·kg−1·min−1 in T1 to 59.93 ± 3.55 ml·kg−1·min−1 in T2 (p<0.05) and then decreased to 56.21 ± 4.56 ml·kg−1·min−1 in T3 (p<0.05). No statistically significant changes in the erythrocyte count were noted. The MCH and haemoglobin concentration decreased between T1 and T2. The maximal exercise test caused a significant (p<0.05) increase in the plasma iron concentration during the competition and transition phases. Progressive but non-significant increases in resting iron concentration, TIBC and UIBC in the analysed annual training cycle were noted. To show global changes in iron metabolism in the human body, it is necessary to determine additional variables, i.e. UIBC, TIBC, haemoglobin, MCH or the erythrocyte count. The direction of changes in iron metabolism depends on both the duration and intensity of the physical activity and the fitness level of the subjects. Dietary intake of iron increases the level of this trace element and prevents anaemia associated with training overloads. PMID:26557195

  6. Iron-Induced Changes in the Proteome of Trichomonas vaginalis Hydrogenosomes

    PubMed Central

    Beltrán, Neritza Campo; Horváthová, Lenka; Jedelský, Petr L.; Šedinová, Miroslava; Rada, Petr; Marcinčiková, Michaela; Hrdý, Ivan; Tachezy, Jan

    2013-01-01

    Iron plays a crucial role in metabolism as a key component of catalytic and redox cofactors, such as heme or iron-sulfur clusters in enzymes and electron-transporting or regulatory proteins. Limitation of iron availability by the host is also one of the mechanisms involved in immunity. Pathogens must regulate their protein expression according to the iron concentration in their environment and optimize their metabolic pathways in cases of limitation through the availability of respective cofactors. Trichomonas vaginalis, a sexually transmitted pathogen of humans, requires high iron levels for optimal growth. It is an anaerobe that possesses hydrogenosomes, mitochondrion-related organelles that harbor pathways of energy metabolism and iron-sulfur cluster assembly. We analyzed the proteomes of hydrogenosomes obtained from cells cultivated under iron-rich and iron-deficient conditions employing two-dimensional peptide separation combining IEF and nano-HPLC with quantitative MALDI-MS/MS. We identified 179 proteins, of which 58 were differentially expressed. Iron deficiency led to the upregulation of proteins involved in iron-sulfur cluster assembly and the downregulation of enzymes involved in carbohydrate metabolism. Interestingly, iron affected the expression of only some of multiple protein paralogues, whereas the expression of others was iron independent. This finding indicates a stringent regulation of differentially expressed multiple gene copies in response to changes in the availability of exogenous iron. PMID:23741475

  7. Iron-induced reactive oxygen species mediate transporter DMT1 endocytosis and iron uptake in intestinal epithelial cells.

    PubMed

    Esparza, Andrés; Gerdtzen, Ziomara P; Olivera-Nappa, Alvaro; Salgado, J Cristian; Núñez, Marco T

    2015-10-15

    Recent evidence shows that iron induces the endocytosis of the iron transporter dimetal transporter 1 (DMT1) during intestinal absorption. We, and others, have proposed that iron-induced DMT1 internalization underlies the mucosal block phenomena, a regulatory response that downregulates intestinal iron uptake after a large oral dose of iron. In this work, we investigated the participation of reactive oxygen species (ROS) in the establishment of this response. By means of selective surface protein biotinylation of polarized Caco-2 cells, we determined the kinetics of DMT1 internalization from the apical membrane after an iron challenge. The initial decrease in DMT1 levels in the apical membrane induced by iron was followed at later times by increased levels of DMT1. Addition of Fe(2+), but not of Cd(2+), Zn(2+), Cu(2+), or Cu(1+), induced the production of intracellular ROS, as detected by 2',7'-dichlorofluorescein (DCF) fluorescence. Preincubation with the antioxidant N-acetyl-l-cysteine (NAC) resulted in increased DMT1 at the apical membrane before and after addition of iron. Similarly, preincubation with the hydroxyl radical scavenger dimethyl sulfoxide (DMSO) resulted in the enhanced presence of DMT1 at the apical membrane. The decrease of DMT1 levels at the apical membrane induced by iron was associated with decreased iron uptake rates. A kinetic mathematical model based on operational rate constants of DMT1 endocytosis and exocytosis is proposed. The model qualitatively captures the experimental observations and accurately describes the effect of iron, NAC, and DMSO on the apical distribution of DMT1. Taken together, our data suggest that iron uptake induces the production of ROS, which modify DMT1 endocytic cycling, thus changing the iron transport activity at the apical membrane.

  8. Metabolomic analysis of cerebrospinal fluid indicates iron deficiency compromises cerebral energy metabolism in the infant monkey.

    PubMed

    Rao, Raghavendra; Ennis, Kathleen; Oz, Gulin; Lubach, Gabriele R; Georgieff, Michael K; Coe, Christopher L

    2013-03-01

    Iron deficiency anemia affects many pregnant women and young infants worldwide. The health impact is significant, given iron's known role in many body functions, including oxidative and lipid metabolism, protein synthesis and brain neurochemistry. The following research determined if (1)H NMR spectroscopy-based metabolomic analysis of cerebrospinal fluid (CSF) could detect the adverse influence of early life iron deficiency on the central nervous system. Using a controlled dietary model in 43 infant primates, distinct differences were found in spectra acquired at 600 MHz from the CSF of anemic monkeys. Three metabolite ratios, citrate/pyruvate, citrate/lactate and pyruvate/glutamine ratios, differed significantly in the iron deficient infant and then normalized following the consumption of dietary iron and improvement of clinical indices of anemia in the heme compartment. This distinctive metabolomic profile associated with anemia in the young infant indicates that CSF can be employed to track the neurological effects of iron deficiency and benefits of iron supplementation.

  9. A Global Investigation of the Bacillus subtilis Iron-Sparing Response Identifies Major Changes in Metabolism

    PubMed Central

    Smaldone, Gregory T.; Revelles, Olga; Gaballa, Ahmed; Sauer, Uwe; Antelmann, Haike

    2012-01-01

    The Bacillus subtilis ferric uptake regulator (Fur) protein is the major sensor of cellular iron status. When iron is limiting for growth, derepression of the Fur regulon increases the cellular capacity for iron uptake and mobilizes an iron-sparing response mediated in large part by a small noncoding RNA named FsrA. FsrA functions, in collaboration with three small basic proteins (FbpABC), to repress many “low-priority” iron-containing enzymes. We have used transcriptome analyses to gain insights into the scope of the iron-sparing response and to define subsets of genes dependent for their repression on FsrA, FbpAB, and/or FbpC. Enzymes of the tricarboxylic acid (TCA) cycle, including aconitase and succinate dehydrogenase (SDH), are major targets of FsrA-mediated repression, and as a consequence, flux through this pathway is significantly decreased in a fur mutant. FsrA also represses the DctP dicarboxylate permease and the iron-sulfur-containing enzyme glutamate synthase (GltAB), which serves as a central link between carbon and nitrogen metabolism. Allele-specific suppression analysis was used to document a direct RNA-RNA interaction between the FsrA small RNA (sRNA) and the gltAB leader region. We further demonstrated that distinct regions of FsrA are required for the translational repression of the GltAB and SDH enzyme complexes. PMID:22389480

  10. The Thermodynamics and Kinetics of Iron Redox Metabolism in Hot Spring Ecosystems

    NASA Astrophysics Data System (ADS)

    St Clair, B. E.; Shock, E.

    2012-12-01

    The oxidation of ferrous iron and the reduction of ferric minerals are widespread sources of metabolic energy for microorganisms in hot spring ecosystems. How these energy sources are used can be determined by combining thermodynamic calculations with kinetic experiments. By measuring concentrations of ferrous iron, total iron, pH, dissolved hydrogen and oxygen, as well as temperature and many other parameters in hot springs at Yellowstone National Park, we can calculate chemical affinities of iron redox reactions, which reveal the maximum amount of energy an organism can derive from the catalysis of a given reaction. Iron redox reactions typically involve protons, and energy yields are greatly affected by pH. The heterotrophic reduction of ferric minerals typically consumes a large stoichiometric number of protons compared to the other components. For example, the reduction of hematite (Fe2O3), to ferrous ions with glucose requires 48 moles of protons per mole of glucose oxidized. Calculations indicate this proton requirement increases the energy yield with decreasing pH. The opposite trend is observed for iron oxidation reactions. The autotrophic oxidation of ferrous iron to hematite releases four protons per mole of hematite formed. As a consequence, the energy yield from this reaction decreases with decreasing pH. How effectively energy sources are tapped depends on the efficiencies of microbial metabolism compared with the rates of abiotic mechanisms for the same redox reactions. Experiments were performed across the pH spectrum on isolated sediments incubated in situ and assayed for biological oxidation and reduction by monitoring changing concentrations of Fe2+. In hot springs with pH values <2, particularly those with large gas flows, abiological reduction is rapid. Biological reduction, nevertheless, occasionally proceeded faster than the abiological rate. The quick abiological reduction rate, combined with the high solubility of ferrous iron, leads to

  11. Using skin to assess iron accumulation in human metabolic disorders

    NASA Astrophysics Data System (ADS)

    Guinote, I.; Fleming, R.; Silva, R.; Filipe, P.; Silva, J. N.; Veríssimo, A.; Napoleão, P.; Alves, L. C.; Pinheiro, T.

    2006-08-01

    The distribution of Fe in skin was assessed to monitor body Fe status in human hereditary hemochromatosis. The paper reports on data from nine patients with hemochromatosis that were studied along the therapeutic programme. Systemic evaluation of Fe metabolism was carried out by measuring with PIXE technique the Fe concentration in plasma and blood cells, and by determining with biochemical methods the indicators of Fe transport in serum (ferritin and transferrin). The Fe distribution and concentration in skin was assessed by nuclear microscopy and Fe deposits in liver estimated through nuclear magnetic resonance. Elevated Fe concentrations in skin were related to increased plasma Fe (p < 0.004), serum ferritin content (p < 0.01) and Fe deposits in liver (p < 0.004). The relationship of Fe deposits in organs and metabolism markers may help to better understand Fe pools mobilisation and to establish the quality of skin as a marker for the disease progression and therapy efficacy.

  12. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells.

    PubMed

    Richardson, D R; Ponka, P

    1997-03-14

    Iron uptake by mammalian cells is mediated by the binding of serum Tf to the TfR. Transferrin is then internalized within an endocytotic vesicle by receptor-mediated endocytosis and the Fe released from the protein by a decrease in endosomal pH. Apart from this process, several cell types also have other efficient mechanisms of Fe uptake from Tf that includes a process consistent with non-specific adsorptive pinocytosis and a mechanism that is stimulated by small-Mr Fe complexes. This latter mechanism appears to be initiated by hydroxyl radicals generated by the Fe complexes, and may play a role in Fe overload disease where a significant amount of serum non-Tf-bound Fe exists. Apart from Tf-bound Fe uptake, mammalian cells also possess a number of mechanisms that can transport Fe from small-Mr Fe complexes into the cell. In fact, recent studies have demonstrated that the membrane-bound Tf homologue, MTf, can bind and internalize Fe from 59Fe-citrate. However, the significance of this Fe uptake process and its pathophysiological relevance remain uncertain. Iron derived from Tf or small-Mr complexes is probably transported into mammalian cells in the Fe(II) state. Once Fe passes through the membrane, it then becomes part of the poorly characterized intracellular labile Fe pool. Iron in the labile Fe pool that is not used for immediate requirements is stored within the Fe-storage protein, ferritin. Cellular Fe uptake and storage are coordinately regulated through a feedback control mechanism mediated at the post-transcriptional level by cytoplasmic factors known as IRP1 and IRP2. These proteins bind to stem-loop structures known as IREs on the 3 UTR of the TfR mRNA and 5 UTR of ferritin and erythroid delta-aminolevulinic acid synthase mRNAs. Interestingly, recent work has suggested that the short-lived messenger molecule, NO (or its by-product, peroxynitrite), can affect cellular Fe metabolism via its interaction with IRP1. Moreover, NO can decrease Fe uptake from Tf

  13. Iron metabolism and oxidative profile of dogs naturally infected by Ehrlichia canis: Acute and subclinical disease.

    PubMed

    Bottari, Nathieli B; Crivellenti, Leandro Z; Borin-Crivellenti, Sofia; Oliveira, Jéssica R; Coelho, Stefanie B; Contin, Catarina M; Tatsch, Etiane; Moresco, Rafael N; Santana, Aureo E; Tonin, Alexandre A; Tinucci-Costa, Mirela; Da Silva, Aleksandro S

    2016-03-01

    The aim of this study was to evaluate the oxidant profile and iron metabolism in serum of dogs infected by Ehrlichia canis. Banked sera samples of dogs were divided into two groups: negative control (n = 17) and infected by E. canis on acute (n = 24), and subclinical (n = 18) phases of the disease. The eritrogram, leucogram, and platelet counts were evaluate as well as iron, ferritin, and transferrin levels, latent iron binding capacity (LIBC), and transferrin saturation index (TSI) concentration. In addition, the advanced oxidation protein products (AOPP) and ferric reducing ability of plasma (FRAP) in sera were also analyzed. Blood samples were examined for the presence of E. canis by PCR techniques. History and clinical signals were recorded for each dog. During the acute phase of the disease, infected animals showed thrombocytopenia and anemia when compared to healthy animals (P < 0.05) as a consequence of lower iron levels. Ferritin and transferrin levels were higher in both phases (acute and subclinical) of the disease. The AOPP and FRAP levels increased in infected animals on the acute phase; however, the opposite occurred in the subclinical phase. We concluded that dogs naturally infected by E. canis showed changes in the iron metabolism and developed an oxidant status in consequence of disease pathophysiology. PMID:26724737

  14. Aggregatibacter actinomycetemcomitans QseBC is activated by catecholamines and iron and regulates genes encoding proteins associated with anaerobic respiration and metabolism.

    PubMed

    Weigel, W A; Demuth, D R; Torres-Escobar, A; Juárez-Rodríguez, M D

    2015-10-01

    Aggregatibacter actinomycetemcomitans QseBC regulates its own expression and is essential for biofilm growth and virulence. However, the signal that activates the QseC sensor has not been identified and the qseBC regulon has not been defined. In this study, we show that QseC is activated by catecholamine hormones and iron but not by either component alone. Activation of QseC requires an EYRDD motif in the periplasmic domain of the sensor and site-specific mutations in EYRDD or the deletion of the periplasmic domain inhibits catecholamine/iron-dependent induction of the ygiW-qseBC operon. Catecholamine/iron-dependent induction of transcription also requires interaction of the QseB response regulator with its binding site in the ygiW-qseBC promoter. Whole genome microarrays were used to compare gene expression profiles of A. actinomycetemcomitans grown in a chemically defined medium with and without catecholamine and iron supplementation. Approximately 11.5% of the A. actinomycetemcomitans genome was differentially expressed by at least two-fold upon exposure to catecholamines and iron. The expression of ferritin was strongly induced, suggesting that intracellular iron storage capacity is increased upon QseBC activation. Consistent with this, genes encoding iron binding and transport proteins were down-regulated by QseBC. Strikingly, 57% of the QseBC up-regulated genes (56/99) encode proteins associated with anaerobic metabolism and respiration. Most of these up-regulated genes were recently reported to be induced during in vivo growth of A. actinomycetemcomitans. These results suggest that detection of catecholamines and iron by QseBC may alter the cellular metabolism of A. actinomycetemcomitans for increased fitness and growth in an anaerobic host environment.

  15. Aggregatibacter actinomycetemcomitans QseBC is activated by catecholamines and iron and regulates genes encoding proteins associated with anaerobic respiration and metabolism

    PubMed Central

    Weigel, WA; Demuth, DR; Torres-Escobar, A; Juárez-Rodríguez, MD

    2015-01-01

    Aggregatibacter actinomycetemcomitans QseBC regulates its own expression and is essential for biofilm growth and virulence. However, the signal that activates the QseC sensor has not been identified and the qseBC regulon has not been defined. In this study, we show that QseC is activated by catecholamine hormones and iron but not by either component alone. Activation of QseC requires an EYRDD motif in the periplasmic domain of the sensor and site-specific mutations in EYRDD or the deletion of the periplasmic domain inhibits catecholamine/iron-dependent induction of the ygiW-qseBC operon. Catecholamine/iron-dependent induction of transcription also requires interaction of the QseB response regulator with its binding site in the ygiW-qseBC promoter. Whole genome microarrays were used to compare gene expression profiles of A. actinomycetemcomitans grown in a chemically defined medium with and without catecholamine and iron supplementation. Approximately 11.5% of the A. actinomycetemcomitans genome was differentially expressed by at least two-fold upon exposure to catecholamines and iron. The expression of ferritin was strongly induced, suggesting that intracellular iron storage capacity is increased upon QseBC activation. Consistent with this, genes encoding iron binding and transport proteins were down-regulated by QseBC. Strikingly, 57% of the QseBC up-regulated genes (56/99) encode proteins associated with anaerobic metabolism and respiration. Most of these up-regulated genes were recently reported to be induced during in vivo growth of A. actinomycetemcomitans. These results suggest that detection of catecholamines and iron by QseBC may alter the cellular metabolism of A. actinomycetemcomitans for increased fitness and growth in an anaerobic host environment. PMID:25923132

  16. Mutational Analysis of a Role for Salicylic Acid in Iron Metabolism of Mycobacterium smegmatis

    PubMed Central

    Adilakshmi, Tadepalli; Ayling, Peter D.; Ratledge, Colin

    2000-01-01

    The role of salicylic acid in iron metabolism was examined in two wild-type strains (mc2155 and NCIMB 8548) and three mutant strains (mc21292 [lacking exochelin], SM3 [lacking iron-dependent repressor protein IdeR] and S99 [a salicylate-requiring auxotroph derived in this study]) of Mycobacterium smegmatis. Synthesis of salicylate in SM3 was derepressed even in the presence of iron, as was synthesis of the siderophores exochelin, mycobactin, and carboxymycobactin. S99 was dependent on salicylate for growth and failed to grow with the three ferrisiderophores, suggesting that salicylate fulfills an additional function(s) other than being a precursor of mycobactin and carboxymycobactin. Salicylic acid at 100 μg/ml repressed the formation of a 29-kDa cell envelope protein (putative exochelin receptor protein) in S99 grown both iron deficiently and iron sufficiently. In contrast, synthesis of this protein was affected only under iron-limited conditions in the parent strain, mc2155, and remained unaltered in SM3, suggesting an interaction between the IdeR protein and salicylate. Thus, salicylate may also function as a signal molecule for recognition of cellular iron status. Growth of all strains and mutants with p-aminosalicylate (PAS) at 100 μg/ml increased salicylate accumulation between three- and eightfold under both iron-limited and iron-sufficient growth conditions and decreased mycobactin accumulation by 40 to 80% but increased carboxymycobactin accumulation by 50 to 55%. Thus, although PAS inhibited salicylate conversion to mycobactin, presumptively by blocking salicylate AMP kinase, PAS also interferes with the additional functions of salicylate, as its effect was heightened in S99 when the salicylate concentration was minimal. PMID:10629169

  17. Insights into the iron and sulfur energetic metabolism of Acidithiobacillus ferrooxidans by microarray transcriptome profiling

    SciTech Connect

    R. Quatrini; C. Appia-Ayme; Y. Denis; J. Ratouchniak; F. Veloso; J. Valdes; C. Lefimil; S. Silver; F. Roberto; O. Orellana; F. Denizot; E. Jedlicki; D. Holmes; V. Bonnefoy

    2006-09-01

    Acidithiobacillus ferrooxidans is a well known acidophilic, chemolithoautotrophic, Gram negative, bacterium involved in bioleaching and acid mine drainage. In aerobic conditions, it gains energy mainly from the oxidation of ferrous iron and/or reduced sulfur compounds present in ores. After initial oxidation of the substrate, electrons from ferrous iron or sulfur enter respiratory chains and are transported through several redox proteins to oxygen. However, the oxidation of ferrous iron and reduced sulfur compounds has also to provide electrons for the reduction of NAD(P) that is subsequently required for many metabolic processes including CO2 fixation. To help to unravel the enzymatic pathways and the electron transfer chains involved in these processes, a genome-wide microarray transcript profiling analysis was carried out. Oligonucleotides corresponding to approximately 3000 genes of the A. ferrooxidans type strain ATCC23270 were spotted onto glass-slides and hybridized with cDNA retrotranscribed from RNA extracted from ferrous iron and sulfur grown cells. The genes which are preferentially transcribed in ferrous iron conditions and those preferentially transcribed in sulfur conditions were analyzed. The expression of a substantial number of these genes has been validated by real-time PCR, Northern blot hybridization and/or immunodetection analysis. Our results support and extend certain models of iron and sulfur oxidation and highlight previous observations regarding the possible presence of alternate electron pathways. Our findings also suggest ways in which iron and sulfur oxidation may be co-ordinately regulated. An accompanying paper (Appia-Ayme et al.) describes results pertaining to other metabolic functions.

  18. Chemical changes induced by ultrasound in iron

    NASA Astrophysics Data System (ADS)

    Albertini, G.; Calbucci, V.; Cardone, F.; Petrucci, A.; Ridolfi, F.

    2014-03-01

    The focus of this work is a careful chemical investigation of structural damage produced by the exposure of an iron bar to pressure waves generated using an ultrasound machine (called the R-1-S reactor). In addition to the emission of neutron bursts, the ultrasound treatment caused the appearance of zones of macroscopic damage (˜1 mm in size) on the exterior of the bar. Reflected-light optical and environmental scanning electron microscopy (ESEM) has shown that these external damage zones are characterized by microcraters and are covered by a thin layer of cracked amorphous material. Under back scattered electron (BSE) observation, this material shows a lower brightness than the intact ferrite surface. In addition, a zone with a high density of deformed cavities (˜1300 per mm2) with irregular walls and a maximum size of 10 μm was found inside the bar. These deformed microcavities are partially filled with a material composed of a chaotic assemblage of submicron-sized (most likely amorphous) particles. A careful compositional investigation of the chaotic material inside the microcavities using the semi-quantitative data obtained with the ESEM X-ray Energy Dispersive System (EDS) has shown that it is primarily composed of carbon, manganese and chromium. These elements are also found in lower amounts within the intact ferrite matrix. In contrast, the damaged surface surrounding the craters is characterized by elements not found in the ferrite at all (i.e., O, Cl, K, Cu); elements the presence of which cannot be attributed to the occurrence of non-metallic inclusions or to contamination during fabrication. These results are also difficult to explain using the generally accepted laws of physics; however, they do appear to agree with a recent theory predicting the deformation of the local spacetime and the violation of the Local Lorentz Invariance. Such a violation should occur following the collapse of micron-sized discontinuities internal to the materials

  19. Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas.

    PubMed

    Fack, Fred; Espedal, Heidi; Keunen, Olivier; Golebiewska, Anna; Obad, Nina; Harter, Patrick N; Mittelbronn, Michel; Bähr, Oliver; Weyerbrock, Astrid; Stuhr, Linda; Miletic, Hrvoje; Sakariassen, Per Ø; Stieber, Daniel; Rygh, Cecilie B; Lund-Johansen, Morten; Zheng, Liang; Gottlieb, Eyal; Niclou, Simone P; Bjerkvig, Rolf

    2015-01-01

    Anti-angiogenic therapy in glioblastoma (GBM) has unfortunately not led to the anticipated improvement in patient prognosis. We here describe how human GBM adapts to bevacizumab treatment at the metabolic level. By performing (13)C6-glucose metabolic flux analysis, we show for the first time that the tumors undergo metabolic re-programming toward anaerobic metabolism, thereby uncoupling glycolysis from oxidative phosphorylation. Following treatment, an increased influx of (13)C6-glucose was observed into the tumors, concomitant to increased lactate levels and a reduction of metabolites associated with the tricarboxylic acid cycle. This was confirmed by increased expression of glycolytic enzymes including pyruvate dehydrogenase kinase in the treated tumors. Interestingly, L-glutamine levels were also reduced. These results were further confirmed by the assessment of in vivo metabolic data obtained by magnetic resonance spectroscopy and positron emission tomography. Moreover, bevacizumab led to a depletion in glutathione levels indicating that the treatment caused oxidative stress in the tumors. Confirming the metabolic flux results, immunohistochemical analysis showed an up-regulation of lactate dehydrogenase in the bevacizumab-treated tumor core as well as in single tumor cells infiltrating the brain, which may explain the increased invasion observed after bevacizumab treatment. These observations were further validated in a panel of eight human GBM patients in which paired biopsy samples were obtained before and after bevacizumab treatment. Importantly, we show that the GBM adaptation to bevacizumab therapy is not mediated by clonal selection mechanisms, but represents an adaptive response to therapy.

  20. Cytochromes and iron sulfur proteins in sulfur metabolism of phototrophic bacteria

    NASA Technical Reports Server (NTRS)

    Fischer, U.

    1985-01-01

    Dissimilatory sulfur metabolism in phototrophic sulfur bacteria provides the bacteria with electrons for photosynthetic electron transport chain and, with energy. Assimilatory sulfate reduction is necessary for the biosynthesis of sulfur-containing cell components. Sulfide, thiosulfate, and elemental sulfur are the sulfur compounds most commonly used by phototrophic bacteria as electron donors for anoxygenic photosynthesis. Cytochromes or other electron transfer proteins, like high-potential-iron-sulfur protein (HIPIP) function as electron acceptors or donors for most enzymatic steps during the oxidation pathways of sulfide or thiosulfate. Yet, heme- or siroheme-containing proteins themselves undergo enzymatic activities in sulfur metabolism. Sirohemes comprise a porphyrin-like prosthetic group of sulfate reductase. eenzymatic reactions involve electron transfer. Electron donors or acceptors are necessary for each reaction. Cytochromes and iron sulfur problems, are able to transfer electrons.

  1. Leu1 plays a role in iron metabolism and is required for virulence in Cryptococcus neoformans

    PubMed Central

    Do, Eunsoo; Hu, Guanggan; Caza, Mélissa; Oliveira, Debora; Kronstad, James W.; Jung, Won Hee

    2015-01-01

    Amino acid biosynthetic pathways that are absent in mammals are considered an attractive target for antifungal therapy. Leucine biosynthesis is one such target pathway, consisting of a five-step conversion process starting from the valine precursor 2-keto-isovalerate. Isopropylmalate dehydrogenase (Leu1) is an Fe-S cluster protein that is required for leucine biosynthesis in the model fungus Saccharomyces cerevisiae. The human pathogenic fungus Cryptococcus neoformans possesses an ortholog of S. cerevisiae Leu1, and our previous transcriptome data showed that the expression of LEU1 is regulated by iron availability. In this study, we characterized the role of Leu1 in iron homeostasis and the virulence of C. neoformans. We found that deletion of LEU1 caused leucine auxotrophy and that Leu1 may play a role in the mitochondrial-cytoplasmic Fe-S cluster balance. Whereas cytoplasmic Fe-S protein levels were not affected, mitochondrial Fe-S proteins were up- regulated in the leu1 mutant, suggesting that Leu1 mainly influences mitochondrial iron metabolism. The leu1 mutant also displayed increased sensitivity to oxidative stress and cell wall/membrane disrupting agents, which may have been caused by mitochondrial dysfunction. Furthermore, the leu1 mutant was deficient in capsule formation and showed attenuated virulence in a mouse inhalation model of cryptococcosis. Overall, our results indicate that Leu1 plays a role in iron metabolism and is required for virulence in C. neoformans. PMID:25554701

  2. Vitamin D, Iron Metabolism, and Diet in Alpinists During a 2-Week High-Altitude Climb.

    PubMed

    Kasprzak, Zbigniew; Śliwicka, Ewa; Hennig, Karol; Pilaczyńska-Szcześniak, Łucja; Huta-Osiecka, Anna; Nowak, Alicja

    2015-09-01

    A defensive mechanism against hypobaric hypoxia at high altitude is erythropoesis. Some authors point to the contribution of vitamin D to the regulation of this process. The aim of the present study was to assess the 25-hydroxycholecalciferol (25(OH)D) level and its associations with iron metabolic and inflammatory indices in participants of a 2-week mountaineering expedition. The study sample included 9 alpinists practicing recreational mountain climbing. Every 2 or 3 days they set up a different base between 3200 and 3616 m with the intention of climbing 4000 m peaks in the Mont Blanc massif. Before their departure for the mountains and 2 days after returning to the sea level anthropometric parameters, hematological parameters, serum levels of 25(OH)D and iron metabolic indices were measured in all the participants. The composition of the participants' diet was also evaluated. The comparative analysis showed a significant decrease in body mass, BMI values, total iron, and 25(OH)D concentrations (p<0.05). Also significant increases in unsaturated iron-binding capacity, hematocrit, and C-reactive protein concentrations (p<0.05) were found. It can be concluded that the 2-week climbing expedition contributed to the reduction of 25(OH)D levels and these changes were associated with modulation of immune processes. Moreover, the climbers' diet requires some serious modifications. PMID:26125641

  3. Zebrafish in the sea of mineral (iron, zinc, and copper) metabolism

    PubMed Central

    Zhao, Lu; Xia, Zhidan; Wang, Fudi

    2014-01-01

    Iron, copper, zinc, and eight other minerals are classified as essential trace elements because they present in minute in vivo quantities and are essential for life. Because either excess or insufficient levels of trace elements can be detrimental to life (causing human diseases such as iron-deficiency anemia, hemochromatosis, Menkes syndrome and Wilson's disease), the endogenous levels of trace minerals must be tightly regulated. Many studies have demonstrated the existence of systems that maintain trace element homeostasis, and these systems are highly conserved in multiple species ranging from yeast to mice. As a model for studying trace mineral metabolism, the zebrafish is indispensable to researchers. Several large-scale mutagenesis screens have been performed in zebrafish, and these screens led to the identification of a series of metal transporters and the generation of several mutagenesis lines, providing an in-depth functional analysis at the system level. Moreover, because of their developmental advantages, zebrafish have also been used in mineral metabolism-related chemical screens and toxicology studies. Here, we systematically review the major findings of trace element homeostasis studies using the zebrafish model, with a focus on iron, zinc, copper, selenium, manganese, and iodine. We also provide a homology analysis of trace mineral transporters in fish, mice and humans. Finally, we discuss the evidence that zebrafish is an ideal experimental tool for uncovering novel mechanisms of trace mineral metabolism and for improving approaches to treat mineral imbalance-related diseases. PMID:24639652

  4. Iron

    MedlinePlus

    ... cereals and breads. White beans, lentils, spinach, kidney beans, and peas. Nuts and some dried fruits, such as raisins. Iron in food comes in two forms: heme iron and nonheme iron. Nonheme iron is found in plant foods and iron-fortified food products. Meat, seafood, ...

  5. The role of iron metabolism as a mediator of macrophage inflammation and lipid handling in atherosclerosis.

    PubMed

    Habib, Anwer; Finn, Aloke V

    2014-01-01

    Iron is an essential mineral needed for normal physiologic processes. While its function in oxygen transport and other important physiologic processes is well known, less is understood about its role in inflammatory diseases such as atherosclerosis. Existing paradigms suggest iron as a driver of atherosclerosis through its actions as a pro-oxidant capable of causing lipid oxidation and tissue damage. Recently we and others have identified hemoglobin (Hb) derived iron as an important factor in determining macrophage differentiation and function in areas of intraplaque hemorrhage within human atherosclerosis. Hb associated macrophages, M(Hb), are distinct from traditional macrophage foam cells because they do not contain large amounts of lipid or inflammatory cytokines, are characterized by high levels of expression of mannose receptor (CD206) and CD163 in addition to producing anti-inflammatory cytokines such as IL-10. Despite the well-known role of iron as an catalyst capable of producing lipid peroxidation through generation of reactive oxygen species (ROS) such as hydroxyl radical, we and others have shown that macrophages in areas of intraplaque hemorrhage demonstrate reduced intracellular iron and ROS which triggers production of anti-inflammatory cytokines as well as genes involved in cholesterol efflux. These data suggest that manipulation of macrophage iron itself may be a promising pharmacologic target for atherosclerosis prevention through its effects on macrophage inflammation and lipid metabolism. In this review we will summarize the current understanding of iron as it relates to plaque inflammation and discuss how further exploration of this subject may lead to new therapies for atherosclerosis.

  6. Omeprazole induces altered bile acid metabolism

    PubMed Central

    Shindo, K; Machida, M; Fukumura, M; Koide, K; Yamazaki, R

    1998-01-01

    Background—It has been reported that the acidity of gastric contents could be an important factor in regulating jejunal flora. 
Aims—To investigate the effects of omeprazole induced changes in gastric pH on jejunal flora and bile acid metabolism. 
Methods—Twenty one patients with gastric ulcer and 19 healthy volunteers were studied. Deconjugation of bile acids was detected using a bile acid breath test. Jejunal fluid was aspirated using a double lumen tube with a rubber cover on the tip and deconjugation was examined using thin layer chromatography. Fat malabsorption was detected by a triolein breath test. 
Results—In the bile acid breath test, expired breath samples from all patients and healthy volunteers showed significantly greater 14CO2 specific activity after omeprazole treatment (20 mg/day) than before treatment. Bacterial overgrowth was found in the jejunal fluid and gastric juice of both ulcer patients and healthy volunteers after omeprazole treatment. The following species were identified: Escherichia coli, Candida albicans, enterococcus, Lactobacillus bifidus, Bacteroides vulgatus, B uniformis, Eubacterium lentum, Eu parvum, and Corynebacterium granulosum. All of these species, except E coli and C albicans, deconjugate bile acids. There was a significant correlation between 14CO2 activity and gastric pH, both before and after omeprazole treatment in both groups. The triolein breath test revealed impaired fat absorption in both groups after omeprazole treatment. 
Conclusions—Both patients with gastric ulcer and healthy volunteers exhibited increased deconjugation of bile acids caused by bacterial overgrowth in the jejunum and fat malabsorption after omeprazole treatment. The bacterial overgrowth consisted of both anaerobes and aerobes with deconjugation ability and was probably associated with an omeprazole induced shift to neutral pH in the gastric juice. 

 Keywords: omeprazole; bacterial overgrowth; deconjugation; bile acid breath

  7. IRON IN MULTIPLE MYELOMA

    PubMed Central

    VanderWall, Kristina; Daniels-Wells, Tracy R; Penichet, Manuel; Lichtenstein, Alan

    2013-01-01

    Multiple myeloma is a non-curable B cell malignancy in which iron metabolism plays an important role. Patients with this disorder almost universally suffer from a clinically significant anemia, which is often symptomatic, and which is due to impaired iron utilization. Recent studies indicate that the proximal cause of dysregulated iron metabolism and anemia in these patients is cytokine-induced upregulation of hepcidin expression. Malignant myeloma cells are dependent on an increased influx of iron and therapeutic efforts are being made to target this requirement. The studies detailing the characteristics and biochemical abnormalities in iron metabolism causing anemia and the initial attempts to target iron therapeutically are described in this review. PMID:23879589

  8. Iron

    MedlinePlus

    Iron is a mineral that our bodies need for many functions. For example, iron is part of hemoglobin, a protein which carries ... It helps our muscles store and use oxygen. Iron is also part of many other proteins and ...

  9. Presence of acute phase changes in zinc, iron, and copper metabolism in turkey embryos

    SciTech Connect

    Klasing, K.C.; Richards, M.P.; Darcey, S.E.; Laurin, D.E.

    1987-01-01

    Acute phase changes in trace mineral metabolism were examined in turkey embryos. An endotoxin injection resulted in increased concentrations of serum copper and liver zinc and decreased concentrations of serum zinc in embryos incubated either in ovo or ex ovo. Changes in zinc and copper metabolism occurred when endotoxin either was injected intramuscularly, into the amnionic fluid, or administered onto the chorioallantoic membrane. Unlike poults, embryos did not respond to an inflammatory challenge with decreased serum iron concentrations. Acute phase changes in embryo serum zinc and copper as well as liver zinc concentrations were similar to those in poults. Increased liver zinc concentrations were associated with increased zinc in metallothionein (MT). An injection of a crude interleukin 1 preparation into embryos resulted in similar increases in hepatic zinc and MT concentrations as an endotoxin injection, suggesting a role for this cytokine in mediating the acute phase changes in embryonic zinc metabolism.

  10. Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency

    NASA Technical Reports Server (NTRS)

    Mukhopadhyay, C. K.; Mazumder, B.; Fox, P. L.

    2000-01-01

    A role of the copper protein ceruloplasmin (Cp) in iron metabolism is suggested by its ferroxidase activity and by the tissue iron overload in hereditary Cp deficiency patients. In addition, plasma Cp increases markedly in several conditions of anemia, e.g. iron deficiency, hemorrhage, renal failure, sickle cell disease, pregnancy, and inflammation. However, little is known about the cellular and molecular mechanism(s) involved. We have reported that iron chelators increase Cp mRNA expression and protein synthesis in human hepatocarcinoma HepG2 cells. Furthermore, we have shown that the increase in Cp mRNA is due to increased rate of transcription. We here report the results of new studies designed to elucidate the molecular mechanism underlying transcriptional activation of Cp by iron deficiency. The 5'-flanking region of the Cp gene was cloned from a human genomic library. A 4774-base pair segment of the Cp promoter/enhancer driving a luciferase reporter was transfected into HepG2 or Hep3B cells. Iron deficiency or hypoxia increased luciferase activity by 5-10-fold compared with untreated cells. Examination of the sequence showed three pairs of consensus hypoxia-responsive elements (HREs). Deletion and mutation analysis showed that a single HRE was necessary and sufficient for gene activation. The involvement of hypoxia-inducible factor-1 (HIF-1) was shown by gel-shift and supershift experiments that showed HIF-1alpha and HIF-1beta binding to a radiolabeled oligonucleotide containing the Cp promoter HRE. Furthermore, iron deficiency (and hypoxia) did not activate Cp gene expression in Hepa c4 hepatoma cells deficient in HIF-1beta, as shown functionally by the inactivity of a transfected Cp promoter-luciferase construct and by the failure of HIF-1 to bind the Cp HRE in nuclear extracts from these cells. These results are consistent with in vivo findings that iron deficiency increases plasma Cp and provides a molecular mechanism that may help to understand these

  11. Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency.

    PubMed

    Mukhopadhyay, C K; Mazumder, B; Fox, P L

    2000-07-14

    A role of the copper protein ceruloplasmin (Cp) in iron metabolism is suggested by its ferroxidase activity and by the tissue iron overload in hereditary Cp deficiency patients. In addition, plasma Cp increases markedly in several conditions of anemia, e.g. iron deficiency, hemorrhage, renal failure, sickle cell disease, pregnancy, and inflammation. However, little is known about the cellular and molecular mechanism(s) involved. We have reported that iron chelators increase Cp mRNA expression and protein synthesis in human hepatocarcinoma HepG2 cells. Furthermore, we have shown that the increase in Cp mRNA is due to increased rate of transcription. We here report the results of new studies designed to elucidate the molecular mechanism underlying transcriptional activation of Cp by iron deficiency. The 5'-flanking region of the Cp gene was cloned from a human genomic library. A 4774-base pair segment of the Cp promoter/enhancer driving a luciferase reporter was transfected into HepG2 or Hep3B cells. Iron deficiency or hypoxia increased luciferase activity by 5-10-fold compared with untreated cells. Examination of the sequence showed three pairs of consensus hypoxia-responsive elements (HREs). Deletion and mutation analysis showed that a single HRE was necessary and sufficient for gene activation. The involvement of hypoxia-inducible factor-1 (HIF-1) was shown by gel-shift and supershift experiments that showed HIF-1alpha and HIF-1beta binding to a radiolabeled oligonucleotide containing the Cp promoter HRE. Furthermore, iron deficiency (and hypoxia) did not activate Cp gene expression in Hepa c4 hepatoma cells deficient in HIF-1beta, as shown functionally by the inactivity of a transfected Cp promoter-luciferase construct and by the failure of HIF-1 to bind the Cp HRE in nuclear extracts from these cells. These results are consistent with in vivo findings that iron deficiency increases plasma Cp and provides a molecular mechanism that may help to understand these

  12. Microbial Metabolism Shifts Towards an Adverse Profile with Supplementary Iron in the TIM-2 In vitro Model of the Human Colon

    PubMed Central

    Kortman, Guus A. M.; Dutilh, Bas E.; Maathuis, Annet J. H.; Engelke, Udo F.; Boekhorst, Jos; Keegan, Kevin P.; Nielsen, Fiona G. G.; Betley, Jason; Weir, Jacqueline C.; Kingsbury, Zoya; Kluijtmans, Leo A. J.; Swinkels, Dorine W.; Venema, Koen; Tjalsma, Harold

    2016-01-01

    Oral iron administration in African children can increase the risk for infections. However, it remains unclear to what extent supplementary iron affects the intestinal microbiome. We here explored the impact of iron preparations on microbial growth and metabolism in the well-controlled TNO's in vitro model of the large intestine (TIM-2). The model was inoculated with a human microbiota, without supplementary iron, or with 50 or 250 μmol/L ferrous sulfate, 50 or 250 μmol/L ferric citrate, or 50 μmol/L hemin. High resolution responses of the microbiota were examined by 16S rDNA pyrosequencing, microarray analysis, and metagenomic sequencing. The metabolome was assessed by fatty acid quantification, gas chromatography-mass spectrometry (GC-MS), and 1H-NMR spectroscopy. Cultured intestinal epithelial Caco-2 cells were used to assess fecal water toxicity. Microbiome analysis showed, among others, that supplementary iron induced decreased levels of Bifidobacteriaceae and Lactobacillaceae, while it caused higher levels of Roseburia and Prevotella. Metagenomic analyses showed an enrichment of microbial motility-chemotaxis systems, while the metabolome markedly changed from a saccharolytic to a proteolytic profile in response to iron. Branched chain fatty acids and ammonia levels increased significantly, in particular with ferrous sulfate. Importantly, the metabolite-containing effluent from iron-rich conditions showed increased cytotoxicity to Caco-2 cells. Our explorations indicate that in the absence of host influences, iron induces a more hostile environment characterized by a reduction of microbes that are generally beneficial, and increased levels of bacterial metabolites that can impair the barrier function of a cultured intestinal epithelial monolayer. PMID:26779139

  13. Microbial Metabolism Shifts Towards an Adverse Profile with Supplementary Iron in the TIM-2 In vitro Model of the Human Colon

    DOE PAGES

    Kortman, Guus A. M.; Dutilh, Bas E.; Maathuis, Annet J. H.; Engelke, Udo F.; Boekhorst, Jos; Keegan, Kevin P.; Nielsen, Fiona G. G.; Betley, Jason; Weir, Jacqueline C.; Kingsbury, Zoya; et al

    2016-01-06

    Oral iron administration in African children can increase the risk for infections. However, it remains unclear to what extent supplementary iron affects the intestinal microbiome. We here explored the impact of iron preparations on microbial growth and metabolism in the well-controlled TNO's in vitro model of the large intestine (TIM-2). The model was inoculated with a human microbiota, without supplementary iron, or with 50 or 250 μmol/L ferrous sulfate, 50 or 250 μmol/L ferric citrate, or 50 μmol/L hemin. High resolution responses of the microbiota were examined by 16S rDNA pyrosequencing, microarray analysis, and metagenomic sequencing. The metabolome was assessedmore » by fatty acid quantification, gas chromatography-mass spectrometry (GC-MS), and 1H-NMR spectroscopy. Cultured intestinal epithelial Caco-2 cells were used to assess fecal water toxicity. Microbiome analysis showed, among others, that supplementary iron induced decreased levels of Bifidobacteriaceae and Lactobacillaceae, while it caused higher levels of Roseburia and Prevotella. Metagenomic analyses showed an enrichment of microbial motility-chemotaxis systems, while the metabolome markedly changed from a saccharolytic to a proteolytic profile in response to iron. Branched chain fatty acids and ammonia levels increased significantly, in particular with ferrous sulfate. Importantly, the metabolite-containing effluent from iron-rich conditions showed increased cytotoxicity to Caco-2 cells. In conclusion, our explorations indicate that in the absence of host influences, iron induces a more hostile environment characterized by a reduction of microbes that are generally beneficial, and increased levels of bacterial metabolites that can impair the barrier function of a cultured intestinal epithelial monolayer.« less

  14. Mechanisms of sulfur mustard-induced metabolic injury

    SciTech Connect

    Martens, M.E.; Smith, W.J.

    1993-05-13

    Studies on the mechanism of metabolic injury induced by sulfur mustard (2, 2'- dichlorodiethyl sulfide, HD) have demonstrated that exposure of human epidermal keratinocytes in culture to HD induces time- and dose-dependent NAD+ depletion and inhibition of glucose metabolism (Martens, Biochem. Pharmacol., in press). Both occurred relatively early after alkylation, preceding the loss of membrane integrity that is indicative of metabolic cell death. The inhibition of glycolysis induced by HD was only partially correlated with the depletion of NAD+ and, thus, was not simply of changes in the NAD+ level. Rather, HD appeared to induce complex shifts in the pattern of glucose metabolism that paralleled both the timing and degree of injury. In line with these findings, recent experiments have shown that partial protection against HD-induced NAD+ depletion by 1 mM niacinamide did not protect against the inhibition of glycolysis. In preliminary experiments examining the effect of HD-induced metabolic changes on the cellular energy state, dose-dependent depletion of ATP was seen at 24 hours after exposure, but not at 4 or 8 hours. As seen for glucose metabolism, 1 mM niacinamide did not prevent the loss of high-energy intermediate (ATP). We conclude from these studies that relationships among HD exposure, glucose metabolism, and intracellular NAD and ATP are more complex than originally proposed (Papirmeister et al, Fund. Appl. Toxicol. 5:S134, 1985).

  15. The effect of BCG on iron metabolism in the early neonatal period: A controlled trial in Gambian neonates.

    PubMed

    Prentice, Sarah; Jallow, Momodou W; Prentice, Andrew M

    2015-06-12

    Bacillus Calmette-Guerin (BCG) vaccination has been reported to protect neonates from non-tuberculous pathogens, but no biological mechanism to explain such effects is known. We hypothesised that BCG produces broad-spectrum anti-microbial protection via a hepcidin-mediated hypoferraemia, limiting iron availability for pathogens. To test this we conducted a trial in 120 Gambian neonates comparing iron status in the first 5-days of life after allocation to: (1) All routine vaccinations at birth (BCG/Oral Polio Vaccine (OPV)/Hepatitis B Vaccine (HBV)); (2) BCG delayed until after the study period (at day 5); and (3) All routine vaccinations delayed until after the study period. Vaccine regime at birth did not significantly impact on any measured parameter of iron metabolism. However, the ability to detect an effect of BCG on iron metabolism may have been limited by short follow-up time and high activation of the inflammatory-iron axis in the study population.

  16. Tensile strain-induced softening of iron at high temperature

    PubMed Central

    Li, Xiaoqing; Schönecker, Stephan; Simon, Eszter; Bergqvist, Lars; Zhang, Hualei; Szunyogh, László; Zhao, Jijun; Johansson, Börje; Vitos, Levente

    2015-01-01

    In weakly ferromagnetic materials, already small changes in the atomic configuration triggered by temperature or chemistry can alter the magnetic interactions responsible for the non-random atomic-spin orientation. Different magnetic states, in turn, can give rise to substantially different macroscopic properties. A classical example is iron, which exhibits a great variety of properties as one gradually removes the magnetic long-range order by raising the temperature towards its Curie point of  = 1043 K. Using first-principles theory, here we demonstrate that uniaxial tensile strain can also destabilise the magnetic order in iron and eventually lead to a ferromagnetic to paramagnetic transition at temperatures far below . In consequence, the intrinsic strength of the ideal single-crystal body-centred cubic iron dramatically weakens above a critical temperature of ~500 K. The discovered strain-induced magneto-mechanical softening provides a plausible atomic-level mechanism behind the observed drop of the measured strength of Fe whiskers around 300–500 K. Alloying additions which have the capability to partially restore the magnetic order in the strained Fe lattice, push the critical temperature for the strength-softening scenario towards the magnetic transition temperature of the undeformed lattice. This can result in a surprisingly large alloying-driven strengthening effect at high temperature as illustrated here in the case of Fe-Co alloy. PMID:26556127

  17. Tensile strain-induced softening of iron at high temperature

    NASA Astrophysics Data System (ADS)

    Li, Xiaoqing; Schönecker, Stephan; Simon, Eszter; Bergqvist, Lars; Zhang, Hualei; Szunyogh, László; Zhao, Jijun; Johansson, Börje; Vitos, Levente

    2015-11-01

    In weakly ferromagnetic materials, already small changes in the atomic configuration triggered by temperature or chemistry can alter the magnetic interactions responsible for the non-random atomic-spin orientation. Different magnetic states, in turn, can give rise to substantially different macroscopic properties. A classical example is iron, which exhibits a great variety of properties as one gradually removes the magnetic long-range order by raising the temperature towards its Curie point of  = 1043 K. Using first-principles theory, here we demonstrate that uniaxial tensile strain can also destabilise the magnetic order in iron and eventually lead to a ferromagnetic to paramagnetic transition at temperatures far below . In consequence, the intrinsic strength of the ideal single-crystal body-centred cubic iron dramatically weakens above a critical temperature of ~500 K. The discovered strain-induced magneto-mechanical softening provides a plausible atomic-level mechanism behind the observed drop of the measured strength of Fe whiskers around 300-500 K. Alloying additions which have the capability to partially restore the magnetic order in the strained Fe lattice, push the critical temperature for the strength-softening scenario towards the magnetic transition temperature of the undeformed lattice. This can result in a surprisingly large alloying-driven strengthening effect at high temperature as illustrated here in the case of Fe-Co alloy.

  18. Tensile strain-induced softening of iron at high temperature.

    PubMed

    Li, Xiaoqing; Schönecker, Stephan; Simon, Eszter; Bergqvist, Lars; Zhang, Hualei; Szunyogh, László; Zhao, Jijun; Johansson, Börje; Vitos, Levente

    2015-01-01

    In weakly ferromagnetic materials, already small changes in the atomic configuration triggered by temperature or chemistry can alter the magnetic interactions responsible for the non-random atomic-spin orientation. Different magnetic states, in turn, can give rise to substantially different macroscopic properties. A classical example is iron, which exhibits a great variety of properties as one gradually removes the magnetic long-range order by raising the temperature towards its Curie point of  TC°= 1043 K. Using first-principles theory, here we demonstrate that uniaxial tensile strain can also destabilise the magnetic order in iron and eventually lead to a ferromagnetic to paramagnetic transition at temperatures far below TC°. In consequence, the intrinsic strength of the ideal single-crystal body-centred cubic iron dramatically weakens above a critical temperature of ~500 K. The discovered strain-induced magneto-mechanical softening provides a plausible atomic-level mechanism behind the observed drop of the measured strength of Fe whiskers around 300-500 K. Alloying additions which have the capability to partially restore the magnetic order in the strained Fe lattice, push the critical temperature for the strength-softening scenario towards the magnetic transition temperature of the undeformed lattice. This can result in a surprisingly large alloying-driven strengthening effect at high temperature as illustrated here in the case of Fe-Co alloy. PMID:26556127

  19. Enzyme clustering can induce metabolic channeling

    NASA Astrophysics Data System (ADS)

    Castellana, Michele

    2015-03-01

    Direct channeling of intermediates via a physical tunnel between enzyme active sites is an established mechanism to improve metabolic efficiency. In this talk, I will present a theoretical model that demonstrates that coclustering multiple enzymes into proximity can yield the full efficiency benefits of direct channeling. The model predicts the separation and size of coclusters that maximize metabolic efficiency, and this prediction is in agreement with the spacing between coclusters in yeast and mammalian cells. The model also predicts that enzyme agglomerates can regulate steady-state flux division at metabolic branch points: we experimentally test this prediction for a fundamental branch point in Escherichia coli, and the results confirm that enzyme colocalization within an agglomerate can accelerate the processing of a shared intermediate by one branch. Our studies establish a quantitative framework to understand coclustering-mediated metabolic channeling and its application to both efficiency improvement and metabolic regulation.

  20. Changes in the proteomic and metabolic profiles of Beta vulgaris root tips in response to iron deficiency and resupply

    PubMed Central

    2010-01-01

    Background Plants grown under iron deficiency show different morphological, biochemical and physiological changes. These changes include, among others, the elicitation of different strategies to improve the acquisition of Fe from the rhizosphere, the adjustment of Fe homeostasis processes and a reorganization of carbohydrate metabolism. The application of modern techniques that allow the simultaneous and untargeted analysis of multiple proteins and metabolites can provide insight into multiple processes taking place in plants under Fe deficiency. The objective of this study was to characterize the changes induced in the root tip proteome and metabolome of sugar beet plants in response to Fe deficiency and resupply. Results Root tip extract proteome maps were obtained by 2-D isoelectric focusing polyacrylamide gel electrophoresis, and approximately 140 spots were detected. Iron deficiency resulted in changes in the relative amounts of 61 polypeptides, and 22 of them were identified by mass spectrometry (MS). Metabolites in root tip extracts were analyzed by gas chromatography-MS, and more than 300 metabolites were resolved. Out of 77 identified metabolites, 26 changed significantly with Fe deficiency. Iron deficiency induced increases in the relative amounts of proteins and metabolites associated to glycolysis, tri-carboxylic acid cycle and anaerobic respiration, confirming previous studies. Furthermore, a protein not present in Fe-sufficient roots, dimethyl-8-ribityllumazine (DMRL) synthase, was present in high amounts in root tips from Fe-deficient sugar beet plants and gene transcript levels were higher in Fe-deficient root tips. Also, a marked increase in the relative amounts of the raffinose family of oligosaccharides (RFOs) was observed in Fe-deficient plants, and a further increase in these compounds occurred upon short term Fe resupply. Conclusions The increases in DMRL synthase and in RFO sugars were the major changes induced by Fe deficiency and resupply

  1. Abnormal Brain Iron Metabolism in Irp2 Deficient Mice Is Associated with Mild Neurological and Behavioral Impairments

    PubMed Central

    Zumbrennen-Bullough, Kimberly B.; Becker, Lore; Garrett, Lillian; Hölter, Sabine M.; Calzada-Wack, Julia; Mossbrugger, Ilona; Quintanilla-Fend, Leticia; Racz, Ildiko; Rathkolb, Birgit; Klopstock, Thomas; Wurst, Wolfgang; Zimmer, Andreas; Wolf, Eckhard; Fuchs, Helmut; Gailus-Durner, Valerie; de Angelis, Martin Hrabě; Romney, Steven J.; Leibold, Elizabeth A.

    2014-01-01

    Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2−/− mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2−/− mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments. PMID:24896637

  2. Abnormal brain iron metabolism in Irp2 deficient mice is associated with mild neurological and behavioral impairments.

    PubMed

    Zumbrennen-Bullough, Kimberly B; Becker, Lore; Garrett, Lillian; Hölter, Sabine M; Calzada-Wack, Julia; Mossbrugger, Ilona; Quintanilla-Fend, Leticia; Racz, Ildiko; Rathkolb, Birgit; Klopstock, Thomas; Wurst, Wolfgang; Zimmer, Andreas; Wolf, Eckhard; Fuchs, Helmut; Gailus-Durner, Valerie; de Angelis, Martin Hrabě; Romney, Steven J; Leibold, Elizabeth A

    2014-01-01

    Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2-/- mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2-/- mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments.

  3. Iron deprivation results in a rapid but not sustained increase of the expression of genes involved in iron metabolism and sulfate uptake in tomato (Solanum lycopersicum L.) seedlings.

    PubMed

    Paolacci, Anna Rita; Celletti, Silvia; Catarcione, Giulio; Hawkesford, Malcolm J; Astolfi, Stefania; Ciaffi, Mario

    2014-01-01

    Characterization of the relationship between sulfur and iron in both Strategy I and Strategy II plants, has proven that low sulfur availability often limits plant capability to cope with iron shortage. Here it was investigated whether the adaptation to iron deficiency in tomato (Solanum lycopersicum L.) plants was associated with an increased root sulfate uptake and translocation capacity, and modified dynamics of total sulfur and thiols accumulation between roots and shoots. Most of the tomato sulfate transporter genes belonging to Groups 1, 2, and 4 were significantly upregulated in iron-deficient roots, as it commonly occurs under S-deficient conditions. The upregulation of the two high affinity sulfate transporter genes, SlST1.1 and SlST1.2, by iron deprivation clearly suggests an increased root capability to take up sulfate. Furthermore, the upregulation of the two low affinity sulfate transporter genes SlST2.1 and SlST4.1 in iron-deficient roots, accompanied by a substantial accumulation of total sulfur and thiols in shoots of iron-starved plants, likely supports an increased root-to-shoot translocation of sulfate. Results suggest that tomato plants exposed to iron-deficiency are able to change sulfur metabolic balance mimicking sulfur starvation responses to meet the increased demand for methionine and its derivatives, allowing them to cope with this stress. PMID:24119307

  4. Determination of plasma temperature and electron density of iron in iron slag samples using laser induced breakdown spectroscopy

    NASA Astrophysics Data System (ADS)

    Hussain, T.; Gondal, M. A.; Shamraiz, M.

    2016-08-01

    Plasma temperature and electron density of iron in iron slag samples taken from a local plant is studied. Optimal experimental conditions were evaluated using Nd: YAG laser at 1064 nm. Some toxic elements were identified and quantitative measurements were also made. Plasma temperature and electron density were estimated using standard equations and well resolved iron spectral lines in the 229.06-358.11 nm region at 10, 20, 30 and 40 mJ laser pulse energy with 4.5 μs delay time. These parameters were found to increase with increase in laser pulse energy. The Boltzmann distribution and experimentally measured line intensities support the assumption that the laser-induced plasma was in local thermal equilibrium. It is worth mentioning that iron and steel sector generates tons of solid waste and residues annually containing variety of contaminants which can be harmful to the environment and therefore knowledge, proper analysis and investigation of such iron slag is important.

  5. Nitrosative stress and apoptosis in non-anemic healthy rats induced by intravenous iron sucrose similars versus iron sucrose originator.

    PubMed

    Toblli, Jorge E; Cao, Gabriel; Angerosa, Margarita

    2015-04-01

    Iron can both induce and inhibit nitrosative stress. Intracellular iron levels play an important role in nitric oxide (NO(•)) signaling mechanisms. Depending on various factors, such as the cell's redox state and transition metal levels, NO(•) generation may lead to lipid peroxidation and DNA damage as well as both anti- and pro-apoptotic effects. Administration of intravenous iron sucrose originator (IS(ORIG)) has been shown not to cause significant tyrosine nitration or significantly increased caspase 3 levels in non-anemic rats. In this study, the potential of several marketed iron sucrose similars (ISSs) to induce tyrosine nitration and caspase 3 expression in non-anemic rats was assessed. Although the physico-chemical properties of most of the analyzed ISSs complied with the United States Pharmacopeia for iron sucrose injection, all ISSs resulted in higher levels of tyrosine nitration and increased the expression of caspase 3 versus IS(ORIG). Moreover, significant differences were detected in tissue iron distribution between IS(ORIG)- and ISS-treated animals. In general, ISORIG resulted in higher levels of ferritin deposits versus ISSs whereas ISSs showed higher Prussian blue-stainable iron(III) deposits than IS(ORIG). This result suggests that some iron from ISSs bypassed the tightly regulated pathway through resident macrophages of the liver, spleen and bone marrow thus, ending up in the cellular compartment that favors oxidative and or nitrosative stress as well as apoptosis. The results also confirm that polynuclear iron(III)-oxyhydroxide carbohydrates, such as iron sucrose, cannot be fully characterized by physico-chemical methods alone.

  6. [Effect of dinitrosyl iron complexes on erythrocyte energy metabolism under thermal trauma conditions].

    PubMed

    Martusevich, A K; Solov'eva, A G; Peretiagin, S P; Vanin, A F

    2014-01-01

    The effect of dinitrosyl iron complexes (DNIC) on the energy metabolism of erythrocytes under combined thermal trauma conditions has been studied on a group of 30 Wistar rats, which was divided into 3 groups: intact (n = 10), control (n = 10), and main (n = 10). Combined thermal trauma (skin burn + thermoinhalation damage) was modeled in animals of the control and main groups. Rats of control group received infusions of sodium chloride solution (n = 10) every day. Rats of the main group obtained infusions of DNIC solution in sodium chloride. Rat blood samples were characterized by the activity of lactate dehydrogenase in direct and reverse reaction, lactate level, and coefficients of the substrate provision and energy reactions balance. It was stated, that DNIC clearly normalized the energy metabolism of erythrocytes beginning with the third day after thermal trauma onset. PMID:24791335

  7. Hepcidin-Induced Iron Deficiency Is Related to Transient Anemia and Hypoferremia in Kawasaki Disease Patients

    PubMed Central

    Huang, Ying-Hsien; Kuo, Ho-Chang; Huang, Fu-Chen; Yu, Hong-Ren; Hsieh, Kai-Sheng; Yang, Ya-Ling; Sheen, Jiunn-Ming; Li, Sung-Chou; Kuo, Hsing-Chun

    2016-01-01

    Kawasaki disease (KD) is a type of systemic vasculitis that primarily affects children under the age of five years old. For sufferers of KD, intravenous immunoglobulin (IVIG) has been found to successfully diminish the occurrence of coronary artery lesions. Anemia is commonly found in KD patients, and we have shown that in appropriately elevated hepcidin levels are related to decreased hemoglobin levels in these patients. In this study, we investigated the time period of anemia and iron metabolism during different stages of KD. A total of 100 patients with KD and 20 control subjects were enrolled in this study for red blood cell and hemoglobin analysis. Furthermore, plasma, urine hepcidin, and plasma IL-6 levels were evaluated using enzyme-linked immunosorbent assay in 20 KD patients and controls. Changes in hemoglobin, plasma iron levels, and total iron binding capacity (TIBC) were also measured in patients with KD. Hemoglobin, iron levels, and TIBC were lower (p < 0.001, p = 0.009, and p < 0.001, respectively) while plasma IL-6 and hepcidin levels (both p < 0.001) were higher in patients with KD than in the controls prior to IVIG administration. Moreover, plasma hepcidin levels were positively and significantly correlated with urine hepcidin levels (p < 0.001) prior to IVIG administration. After IVIG treatment, plasma hepcidin and hemoglobin levels significantly decreased (both p < 0.001). Of particular note was a subsequent gradual increase in hemoglobin levels during the three weeks after IVIG treatment; nevertheless, the hemoglobin levels stayed lower in KD patients than in the controls (p = 0.045). These findings provide a longitudinal study of hemoglobin changes and among the first evidence that hepcidin induces transient anemia and hypoferremia during KD’s acute inflammatory phase. PMID:27187366

  8. The effects of maternal iron deficiency on infant fibroblast growth factor-23 and mineral metabolism

    PubMed Central

    Braithwaite, V.S.; Prentice, A.; Darboe, M.K.; Prentice, A.M.; Moore, S.E.

    2016-01-01

    Fibroblast growth factor-23 (FGF23), a phosphate(Phos)-regulating hormone, is abnormally elevated in hypophosphataemic syndromes and an elevated FGF23 is a predictor of mortality in kidney disease. Recent findings suggest iron deficiency as a potential mediator of FGF23 expression and murine studies have shown in utero effects of maternal iron deficiency on offspring FGF23 and phosphate metabolism. Our aim was to investigate the impact of maternal iron status on infant FGF23 and mineral metabolites over the first 2 years of life. Infants born to mothers with normal (NIn = 25,) and low (LIn = 25) iron status during pregnancy, from a mother-infant trial (ISRCTN49285450) in rural Gambia, West Africa, had blood and plasma samples analysed at 12, 24, 52, 78 and 104 weeks (wk) of age. Circulating intact-FGF23 (I-FGF23), Phos, total alkaline phosphatase (TALP) and haemoglobin (Hb) decreased and estimated glomerular filtration rate increased over time [all P ≤ 0.0001)]. C-terminal-FGF23 (C-FGF23) and TALP were significantly higher in LI compared with NI, from 52 wk for C-FGF23 [Beta coefficient (SE) 18.1 (0.04) %, P = 0.04] and from 24 wk for TALP [44.7 (29.6) U/L, P = 0.04]. Infant Hb was the strongest negative predictor of C-FGF23 concentration [− 21% (4%) RU/mL, P ≤ 0.0001], Phos was the strongest positive predictor of I-FGF23 [32.0(3.9) pg/mL, P ≤ 0.0001] and I-FGF23 did not predict C-FGF23 over time [− 0.5% (0.5%), P = 0.3]. In conclusion, this study suggests that poor maternal iron status is associated with a higher infant C-FGF23 and TALP but similar I-FGF23 concentrations in infants and young children. These findings further highlight the likely public health importance of preventing iron deficiency during pregnancy. Whether or not children who are born to iron deficient mothers have persistently high concentrations of these metabolites and are more likely to be at risk of impaired bone development and pre-disposed to rickets

  9. The effects of maternal iron deficiency on infant fibroblast growth factor-23 and mineral metabolism.

    PubMed

    Braithwaite, V S; Prentice, A; Darboe, M K; Prentice, A M; Moore, S E

    2016-02-01

    Fibroblast growth factor-23 (FGF23), a phosphate(Phos)-regulating hormone, is abnormally elevated in hypophosphataemic syndromes and an elevated FGF23 is a predictor of mortality in kidney disease. Recent findings suggest iron deficiency as a potential mediator of FGF23 expression and murine studies have shown in utero effects of maternal iron deficiency on offspring FGF23 and phosphate metabolism. Our aim was to investigate the impact of maternal iron status on infant FGF23 and mineral metabolites over the first 2years of life. Infants born to mothers with normal (NIn=25,) and low (LIn=25) iron status during pregnancy, from a mother-infant trial (ISRCTN49285450) in rural Gambia, West Africa, had blood and plasma samples analysed at 12, 24, 52, 78 and 104weeks (wk) of age. Circulating intact-FGF23 (I-FGF23), Phos, total alkaline phosphatase (TALP) and haemoglobin (Hb) decreased and estimated glomerular filtration rate increased over time [all P≤0.0001)]. C-terminal-FGF23 (C-FGF23) and TALP were significantly higher in LI compared with NI, from 52wk for C-FGF23 [Beta coefficient (SE) 18.1 (0.04) %, P=0.04] and from 24wk for TALP [44.7 (29.6) U/L, P=0.04]. Infant Hb was the strongest negative predictor of C-FGF23 concentration [-21% (4%) RU/mL, P≤0.0001], Phos was the strongest positive predictor of I-FGF23 [32.0(3.9) pg/mL, P≤0.0001] and I-FGF23 did not predict C-FGF23 over time [-0.5% (0.5%), P=0.3]. In conclusion, this study suggests that poor maternal iron status is associated with a higher infant C-FGF23 and TALP but similar I-FGF23 concentrations in infants and young children. These findings further highlight the likely public health importance of preventing iron deficiency during pregnancy. Whether or not children who are born to iron deficient mothers have persistently high concentrations of these metabolites and are more likely to be at risk of impaired bone development and pre-disposed to rickets requires further research.

  10. Growth-Induced Instability in Metabolic Networks

    SciTech Connect

    Goyal, Sidhartha; Wingreen, Ned S.

    2007-03-30

    Product-feedback inhibition is a ubiquitous regulatory scheme for maintaining homeostasis in living cells. Individual metabolic pathways with product-feedback inhibition are stable as long as one pathway step is rate limiting. However, pathways are often coupled both by the use of a common substrate and by stoichiometric utilization of their products for cell growth. We show that such a coupled network with product-feedback inhibition may exhibit limit-cycle oscillations which arise via a Hopf bifurcation. Our results highlight novel evolutionary constraints on the architecture of metabolism.

  11. Non-heme induction of heme oxygenase-1 does not alter cellular iron metabolism.

    PubMed

    Sheftel, Alex D; Kim, Sangwon F; Ponka, Prem

    2007-04-01

    The catabolism of heme is carried out by members of the heme oxygenase (HO) family. The products of heme catabolism by HO-1 are ferrous iron, biliverdin (subsequently converted to bilirubin), and carbon monoxide. In addition to its function in the recycling of hemoglobin iron, this microsomal enzyme has been shown to protect cells in various stress models. Implicit in the reports of HO-1 cytoprotection to date are its effects on the cellular handling of heme/iron. However, the limited amount of uncommitted heme in non-erythroid cells brings to question the source of substrate for this enzyme in non-hemolytic circumstances. In the present study, HO-1 was induced by either sodium arsenite (reactive oxygen species producer) or hemin or overexpressed in the murine macrophage-like cell line, RAW 264.7. Both of the inducers elicited an increase in active HO-1; however, only hemin exposure caused an increase in the synthesis rate of the iron storage protein, ferritin. This effect of hemin was the direct result of the liberation of iron from heme by HO. Cells stably overexpressing HO-1, although protected from oxidative stress, did not display elevated basal ferritin synthesis. However, these cells did exhibit an increase in ferritin synthesis, compared with untransfected controls, in response to hemin treatment, suggesting that heme levels, and not HO-1, limit cellular heme catabolism. Our results suggest that the protection of cells from oxidative insult afforded by HO-1 is not due to the catabolism of significant amounts of cellular heme as thought previously.

  12. Bypasses in intracellular glucose metabolism in iron-limited Pseudomonas putida.

    PubMed

    Sasnow, Samantha S; Wei, Hua; Aristilde, Ludmilla

    2016-02-01

    Decreased biomass growth in iron (Fe)-limited Pseudomonas is generally attributed to downregulated expression of Fe-requiring proteins accompanied by an increase in siderophore biosynthesis. Here, we applied a stable isotope-assisted metabolomics approach to explore the underlying carbon metabolism in glucose-grown Pseudomonas putida KT2440. Compared to Fe-replete cells, Fe-limited cells exhibited a sixfold reduction in growth rate but the glucose uptake rate was only halved, implying an imbalance between glucose uptake and biomass growth. This imbalance could not be explained by carbon loss via siderophore production, which accounted for only 10% of the carbon-equivalent glucose uptake. In lieu of the classic glycolytic pathway, the Entner-Doudoroff (ED) pathway in Pseudomonas is the principal route for glucose catabolism following glucose oxidation to gluconate. Remarkably, gluconate secretion represented 44% of the glucose uptake in Fe-limited cells but only 2% in Fe-replete cells. Metabolic (13) C flux analysis and intracellular metabolite levels under Fe limitation indicated a decrease in carbon fluxes through the ED pathway and through Fe-containing metabolic enzymes. The secreted siderophore was found to promote dissolution of Fe-bearing minerals to a greater extent than the high extracellular gluconate. In sum, bypasses in the Fe-limited glucose metabolism were achieved to promote Fe availability via siderophore secretion and to reroute excess carbon influx via enhanced gluconate secretion. PMID:26377487

  13. Glutathione revisited: a vital function in iron metabolism and ancillary role in thiol-redox control

    PubMed Central

    Kumar, Chitranshu; Igbaria, Aeid; D'Autreaux, Benoît; Planson, Anne-Gaëlle; Junot, Christophe; Godat, Emmanuel; Bachhawat, Anand K; Delaunay-Moisan, Agnès; Toledano, Michel B

    2011-01-01

    Glutathione contributes to thiol-redox control and to extra-mitochondrial iron–sulphur cluster (ISC) maturation. To determine the physiological importance of these functions and sort out those that account for the GSH requirement for viability, we performed a comprehensive analysis of yeast cells depleted of or containing toxic levels of GSH. Both conditions triggered an intense iron starvation-like response and impaired the activity of extra-mitochondrial ISC enzymes but did not impact thiol-redox maintenance, except for high glutathione levels that altered oxidative protein folding in the endoplasmic reticulum. While iron partially rescued the ISC maturation and growth defects of GSH-depleted cells, genetic experiments indicated that unlike thioredoxin, glutathione could not support by itself the thiol-redox duties of the cell. We propose that glutathione is essential by its requirement in ISC assembly, but only serves as a thioredoxin backup in cytosolic thiol-redox maintenance. Glutathione-high physiological levels are thus meant to insulate its cytosolic function in iron metabolism from variations of its concentration during redox stresses, a model challenging the traditional view of it as prime actor in thiol-redox control. PMID:21478822

  14. Influence of high dietary iron as ferrous carbonate and ferrous sulfate on iron metabolism in young calves.

    PubMed

    McGuire, S O; Miller, W J; Gentry, R P; Neathery, M W; Ho, S Y; Blackmon, D M

    1985-10-01

    Twelve intact male Holstein calves averaging 90 kg and 12 wk of age were fed one of three dietary treatments for 28 d. The diets were A) control, B) control plus 1000 ppm iron as ferrous carbonate, and C) control plus 1000 ppm iron as ferrous sulfate monohydrate. Calves were dosed orally on d 15 of the treatment period with 1 mCi of iron-59. Neither source of added iron had a significant effect on weight gains, feed consumption, hemoglobin, packed cell volume, serum total iron, serum total iron-binding capacity, unbound iron-binding capacity, serum copper, tissue copper, fecal dry matter, or a consistent effect on fecal pH. The ferrous carbonate had no significant effect on stable zinc or stable iron in any tissue studied. Calves fed ferrous sulfate had higher average stable iron in most tissues and significantly more in the small intestine. Tissue zinc was lower in spleen and pancreas of ferrous sulfate-fed calves. Both sources of added iron sharply reduced iron-59 in serum, whole blood, and body tissues. The reduction was substantially greater in calves fed the ferrous sulfate iron. Iron in ferrous sulfate had a higher biological availability than that in the ferrous carbonate; however, bioavailability of the ferrous carbonate iron appeared to be substantial and considerably more than that noted in previous studies in which a different source of ferrous carbonate was used. The maximum safe level of dietary iron is materially influenced by the source of iron with a higher tolerance indicated for ferrous carbonated than ferrous sulfate monohydrate.

  15. Fungal Morphology, Iron Homeostasis, and Lipid Metabolism Regulated by a GATA Transcription Factor in Blastomyces dermatitidis

    PubMed Central

    Marty, Amber J.; Broman, Aimee T.; Zarnowski, Robert; Dwyer, Teigan G.; Bond, Laura M.; Lounes-Hadj Sahraoui, Anissa; Fontaine, Joël; Ntambi, James M.; Keleş, Sündüz; Kendziorski, Christina; Gauthier, Gregory M.

    2015-01-01

    In response to temperature, Blastomyces dermatitidis converts between yeast and mold forms. Knowledge of the mechanism(s) underlying this response to temperature remains limited. In B. dermatitidis, we identified a GATA transcription factor, SREB, important for the transition to mold. Null mutants (SREBΔ) fail to fully complete the conversion to mold and cannot properly regulate siderophore biosynthesis. To capture the transcriptional response regulated by SREB early in the phase transition (0–48 hours), gene expression microarrays were used to compare SREB∆ to an isogenic wild type isolate. Analysis of the time course microarray data demonstrated SREB functioned as a transcriptional regulator at 37°C and 22°C. Bioinformatic and biochemical analyses indicated SREB was involved in diverse biological processes including iron homeostasis, biosynthesis of triacylglycerol and ergosterol, and lipid droplet formation. Integration of microarray data, bioinformatics, and chromatin immunoprecipitation identified a subset of genes directly bound and regulated by SREB in vivo in yeast (37°C) and during the phase transition to mold (22°C). This included genes involved with siderophore biosynthesis and uptake, iron homeostasis, and genes unrelated to iron assimilation. Functional analysis suggested that lipid droplets were actively metabolized during the phase transition and lipid metabolism may contribute to filamentous growth at 22°C. Chromatin immunoprecipitation, RNA interference, and overexpression analyses suggested that SREB was in a negative regulatory circuit with the bZIP transcription factor encoded by HAPX. Both SREB and HAPX affected morphogenesis at 22°C; however, large changes in transcript abundance by gene deletion for SREB or strong overexpression for HAPX were required to alter the phase transition. PMID:26114571

  16. Radiation induced chemical activity at iron and copper oxide surfaces

    NASA Astrophysics Data System (ADS)

    Reiff, Sarah C.

    The radiolysis of three iron oxides, two copper oxides, and aluminum oxide with varying amounts of water were performed using gamma-rays and 5 MeV 4He ions. The adsorbed water on the surfaces was characterized using temperature programmed desorption and diffuse reflectance infrared spectroscopy, which indicated that all of the oxides had chemisorbed water on the surface. Physisorbed water was observed on the Fe2O 3 and Al2O3 surfaces as well. Molecular hydrogen was produced from adsorbed water only on Fe2O3 and Al 2O3, while the other compounds did not show any hydrogen production due to the low amounts of water on the surfaces. Slurries of varying amounts of water were also examined for hydrogen production, and they showed yields that were greater than the yield for bulk water. However, the yields of hydrogen from the copper compounds were much lower than those of the iron suggesting that the copper oxides are relatively inert to radiation induced damage to nearby water. X-ray diffraction measurements did not show any indication of changes to the bulk crystal structure due to radiolysis for any of the oxides. The surfaces of the oxides were analyzed using Raman spectroscopy and X-ray photoelectron spectroscopy (XPS). For the iron samples, FeO and Fe3O4, Raman spectroscopy revealed areas of Fe2O3 had formed following irradiation with He ions. XPS indicated the formation of a new oxygen species on the iron oxide surfaces. Raman spectroscopy of the copper oxides did not reveal any changes in the surface composition, however, XPS measurements showed a decrease in the amount of OH groups on the surface of Cu2O, while for the CuO samples the amount of OH groups were found to increase following radiolysis. Pristine Al2O3 showed the presence of a surface oxyhydroxide layer which was observed to decrease following radiolysis, consistent with the formation of molecular hydrogen.

  17. Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

    SciTech Connect

    Salama, Samir A.; Omar, Hany A.; Maghrabi, Ibrahim A.; AlSaeed, Mohammed S.; EL-Tarras, Adel E.

    2014-01-01

    Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000 ft above the sea level). Iron supplementation (2 mg elemental iron/kg, once daily for 15 days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25 mg/kg, once daily for the last 7 days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures. - Highlights: • Iron supplementation at high altitudes induced lung histological changes in rats. • Iron induced oxidative stress in lung tissues of rats at high altitudes. • Iron

  18. Influence of artistic gymnastics on iron nutritional status and exercise-induced hemolysis in female athletes.

    PubMed

    Sureira, Thaiz Mattos; Amancio, Olga Silverio; Pellegrini Braga, Josefina Aparecida

    2012-08-01

    This study evaluates the relationship between body iron losses and gains in artistic gymnastics female athletes. It shows that despite the low iron intake and exercise-induced hemolysis, iron deficiency or iron-deficiency anemia does not occur, but partial changes in the hematological profile do. The hypothesis that gymnasts' nutritional behavior contributes to anemia, which may be aggravated by exercise-induced hemolysis, led to this cross-sectional study, conducted with 43 female artistic gymnasts 6-16 yr old. The control group was formed by 40 nontraining girls, paired by age. Hemogram, serum iron, ferritin, soluble transferrin receptor, haptoglobin, total and fractional bilirubin, Type I urine, and parasitologic and occult fecal blood tests were evaluated. The athletes presented mean hematimetric and serum iron values (p = .020) higher than those of the control group. The bilirubin result discarded any hemolytic alteration in both groups. The haptoglobin results were lower in the athlete group (p = .002), confirming the incidence of exercise-induced hemolysis. Both groups presented low iron intake. The results suggest that artistic gymnastics practice leads to exercise-induced hemolysis and partially changes the hematological profile, although not causing iron deficiency or iron-deficiency anemia, even in the presence of low iron intake. PMID:22645172

  19. Influence of artistic gymnastics on iron nutritional status and exercise-induced hemolysis in female athletes.

    PubMed

    Sureira, Thaiz Mattos; Amancio, Olga Silverio; Pellegrini Braga, Josefina Aparecida

    2012-08-01

    This study evaluates the relationship between body iron losses and gains in artistic gymnastics female athletes. It shows that despite the low iron intake and exercise-induced hemolysis, iron deficiency or iron-deficiency anemia does not occur, but partial changes in the hematological profile do. The hypothesis that gymnasts' nutritional behavior contributes to anemia, which may be aggravated by exercise-induced hemolysis, led to this cross-sectional study, conducted with 43 female artistic gymnasts 6-16 yr old. The control group was formed by 40 nontraining girls, paired by age. Hemogram, serum iron, ferritin, soluble transferrin receptor, haptoglobin, total and fractional bilirubin, Type I urine, and parasitologic and occult fecal blood tests were evaluated. The athletes presented mean hematimetric and serum iron values (p = .020) higher than those of the control group. The bilirubin result discarded any hemolytic alteration in both groups. The haptoglobin results were lower in the athlete group (p = .002), confirming the incidence of exercise-induced hemolysis. Both groups presented low iron intake. The results suggest that artistic gymnastics practice leads to exercise-induced hemolysis and partially changes the hematological profile, although not causing iron deficiency or iron-deficiency anemia, even in the presence of low iron intake.

  20. The factors influencing urinary arsenic excretion and metabolism of workers in steel and iron smelting foundry.

    PubMed

    Shuhua, Xi; Qingshan, Sun; Fei, Wang; Shengnan, Liu; Ling, Yan; Lin, Zhang; Yingli, Song; Nan, Yan; Guifan, Sun

    2014-01-01

    In order to evaluate the degree of arsenic (As) exposure and the factors influencing urinary As excretion and metabolism, 192 workers from a steel and iron smelting plant, with different type of work in production such as roller, steel smelting, iron smelting and metallic charge preparation, were recruited. Information about characteristics of each subject was obtained by questionnaire and inorganic As (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) in urine were determined. The results showed that steel smelters had significantly higher concentrations of DMA and total As (TAs) than rollers and metallic charge preparation workers, and iron and steel smelters had a higher value of primary methylation index and lower proportion of the iAs (iAs%) than rollers and metallic charge preparation workers. In steel smelters, urinary As level exceeded the biological exposure index (BEI) limit for urinary As of 35 μg/l by 65.52%, and higher than metallic charge preparation workers (35.14%). The individuals consumed seafood in recent 3 days had a higher TAs than the individuals without seafood consumption. Multivariate logistic regression analysis showed that different jobs, taken Chinese medicine of bezoar and seafood consumption in recent 3 days were significantly associated with urinary TAs exceeded BEI limit value 35 μg/l. Our results suggest that workers in steel and iron smelting plant had a lower level of As exposure, and seafood consumption and taking Chinese medicine of bezoar also could increase the risk of urinary TAs exceeded BEI limit value.

  1. Iron induced genotoxicity: attenuation by vitamin C and its optimization

    PubMed Central

    Parveen, Nuzhat; Ahmad, Shoeb

    2014-01-01

    Vitamin C (VC) is a well-known antioxidant and strong free radical scavenger. Its antioxidant activity is useful for protection of cellular macromolecules, particularly DNA, from oxidative damage induced by different agents. This study was undertaken to evaluate the optimum level of VC in attenuating the chromosome aberrations (CAs) and DNA damage after iron sulfate (FeSO4) acute administration in Wistar rats. The results exhibited that the increase of CAs and DNA damage induced by FeSO4, 200 mg Fe/kg, could be reduced significantly by VC pretreatment at the dose of 500 mg/kg (p<0.001), but not in the 100 mg/kg group. The findings provide evidence that VC at the dose of 500 mg/kg exerted a possible protective effect against FeSO4 induced CAs and DNA damage. The possible mechanisms of VC may be attributed to its property as a free radical scavenger or to its indirect action in reducing the level of reactive oxygen species (ROS). PMID:26109893

  2. Iron metabolism in obesity: how interaction between homoeostatic mechanisms can interfere with their original purpose. Part I: underlying homoeostatic mechanisms of energy storage and iron metabolisms and their interaction.

    PubMed

    Becker, Christiane; Orozco, Mónica; Solomons, Noel W; Schümann, Klaus

    2015-04-01

    Adipose tissue plasticity mediated by inflammation is an important evolutionary achievement to survive seasonal climate changes. It permits to store excessive calories and to release them if required, using inflammatory cells to remove the debris. This process is regulated by a complex interaction of cytokines (TNF-α, IL-6), adipokines (adiponectin, apelin, liptin), adhesion molecules (ICAM-1, VCAM-1, E-selectin) and transcription factors (NF-κB, HIF-1α). Iron mediates electron transfer as an essential component of e.g. myeloperoxidase, hemoglobin, cytochrome C and ribonucleotide reductase. Conversely, unbound iron can catalyze oxidation of lipids, proteins, and DNA. To balance the essential with the potentially toxic function requires an efficient iron homoeostasis. This is mediated by hepcidin's interaction with the iron-exporter ferroportin, to adapt intestinal iron absorption and body iron-sequestration to changes in demand. In addition, the interaction of iron-responsive elements (IRE) and iron-responsive proteins (IRP), the IRE/IRP-mechanism, regulates cellular iron homoeostasis. Obesity-induced inflammation interacts with both these mechanisms and disturbs iron availability by impairing its absorption, and by sequestering it in the reticuloendothelial system. Both mechanisms lead to anemia and reduce physical fitness which, in a vicious cycle, can support the development of pathological obesity. Thus, interaction between these two sets of beneficial regulatory mechanisms can become detrimental in situations of ample calorie supply.

  3. Attenuation of Some Metabolic Deteriorations Induced by Diabetes Mellitus Using Carnosine

    NASA Astrophysics Data System (ADS)

    Soliman, K. M.; Mohamed, A. M.; Metwally, N. S.

    The protective ability of carnosine against some metabolic disorders and oxidative stress in Strepotzotocin (STZ) diabetic-induced model was studied. Diabetic rats showed significant increase in serum glucose and cortisol levels indicating disturbance of carbohydrate metabolism, increased triglycerides, total cholesterol, LDL-cholesterol as well as iron level indicating abnormal lipid metabolism and iron overload. Marked increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and sorbitol dehydrogenase (SD) were also demonstrated implying impairment of liver function. Concomitantly, the results revealed an impairment of antioxidant status of diabetic animals as evidenced by significant decrease in vitamin E and HDL-C levels. Administration of either two doses of carnosine (10 mg/100 g b.w. or 20 mg/100 g b.w.) two weeks before and after diabetic induction, was effective in ameliorating serum glucose level of diabetic animals and improving the deterioration in the studied parameters. The best results were obtained with the higher dose. No significant changes were noted in serum bilirubin level among the different studied groups. These data suggest that carnosine is a potential multi-protective agent for diabetic complications prevention or therapy.

  4. Comparative proteomics of a tor inducible Aspergillus fumigatus mutant reveals involvement of the Tor kinase in iron regulation.

    PubMed

    Baldin, Clara; Valiante, Vito; Krüger, Thomas; Schafferer, Lukas; Haas, Hubertus; Kniemeyer, Olaf; Brakhage, Axel A

    2015-07-01

    The Tor (target of rapamycin) kinase is one of the major regulatory nodes in eukaryotes. Here, we analyzed the Tor kinase in Aspergillus fumigatus, which is the most important airborne fungal pathogen of humans. Because deletion of the single tor gene was apparently lethal, we generated a conditional lethal tor mutant by replacing the endogenous tor gene by the inducible xylp-tor gene cassette. By both 2DE and gel-free LC-MS/MS, we found that Tor controls a variety of proteins involved in nutrient sensing, stress response, cell cycle progression, protein biosynthesis and degradation, but also processes in mitochondria, such as respiration and ornithine metabolism, which is required for siderophore formation. qRT-PCR analyses indicated that mRNA levels of ornithine biosynthesis genes were increased under iron limitation. When tor was repressed, iron regulation was lost. In a deletion mutant of the iron regulator HapX also carrying the xylp-tor cassette, the regulation upon iron deprivation was similar to that of the single tor inducible mutant strain. In line, hapX expression was significantly reduced when tor was repressed. Thus, Tor acts either upstream of HapX or independently of HapX as a repressor of the ornithine biosynthesis genes and thereby regulates the production of siderophores.

  5. Metabolic Acidosis-Induced Insulin Resistance and Cardiovascular Risk

    PubMed Central

    Souto, Gema; Donapetry, Cristóbal; Calviño, Jesús

    2011-01-01

    Abstract Microalbuminuria has been conclusively established as an independent cardiovascular risk factor, and there is evidence of an association between insulin resistance and microalbuminuria, the former preceding the latter in prospective studies. It has been demonstrated that even the slightest degree of metabolic acidosis produces insulin resistance in healthy humans. Many recent epidemiological studies link metabolic acidosis indicators with insulin resistance and systemic hypertension. The strongly acidogenic diet consumed in developed countries produces a lifetime acidotic state, exacerbated by excess body weight and aging, which may result in insulin resistance, metabolic syndrome, and type 2 diabetes, contributing to cardiovascular risk, along with genetic causes, lack of physical exercise, and other factors. Elevated fruits and vegetables consumption has been associated with lower diabetes incidence. Diseases featuring severe atheromatosis and elevated cardiovascular risk, such as diabetes mellitus and chronic kidney failure, are typically characterized by a chronic state of metabolic acidosis. Diabetic patients consume particularly acidogenic diets, and deficiency of insulin action generates ketone bodies, creating a baseline state of metabolic acidosisworsened by inadequate metabolic control, which creates a vicious circle by inducing insulin resistance. Even very slight levels of chronic kidney insufficiency are associated with increased cardiovascular risk, which may be explained at least in part by deficient acid excretory capacity of the kidney and consequent metabolic acidosis-induced insulin resistance. PMID:21352078

  6. Catalytic function of the mycobacterial binuclear iron monooxygenase in acetone metabolism.

    PubMed

    Furuya, Toshiki; Nakao, Tomomi; Kino, Kuniki

    2015-10-01

    Mycobacteria such as Mycobacterium smegmatis strain mc(2)155 and Mycobacterium goodii strain 12523 are able to grow on acetone and use it as a source of carbon and energy. We previously demonstrated by gene deletion analysis that the mimABCD gene cluster, which encodes a binuclear iron monooxygenase, plays an essential role in acetone metabolism in these mycobacteria. In the present study, we determined the catalytic function of MimABCD in acetone metabolism. Whole-cell assays were performed using Escherichia coli cells expressing the MimABCD complex. When the recombinant E. coli cells were incubated with acetone, a product was detected by gas chromatography (GC) analysis. Based on the retention time and the gas chromatography-mass spectrometry (GC-MS) spectrum, the reaction product was identified as acetol (hydroxyacetone). The recombinant E. coli cells produced 1.02 mM of acetol from acetone within 24 h. Furthermore, we demonstrated that MimABCD also was able to convert methylethylketone (2-butanone) to 1-hydroxy-2-butanone. Although it has long been known that microorganisms such as mycobacteria metabolize acetone via acetol, this study provides the first biochemical evidence for the existence of a microbial enzyme that catalyses the conversion of acetone to acetol.

  7. In Absence of the Cellular Prion Protein, Alterations in Copper Metabolism and Copper-Dependent Oxidase Activity Affect Iron Distribution

    PubMed Central

    Gasperini, Lisa; Meneghetti, Elisa; Legname, Giuseppe; Benetti, Federico

    2016-01-01

    Essential elements as copper and iron modulate a wide range of physiological functions. Their metabolism is strictly regulated by cellular pathways, since dysregulation of metal homeostasis is responsible for many detrimental effects. Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and prion diseases are characterized by alterations of metal ions. These neurodegenerative maladies involve proteins that bind metals and mediate their metabolism through not well-defined mechanisms. Prion protein, for instance, interacts with divalent cations via multiple metal-binding sites and it modulates several metal-dependent physiological functions, such as S-nitrosylation of NMDA receptors. In this work we focused on the effect of prion protein absence on copper and iron metabolism during development and adulthood. In particular, we investigated copper and iron functional values in serum and several organs such as liver, spleen, total brain and isolated hippocampus. Our results show that iron content is diminished in prion protein-null mouse serum, while it accumulates in liver and spleen. Our data suggest that these alterations can be due to impairments in copper-dependent cerulopalsmin activity which is known to affect iron mobilization. In prion protein-null mouse total brain and hippocampus, metal ion content shows a fluctuating trend, suggesting the presence of homeostatic compensatory mechanisms. However, copper and iron functional values are likely altered also in these two organs, as indicated by the modulation of metal-binding protein expression levels. Altogether, these results reveal that the absence of the cellular prion protein impairs copper metabolism and copper-dependent oxidase activity, with ensuing alteration of iron mobilization from cellular storage compartments. PMID:27729845

  8. Secoisolariciresinol diglucoside abrogates oxidative stress-induced damage in cardiac iron overload condition.

    PubMed

    Puukila, Stephanie; Bryan, Sean; Laakso, Anna; Abdel-Malak, Jessica; Gurney, Carli; Agostino, Adrian; Belló-Klein, Adriane; Prasad, Kailash; Khaper, Neelam

    2015-01-01

    Cardiac iron overload is directly associated with cardiac dysfunction and can ultimately lead to heart failure. This study examined the effect of secoisolariciresinol diglucoside (SDG), a component of flaxseed, on iron overload induced cardiac damage by evaluating oxidative stress, inflammation and apoptosis in H9c2 cardiomyocytes. Cells were incubated with 50 μ5M iron for 24 hours and/or a 24 hour pre-treatment of 500 μ M SDG. Cardiac iron overload resulted in increased oxidative stress and gene expression of the inflammatory mediators tumor necrosis factor-α, interleukin-10 and interferon γ, as well as matrix metalloproteinases-2 and -9. Increased apoptosis was evident by increased active caspase 3/7 activity and increased protein expression of Forkhead box O3a, caspase 3 and Bax. Cardiac iron overload also resulted in increased protein expression of p70S6 Kinase 1 and decreased expression of AMP-activated protein kinase. Pre-treatment with SDG abrogated the iron-induced increases in oxidative stress, inflammation and apoptosis, as well as the increased p70S6 Kinase 1 and decreased AMP-activated protein kinase expression. The decrease in superoxide dismutase activity by iron treatment was prevented by pre-treatment with SDG in the presence of iron. Based on these findings we conclude that SDG was cytoprotective in an in vitro model of iron overload induced redox-inflammatory damage, suggesting a novel potential role for SDG in cardiac iron overload.

  9. Secondary psychosis induced by metabolic disorders

    PubMed Central

    Bonnot, Olivier; Herrera, Paula M.; Tordjman, Sylvie; Walterfang, Mark

    2015-01-01

    Metabolic disorders are not well-recognized by psychiatrists as a possible source of secondary psychoses. Inborn errors of metabolism (IEMs) are not frequent. Although their prompt diagnosis may lead to suitable treatments. IEMs are well-known to pediatricians, in particular for their most serious forms, having an early expression most of the time. Recent years discoveries have unveiled later expression forms, and sometimes very discreet first physical signs. There is a growing body of evidence that supports the hypothesis that IEMs can manifest as atypical psychiatric symptoms, even in the absence of clear neurological symptoms. In the present review, we propose a detailed overview at schizophrenia-like and autism-like symptoms that can lead practitioners to bear in mind an IEM. Other psychiatric manifestations are also found, as behavioral, cognitive, learning, and mood disorders. However, they are less frequent. Ensuring an accurate IEM diagnosis, in front of these psychiatric symptoms should be a priority, in order to grant suitable and valuable treatment for these pathologies. PMID:26074754

  10. Interactions between isolated hepatocytes and Kupffer cells in iron metabolism: a possible role for ferritin as an iron carrier protein.

    PubMed

    Sibille, J C; Kondo, H; Aisen, P

    1988-01-01

    Like the rat peritoneal macrophage, the isolated Kupffer cell is capable of processing and releasing iron acquired by phagocytosis of immunosensitized homologous red blood cells. When erythrophagocytosis is restrained to levels which do not affect cell viability, about one red cell per macrophage, close to 50% of iron acquired from red cells is released within 24 hr in the form of ferritin. Immunoradiometric assay of the extracellular medium indicates that 160 ng ferritin are released by 10(6) Kupffer cells after 24-hr incubation at 37 degrees C. Iron release is temperature-dependent, the rate at 37 degrees C being nearly 5-fold greater than at 4 degrees C. As estimated by sucrose-gradient ultracentrifugation, ferritin released by the erythrophagocytosing Kupffer cell averages 2,400 iron atoms per molecule. When reincubated with isolated hepatocytes, this released ferritin is rapidly taken up by the cells. Via this process, hepatocytes may accumulate more than 160,000 iron atoms per cell per min. Such accumulation is not impeded by the presence of iron-loaded transferrin in the culture medium, but is markedly depressed by rat liver ferritin. In contrast to the conservation of transferrin during its interaction with hepatocytes, the protein shell of the ferritin molecule is rapidly degraded into trichloroacetic acid-soluble fragments. Ferritin-mediated transfer of iron from Kupffer cells to hepatocytes may help explain the resistance of the liver to iron deficiency as well as the liver's susceptibility to iron overload. PMID:3356411

  11. Knocking down mitochondrial iron transporter (MIT) reprograms primary and secondary metabolism in rice plants.

    PubMed

    Vigani, Gianpiero; Bashir, Khurram; Ishimaru, Yasuhiro; Lehmann, Martin; Casiraghi, Fabio Marco; Nakanishi, Hiromi; Seki, Motoaki; Geigenberger, Peter; Zocchi, Graziano; Nishizawa, Naoko K

    2016-03-01

    Iron (Fe) is an essential micronutrient for plant growth and development, and its reduced bioavailability strongly impairs mitochondrial functionality. In this work, the metabolic adjustment in the rice (Oryza sativa) mitochondrial Fe transporter knockdown mutant (mit-2) was analysed. Biochemical characterization of purified mitochondria from rice roots showed alteration in the respiratory chain of mit-2 compared with wild-type (WT) plants. In particular, proteins belonging to the type II alternative NAD(P)H dehydrogenases accumulated strongly in mit-2 plants, indicating that alternative pathways were activated to keep the respiratory chain working. Additionally, large-scale changes in the transcriptome and metabolome were observed in mit-2 rice plants. In particular, a strong alteration (up-/down-regulation) in the expression of genes encoding enzymes of both primary and secondary metabolism was found in mutant plants. This was reflected by changes in the metabolic profiles in both roots and shoots of mit-2 plants. Significant alterations in the levels of amino acids belonging to the aspartic acid-related pathways (aspartic acid, lysine, and threonine in roots, and aspartic acid and ornithine in shoots) were found that are strictly connected to the Krebs cycle. Furthermore, some metabolites (e.g. pyruvic acid, fumaric acid, ornithine, and oligosaccharides of the raffinose family) accumulated only in the shoot of mit-2 plants, indicating possible hypoxic responses. These findings suggest that the induction of local Fe deficiency in the mitochondrial compartment of mit-2 plants differentially affects the transcript as well as the metabolic profiles in root and shoot tissues. PMID:26685186

  12. Effect of saccharated ferric oxide and iron dextran on the metabolism of phosphorus in rats.

    PubMed

    Sanai, Toru; Oochi, Nobuaki; Okada, Mitsuo; Imamura, Kenzaburo; Okuda, Seiya; Iida, Mitsuo

    2005-07-01

    As a means of investigating the physiologic damage to and histologic deterioration of the kidney caused by saccharated ferric oxide (SFO) and iron dextran (ID), we administered these substances intraperitoneally to rats. The rats were divided into 3 groups. Group 1 rats ( n = 7) were given SFO, 28 mg/kg for 9 days and 20 mg/kg for 19 days. Group 2 rats ( n = 5) were given ID, 28 mg/kg for 9 days and 20 mg/kg for 19 days. Group 3 rats (control, n = 9) were given normal saline solution. After 28 days, serum calcium, total protein, and albumin concentrations were significantly lower in the SFO group than in the ID group. Serum phosphorus concentrations were significantly lower in the SFO group than in the control group. Serum iron concentrations were significantly higher in the ID group than in the SFO group or the control, and the fractional excretion of sodium was significantly lower in the ID group than in the control group. The percent tubular reabsorption of phosphorus was significantly greater in the ID group than in the SFO group or the control group, and the theoretical threshold concentration of phosphorus was also significantly lower in the SFO group than in the ID or the control group. Histologic examination of the kidney after treatment revealed neither iron in the tubules nor any structural damage to the tubules. ID was not found to induce hypophosphatemia, whereas SFO did. We believe that the cause of such hypophosphatemia is impaired tubular reabsorption.

  13. Reconstruction of Gene Networks of Iron Response in Shewanella oneidensis

    SciTech Connect

    Yang, Yunfeng; Harris, Daniel P; Luo, Feng; Joachimiak, Marcin; Wu, Liyou; Dehal, Paramvir; Jacobsen, Janet; Yang, Zamin Koo; Gao, Haichun; Arkin, Adam; Palumbo, Anthony Vito; Zhou, Jizhong

    2009-01-01

    It is of great interest to study the iron response of the -proteobacterium Shewanella oneidensis since it possesses a high content of iron and is capable of utilizing iron for anaerobic respiration. We report here that the iron response in S. oneidensis is a rapid process. To gain more insights into the bacterial response to iron, temporal gene expression profiles were examined for iron depletion and repletion, resulting in identification of iron-responsive biological pathways in a gene co-expression network. Iron acquisition systems, including genes unique to S. oneidensis, were rapidly and strongly induced by iron depletion, and repressed by iron repletion. Some were required for iron depletion, as exemplified by the mutational analysis of the putative siderophore biosynthesis protein SO3032. Unexpectedly, a number of genes related to anaerobic energy metabolism were repressed by iron depletion and induced by repletion, which might be due to the iron storage potential of their protein products. Other iron-responsive biological pathways include protein degradation, aerobic energy metabolism and protein synthesis. Furthermore, sequence motifs enriched in gene clusters as well as their corresponding DNA-binding proteins (Fur, CRP and RpoH) were identified, resulting in a regulatory network of iron response in S. oneidensis. Together, this work provides an overview of iron response and reveals novel features in S. oneidensis, including Shewanella-specific iron acquisition systems, and suggests the intimate relationship between anaerobic energy metabolism and iron response.

  14. Iron metabolism in African American women during the 2nd and 3rd trimester of a high-risk pregnancy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: To examine iron metabolism during the 2nd and 3rd trimester in African American women classified as a high-risk pregnancy. Design: Longitudinal. Setting: Large, university-based, urban Midwestern medical center. Participants: Convenience sample of 47 African American women classified a...

  15. Crosstalk between inflammation, iron metabolism and endothelial function in Behçet's disease.

    PubMed

    Oliveira, Rita; Napoleão, Patricia; Banha, João; Paixão, Eleonora; Bettencourt, Andreia; da Silva, Berta Martins; Pereira, Dina; Barcelos, Filipe; Teixeira, Ana; Patto, José Vaz; Viegas-Crespo, Ana Maria; Costa, Luciana

    2014-01-01

    Behçet's disease (BD) is a rare chronic vasculitis of unclear etiology. It has been suggested that inflammatory response has an important role in BD pathophysiology. Herein, we aimed to study the interplay between inflammation, iron metabolism and endothelial function in BD and search for its putative association with disease activity. Twenty five patients clinically diagnosed with BD were selected and twenty four healthy age-sex matched individuals participated as controls. Results showed an increase of total number of circulating white blood cells and neutrophils, serum transferrin, total iron binding capacity, mieloperoxidase (MPO), ceruloplasmin (Cp), C reactive protein, β2 microglobulin and Cp surface expression in peripheral blood monocytes in BD patients comparatively to healthy individuals (p < 0,05). Of notice, the alterations observed were associated to disease activity status. No significant differences between the two groups were found in serum nitric oxide concentration. The results obtained suggest an important contribution from innate immunity in the pathogenesis of this disease. In particular, surface expression of leukocyte-derived Cp may constitute a new and relevant biomarker to understand BD etiology.

  16. Effects of Radiation and Dietary Iron on Expression of Genes and Proteins Involved in Drug Metabolism

    NASA Technical Reports Server (NTRS)

    Faust, K. M.; Wotring, V. E.

    2014-01-01

    Liver function, especially the rate of metabolic enzyme activities, determines the concentration of circulating drugs and the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand any effects of spaceflight on the enzymes of the liver. Dietary factors and exposure to radiation are aspects of spaceflight that are potential oxidative stressors and both can be modeled in ground experiments. In this experiment, we examined the effects of high dietary iron and low dose gamma radiation (individually and combined) on the gene expression of enzymes involved in drug metabolism, redox homeostasis, and DNA repair. METHODS All procedures were approved by the JSC Animal Care and Use Committee. Male Sprague-Dawley rats were divided into 4 groups (n=8); control, high Fe diet (650 mg iron/kg), radiation (fractionated 3 Gy exposure from a Cs- 137 source) and combined high Fe diet + radiation exposure. Animals were euthanized 24h after the last treatment of radiation; livers were removed immediately and flash -frozen in liquid nitrogen. Expression of genes thought to be involved in redox homeostasis, drug metabolism and DNA damage repair was measured by RT-qPCR. Where possible, protein expression of the same genes was measured by western blotting. All data are expressed as % change in expression normalized to reference gene expression; comparisons were then made of each treatment group to the sham exposed/ normal diet control group. Data was considered significant at p< 0

  17. Cysteine Prevents the Reduction in Keratin Synthesis Induced by Iron Deficiency in Human Keratinocytes.

    PubMed

    Miniaci, Maria Concetta; Irace, Carlo; Capuozzo, Antonella; Piccolo, Marialuisa; Di Pascale, Antonio; Russo, Annapina; Lippiello, Pellegrino; Lepre, Fabio; Russo, Giulia; Santamaria, Rita

    2016-02-01

    L-cysteine is currently recognized as a conditionally essential sulphur amino acid. Besides contributing to many biological pathways, cysteine is a key component of the keratin protein by its ability to form disulfide bridges that confer strength and rigidity to the protein. In addition to cysteine, iron represents another critical factor in regulating keratins expression in epidermal tissues, as well as in hair follicle growth and maturation. By focusing on human keratinocytes, the aim of this study was to evaluate the effect of cysteine supplementation as nutraceutical on keratin biosynthesis, as well as to get an insight on the interplay of cysteine availability and cellular iron status in regulating keratins expression in vitro. Herein we demonstrate that cysteine promotes a significant up-regulation of keratins expression as a result of de novo protein synthesis, while the lack of iron impairs keratin expression. Interestingly, cysteine supplementation counteracts the adverse effect of iron deficiency on cellular keratin expression. This effect was likely mediated by the up-regulation of transferrin receptor and ferritin, the main cellular proteins involved in iron homeostasis, at last affecting the labile iron pool. In this manner, cysteine may also enhance the metabolic iron availability for DNA synthesis without creating a detrimental condition of iron overload. To the best of our knowledge, this is one of the first study in an in vitro keratinocyte model providing evidence that cysteine and iron cooperate for keratins expression, indicative of their central role in maintaining healthy epithelia.

  18. IscR of Rhodobacter sphaeroides functions as repressor of genes for iron-sulfur metabolism and represents a new type of iron-sulfur-binding protein.

    PubMed

    Remes, Bernhard; Eisenhardt, Benjamin D; Srinivasan, Vasundara; Klug, Gabriele

    2015-10-01

    IscR proteins are known as transcriptional regulators for Fe-S biogenesis. In the facultatively phototrophic bacterium, Rhodobacter sphaeroides IscR is the product of the first gene in the isc-suf operon. A major role of IscR in R. sphaeroides iron-dependent regulation was suggested in a bioinformatic study (Rodionov et al., PLoS Comput Biol 2:e163, 2006), which predicted a binding site in the upstream regions of several iron uptake genes, named Iron-Rhodo-box. Most known IscR proteins have Fe-S clusters featuring (Cys)3 (His)1 ligation. However, IscR proteins from Rhodobacteraceae harbor only a single-Cys residue and it was considered unlikely that they can ligate an Fe-S cluster. In this study, the role of R. sphaeroides IscR as transcriptional regulator and sensor of the Fe-S cluster status of the cell was analyzed. A mutant lacking IscR is more impaired in growth under iron limitation than the wild-type and exhibits significantly increased ROS levels in iron-replete and iron-deplete conditions. Expression studies reveal that R. sphaeroides IscR in its cluster-bound form functions as transcriptional repressor of genes involved in iron metabolism by direct binding to the promoter region of genes preceded by the motif. A total of 110 genes are directly or indirectly affected by IscR. Furthermore, IscR possesses a unique Fe-S cluster ligation scheme with only a single cysteine involved.

  19. Cooperation of two mRNA-binding proteins drives metabolic adaptation to iron deficiency

    PubMed Central

    Puig, Sergi; Vergara, Sandra V.; Thiele, Dennis J.

    2008-01-01

    Summary Iron (Fe) is an essential co-factor for a wide range of cellular processes. We have previously demonstrated that during Fe-deficiency yeast Cth2 is expressed and promotes degradation of a battery of mRNAs leading to reprogramming of Fe-dependent metabolism and Fe-storage. We report that the Cth2-homologous protein, Cth1, is transiently expressed during Fe-deprivation and participates in the response to Fe-deficiency through the degradation of mRNAs primarily involved in mitochondrially-localized activities including respiration and amino acid biosynthesis. In parallel, wild type but not cth1Δ cth2Δ cells accumulate mRNAs encoding proteins that function in glucose import and storage and store high levels of glycogen. In addition, Fe-deficiency leads to Snf1 phosphorylation, a member of the AMP-activated protein kinase family required for the cellular response to glucose starvation. These studies demonstrate a metabolic reprogramming as a consequence of Fe-starvation that is dependent on the coordinated activities of two mRNA-binding proteins. PMID:18522836

  20. Metabolic depletion inhibits the uptake of nontransferrin-bound iron by K562 cells.

    PubMed

    Gutierrez, J A; Inman, R S; Akompong, T; Yu, J; Wessling-Resnick, M

    1998-12-01

    The effect of metabolic inhibitors on nontransferrin bound iron transport by K562 cells was investigated. Incubation with 1 microM rotenone, 10 microM antimycin, or 0.5 mM 2,4-dinitrophenol effectively reduced ATP levels by approximately 50%. Both the rate and extent of Fe+3 uptake were impaired in ATP-depleted cells, which display a reduced Vmax for uptake. K562 cell ferrireductase activity was also lowered by metabolic inhibitors, suggesting that the apparent energy requirements for transport reside in the reduction of Fe+3 to Fe+2. However, ATP depletion was found to inhibit the rate and extent of Fe+2 uptake as well. Thus, the transbilayer passage of Fe+2 and/or Fe+3 appears to be an energy-requiring process. These features possibly reflect properties of the transport mechanism associated with a recently identified K562 cell transport protein, called SFT for "Stimulator of Fe Transport," since exogenous expression of its activity is also affected by ATP depletion.

  1. Infrared and collision-induced fragmentation of iron ethoxide cations

    NASA Astrophysics Data System (ADS)

    Kirkwood, D. A.; Stace, A. J.

    1997-12-01

    The multi-photon infrared photo-dissociation (MPD) of iron ethoxide cations of the general form Fe+(EtOH)m(EtO)n has been studied in an ion trap using a line tuneable CO2 laser. The ions exhibit very characteristic infrared absorption profiles which are shown to be quite different from those recorded for Fe+(EtOH)n cluster ions. From a comparison with solid state data, it is suggested that the mode responsible for absorption is a C---O stretch in the ethoxide group. To complement the interpretation of the MPD data, the collision-induced dissociation (CID) of the same series of ions was promoted by the application of a tickle voltage to the end caps of the ion trap. Both MPD and CID generate the same fragment ions, but the relative intensities are different. A detailed study of Fe+(EtOH)(EtO) using isotopes reveals fragmentation pathways leading primarily to the loss of H2, CH2O and CH3CHO, all of which can be accounted for via a series of insertion and radical transfer steps. Central to many of the reactions is an initial insertion step which results in the formation of HFe+(EtO)2.

  2. Drosophila mitoferrin is essential for male fertility: evidence for a role of mitochondrial iron metabolism during spermatogenesis

    PubMed Central

    2010-01-01

    Background Mammals and Drosophila melanogaster share some striking similarities in spermatogenesis. Mitochondria in spermatids undergo dramatic morphological changes and syncytial spermatids are stripped from their cytoplasm and then individually wrapped by single membranes in an individualization process. In mammalian and fruit fly testis, components of the mitochondrial iron metabolism are expressed, but so far their function during spermatogenesis is unknown. Here we investigate the role of Drosophila mitoferrin (dmfrn), which is a mitochondrial carrier protein with an established role in the mitochondrial iron metabolism, during spermatogenesis. Results We found that P-element insertions into the 5'-untranslated region of the dmfrn gene cause recessive male sterility, which was rescued by a fluorescently tagged transgenic dmfrn genomic construct (dmfrnvenus). Testes of mutant homozygous dmfrnSH115 flies were either small with unorganized content or contained some partially elongated spermatids, or testes were of normal size but lacked mature sperm. Testis squashes indicated that spermatid elongation was defective and electron micrographs showed mitochondrial defects in elongated spermatids and indicated failed individualization. Using a LacZ reporter and the dmfrnvenus transgene, we found that dmfrn expression in testes was highest in spermatids, coinciding with the stages that showed defects in the mutants. Dmfrn-venus protein accumulated in mitochondrial derivatives of spermatids, where it remained until most of it was stripped off during individualization and disposed of in waste bags. Male sterility in flies with the hypomorph alleles dmfrnBG00456 and dmfrnEY01302 over the deletion Df(3R)ED6277 was increased by dietary iron chelation and suppressed by iron supplementation of the food, while male sterility of dmfrnSH115/Df(3R)ED6277 flies was not affected by food iron levels. Conclusions In this work, we show that mutations in the Drosophila mitoferrin gene

  3. Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice.

    PubMed

    Cloonan, Suzanne M; Glass, Kimberly; Laucho-Contreras, Maria E; Bhashyam, Abhiram R; Cervo, Morgan; Pabón, Maria A; Konrad, Csaba; Polverino, Francesca; Siempos, Ilias I; Perez, Elizabeth; Mizumura, Kenji; Ghosh, Manik C; Parameswaran, Harikrishnan; Williams, Niamh C; Rooney, Kristen T; Chen, Zhi-Hua; Goldklang, Monica P; Yuan, Guo-Cheng; Moore, Stephen C; Demeo, Dawn L; Rouault, Tracey A; D'Armiento, Jeanine M; Schon, Eric A; Manfredi, Giovanni; Quackenbush, John; Mahmood, Ashfaq; Silverman, Edwin K; Owen, Caroline A; Choi, Augustine M K

    2016-02-01

    Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element-binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondrial iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.

  4. Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice.

    PubMed

    Cloonan, Suzanne M; Glass, Kimberly; Laucho-Contreras, Maria E; Bhashyam, Abhiram R; Cervo, Morgan; Pabón, Maria A; Konrad, Csaba; Polverino, Francesca; Siempos, Ilias I; Perez, Elizabeth; Mizumura, Kenji; Ghosh, Manik C; Parameswaran, Harikrishnan; Williams, Niamh C; Rooney, Kristen T; Chen, Zhi-Hua; Goldklang, Monica P; Yuan, Guo-Cheng; Moore, Stephen C; Demeo, Dawn L; Rouault, Tracey A; D'Armiento, Jeanine M; Schon, Eric A; Manfredi, Giovanni; Quackenbush, John; Mahmood, Ashfaq; Silverman, Edwin K; Owen, Caroline A; Choi, Augustine M K

    2016-02-01

    Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element-binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondrial iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD. PMID:26752519

  5. Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress

    PubMed Central

    2013-01-01

    Background A variety of oncogenic and environmental factors alter tumor metabolism to serve the distinct cellular biosynthetic and bioenergetic needs present during oncogenesis. Extracellular acidosis is a common microenvironmental stress in solid tumors, but little is known about its metabolic influence, particularly when present in the absence of hypoxia. In order to characterize the extent of tumor cell metabolic adaptations to acidosis, we employed stable isotope tracers to examine how acidosis impacts glucose, glutamine, and palmitate metabolism in breast cancer cells exposed to extracellular acidosis. Results Acidosis increased both glutaminolysis and fatty acid β-oxidation, which contribute metabolic intermediates to drive the tricarboxylic acid cycle (TCA cycle) and ATP generation. Acidosis also led to a decoupling of glutaminolysis and novel glutathione (GSH) synthesis by repressing GCLC/GCLM expression. We further found that acidosis redirects glucose away from lactate production and towards the oxidative branch of the pentose phosphate pathway (PPP). These changes all serve to increase nicotinamide adenine dinucleotide phosphate (NADPH) production and counter the increase in reactive oxygen species (ROS) present under acidosis. The reduced novel GSH synthesis under acidosis may explain the increased demand for NADPH to recycle existing pools of GSH. Interestingly, acidosis also disconnected novel ribose synthesis from the oxidative PPP, seemingly to reroute PPP metabolites to the TCA cycle. Finally, we found that acidosis activates p53, which contributes to both the enhanced PPP and increased glutaminolysis, at least in part, through the induction of G6PD and GLS2 genes. Conclusions Acidosis alters the cellular metabolism of several major metabolites, which induces a significant degree of metabolic inflexibility. Cells exposed to acidosis largely rely upon mitochondrial metabolism for energy generation to the extent that metabolic intermediates are

  6. Chronic iron overload in rats induces oval cells in the liver.

    PubMed Central

    Smith, P. G.; Yeoh, G. C.

    1996-01-01

    Liver damage induced by a variety of agents including hepatocarcinogens, alcohol, and virus induces proliferation of oval cells. In this study, iron overloading of the liver is used as a means of inducing liver damage over an extended period to ascertain whether it promotes the appearance of oval cells. Rats were fed a 2% carbonyl-iron-supplemented diet for 3 or 6 months. Extensive iron deposits appeared periportally in hepatocytes and some Kupffer cells. Iron deposition was less pronounced pericentrally. Small oval-like cells, morphologically and immunocytochemically similar to CDE-derived oval cells, were identified and quantified. They first emerged periportally and subsequently in small tracts or foci nearer central regions and stained positively for alpha-fetoprotein, pi-class glutathione S-transferase, and the embryonic form of pyruvate kinase. They contained very few iron deposits and were classified as iron free. The major difference between CDE- and iron-overload-derived oval cells was that the latter were negative for transferrin. This study shows that cellular changes occurring in iron-overloaded rat liver are similar to those observed in rats placed on a hepatocarcinogenic diet and in rats chronically exposed to alcohol. Images Figure 1 Figure 2 Figure 3 PMID:8701979

  7. [Relation of iron supply and iron metabolism to infectious diseases and parasitoses and the competence of the immune system].

    PubMed

    Kolb, E

    1988-11-01

    In many infectious diseases and in several parasitoses the iron content in the blood plasma occasionally decreases. By reduction of the saturation of the transferrins with iron the bactericidal effect of the blood plasma is increased. In these cases the iron absorption into the liver is increased and the iron excretion from the reticulohistiocytic system decreased. The oral intake of easily soluble iron compounds which goes far beyond the need repeatedly an enteral increase of germs of Yersinia enterocolitica and a transition into the blood, respectively, was stated. The parenteral administration of Fe-dextran from time to time leads to an enrichment of this compound in macrophages, the performance of phagocytosis of which is thus restricted. The iron deficiency decreases the functional capacity of the immune system. The functional ability of the T- and B-lymphocytes as well as of the macrophages is reduced. The importance of the transferrins, of haemopexin, of haptoglobin and of lactoferrin for the defense of infections is demonstrated.

  8. The role of iron and zinc in chemotherapy-induced alopecia

    NASA Astrophysics Data System (ADS)

    Buyukavci, Mustafa; Gurol, Ali; Karabulut, Abdulhalik; Budak, Gokhan; Karacan, Mehmet

    2005-10-01

    Chemotherapy-induced alopecia is a common and distressing side effect in children with cancer. Iron and zinc are the well known trace elements which are associated with hair shedding. In this study, we investigated the hair content of iron and zinc in children with cancer consists of two groups: group A, newly diagnosed patients; group B, the patients received a course of chemotherapy. We compared the results between each others and healthy controls. Hair content of iron and zinc was not different between the patient groups. Iron concentrations of patient samples, either at diagnosis or after chemotherapy, were significantly lower than healthy controls. However, there was no statistically significant difference between the groups regarding the zinc values. In conclusion, hair content of iron and zinc do not have a role in chemotherapy-induced alopecia.

  9. Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice

    PubMed Central

    Cloonan, Suzanne M.; Glass, Kimberly; Laucho-Contreras, Maria E.; Bhashyam, Abhiram R.; Cervo, Morgan; Pabón, Maria A.; Konrad, Csaba; Polverino, Francesca; Siempos, Ilias I.; Perez, Elizabeth; Mizumura, Kenji; Ghosh, Manik C.; Parameswaran, Harikrishnan; Williams, Niamh C.; Rooney, Kristen T.; Chen, Zhi-Hua; Goldklang, Monica P.; Yuan, Guo-Cheng; Moore, Stephen C.; Demeo, Dawn L.; Rouault, Tracey A.; D’Armiento, Jeanine M.; Schon, Eric A.; Manfredi, Giovanni; Quackenbush, John; Mahmood, Ashfaq; Silverman, Edwin K.; Owen, Caroline A.; Choi, Augustine M.K.

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as an important COPD susceptibility gene, with IRP2 protein increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RIP-Seq, RNA-Seq, gene expression and functional enrichment clustering analysis, we identified IRP2 as a regulator of mitochondrial function in the lung. IRP2 increased mitochondrial iron loading and cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice with higher mitochondrial iron loading had impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas synthesis of cytochrome c oxidase (Sco2)-deficient mice with reduced COX were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD. PMID:26752519

  10. Cationic Peptides Facilitate Iron-induced Mutagenesis in Bacteria

    PubMed Central

    Rodríguez-Rojas, Alexandro; Makarova, Olga; Müller, Uta; Rolff, Jens

    2015-01-01

    Pseudomonas aeruginosa is the causative agent of chronic respiratory infections and is an important pathogen of cystic fibrosis patients. Adaptive mutations play an essential role for antimicrobial resistance and persistence. The factors that contribute to bacterial mutagenesis in this environment are not clear. Recently it has been proposed that cationic antimicrobial peptides such as LL-37 could act as mutagens in P. aeruginosa. Here we provide experimental evidence that mutagenesis is the product of a joint action of LL-37 and free iron. By estimating mutation rate, mutant frequencies and assessing mutational spectra in P. aeruginosa treated either with LL-37, iron or a combination of both we demonstrate that mutation rate and mutant frequency were increased only when free iron and LL-37 were present simultaneously. Colistin had the same effect. The addition of an iron chelator completely abolished this mutagenic effect, suggesting that LL-37 enables iron to enter the cells resulting in DNA damage by Fenton reactions. This was also supported by the observation that the mutational spectrum of the bacteria under LL-37-iron regime showed one of the characteristic Fenton reaction fingerprints: C to T transitions. Free iron concentration in nature and within hosts is kept at a very low level, but the situation in infected lungs of cystic fibrosis patients is different. Intermittent bleeding and damage to the epithelial cells in lungs may contribute to the release of free iron that in turn leads to generation of reactive oxygen species and deterioration of the respiratory tract, making it more susceptible to the infection. PMID:26430769

  11. Iron induces bimodal population development by Escherichia coli.

    PubMed

    DePas, William H; Hufnagel, David A; Lee, John S; Blanco, Luz P; Bernstein, Hans C; Fisher, Steve T; James, Garth A; Stewart, Philip S; Chapman, Matthew R

    2013-02-12

    Bacterial biofilm formation is a complex developmental process involving cellular differentiation and the formation of intricate 3D structures. Here we demonstrate that exposure to ferric chloride triggers rugose biofilm formation by the uropathogenic Escherichia coli strain UTI89 and by enteric bacteria Citrobacter koseri and Salmonella enterica serovar typhimurium. Two unique and separable cellular populations emerge in iron-triggered, rugose biofilms. Bacteria at the air-biofilm interface express high levels of the biofilm regulator csgD, the cellulose activator adrA, and the curli subunit operon csgBAC. Bacteria in the interior of rugose biofilms express low levels of csgD and undetectable levels of matrix components curli and cellulose. Iron activation of rugose biofilms is linked to oxidative stress. Superoxide generation, either through addition of phenazine methosulfate or by deletion of sodA and sodB, stimulates rugose biofilm formation in the absence of high iron. Additionally, overexpression of Mn-superoxide dismutase, which can mitigate iron-derived reactive oxygen stress, decreases biofilm formation in a WT strain upon iron exposure. Not only does reactive oxygen stress promote rugose biofilm formation, but bacteria in the rugose biofilms display increased resistance to H(2)O(2) toxicity. Altogether, we demonstrate that iron and superoxide stress trigger rugose biofilm formation in UTI89. Rugose biofilm development involves the elaboration of two distinct bacterial populations and increased resistance to oxidative stress.

  12. Spectral induced polarization and electrodic potential monitoring of microbially mediated iron sulfide transformations

    NASA Astrophysics Data System (ADS)

    Personna, Yves Robert; Ntarlagiannis, Dimitrios; Slater, Lee; Yee, Nathan; O'Brien, Michael; Hubbard, Susan

    2008-06-01

    Stimulated sulfate-reduction is a bioremediation technique utilized for the sequestration of heavy metals in the subsurface. We performed laboratory column experiments to investigate the geoelectrical response of iron sulfide transformations by Desulfovibrio vulgaris. Two geoelectrical methods, (1) spectral induced polarization (SIP), and (2) electrodic potential measurements, were investigated. Aqueous geochemistry (sulfate, lactate, sulfide, and acetate), observations of precipitates (identified from electron microscopy as iron sulfide), and electrodic potentials on bisulfide ion (HS-) sensitive silver-silver chloride (Ag-AgCl) electrodes (˜-630 mV) were diagnostic of induced transitions between anaerobic iron sulfide forming conditions and aerobic conditions promoting iron sulfide dissolution. The SIP data showed ˜10 mrad anomalies during iron sulfide mineralization accompanying microbial activity under an anaerobic transition. These anomalies disappeared during iron sulfide dissolution under the subsequent aerobic transition. SIP model parameters based on a Cole-Cole relaxation model of the polarization at the mineral-fluid interface were converted to (1) estimated biomineral surface area to pore volume (Sp), and (2) an equivalent polarizable sphere diameter (d) controlling the relaxation time. The temporal variation in these model parameters is consistent with filling and emptying of pores by iron sulfide biofilms, as the system transitions between anaerobic (pore filling) and aerobic (pore emptying) conditions. The results suggest that combined SIP and electrodic potential measurements might be used to monitor spatiotemporal variability in microbial iron sulfide transformations in the field.

  13. Spectral induced polarization and electrodic potential monitoring of microbially mediated iron sulfide transformations

    SciTech Connect

    Hubbard, Susan; Personna, Y.R.; Ntarlagiannis, D.; Slater, L.; Yee, N.; O'Brien, M.; Hubbard, S.

    2008-02-15

    Stimulated sulfate-reduction is a bioremediation technique utilized for the sequestration of heavy metals in the subsurface.We performed laboratory column experiments to investigate the geoelectrical response of iron sulfide transformations by Desulfo vibriovulgaris. Two geoelectrical methods, (1) spectral induced polarization (SIP), and (2) electrodic potential measurements, were investigated. Aqueous geochemistry (sulfate, lactate, sulfide, and acetate), observations of precipitates (identified from electron microscopy as iron sulfide), and electrodic potentials on bisulfide ion (HS) sensitive silver-silver chloride (Ag-AgCl) electrodes (630 mV) were diagnostic of induced transitions between an aerobic iron sulfide forming conditions and aerobic conditions promoting iron sulfide dissolution. The SIP data showed 10m rad anomalies during iron sulfide mineralization accompanying microbial activity under an anaerobic transition. These anomalies disappeared during iron sulfide dissolution under the subsequent aerobic transition. SIP model parameters based on a Cole-Cole relaxation model of the polarization at the mineral-fluid interface were converted to (1) estimated biomineral surface area to pore volume (Sp), and (2) an equivalent polarizable sphere diameter (d) controlling the relaxation time. The temporal variation in these model parameters is consistent with filling and emptying of pores by iron sulfide biofilms, as the system transitions between anaerobic (pore filling) and aerobic (pore emptying) conditions. The results suggest that combined SIP and electrodic potential measurements might be used to monitor spatiotemporal variability in microbial iron sulfide transformations in the field.

  14. Iron excess disturbs metabolic status and relative gonad mass in rats on high fat, fructose, and salt diets.

    PubMed

    Suliburska, Joanna; Bogdański, Paweł; Szulińska, Monika

    2013-02-01

    The aim of this study was to assess the metabolic and physiological changes in rats fed a diet high in fat, fructose, and salt, and with excess iron level. Mineral status was also estimated. Wistar rats were assigned to groups fed either a standard control diet (C) or a diet high in fat, fructose, and salt. The noncontrol diets contained either normal (M) or high level (MFe) of iron. After 6 weeks, the length and weight of the rats were measured, and the animals were euthanized. The kidneys and gonads were collected, and blood samples were taken. Serum levels of insulin, nitric oxide, and iron were measured. The iron, zinc, copper, and calcium concentrations of tissues were determined. It was found that the M diet led to a significant increase in the relative kidney mass of the rats compared with the control group. Among the rats fed the M diet, markedly higher serum level of iron and lower levels of zinc and copper were observed in tissues, while significantly higher calcium levels were found in the gonads. The MFe diet resulted in decreased obesity index, insulin level, and nitric oxide serum concentration in the rats, when compared with both the M and C diets. The high iron level in the modified diet increased the relative mass of the gonads. The excess iron level in the diet disturbed the zinc, copper, and calcium status of tissues. The decrease in insulin and nitric oxide in rats fed the diet high in iron, fat, fructose, and salt was associated with disorders of zinc, copper, and calcium status, as well as with an increase in the relative mass of the gonads.

  15. Biosynthetic and iron metabolism is regulated by thiol proteome changes dependent on glutaredoxin-2 and mitochondrial peroxiredoxin-1 in Saccharomyces cerevisiae.

    PubMed

    McDonagh, Brian; Padilla, C Alicia; Pedrajas, José Rafael; Bárcena, José Antonio

    2011-04-29

    Redoxins are involved in maintenance of thiol redox homeostasis, but their exact sites of action are only partly known. We have applied a combined redox proteomics and transcriptomics experimental strategy to discover specific functions of two interacting redoxins: dually localized glutaredoxin 2 (Grx2p) and mitochondrial peroxiredoxin 1 (Prx1p). We have identified 139 proteins showing differential postranslational thiol redox modifications when the cells do not express Grx2p, Prx1p, or both and have mapped the precise cysteines involved in each case. Some of these modifications constitute functional switches that affect metabolic and signaling pathways as the primary effect, leading to gene transcription remodeling as the secondary adaptive effect as demonstrated by a parallel high throughput gene expression analysis. The results suggest that in the absence of Grx2p, the metabolic flow toward nucleotide and aromatic amino acid biosynthesis is slowed down by redox modification of the key enzymes Rpe1p (D-ribulose-5-phosphate 3-epimerase), Tkl1p (transketolase) and Aro4p (3-deoxy-D-arabino-heptulosonate-7-phosphate synthase). The glycolytic mainstream is then diverted toward carbohydrate storage by induction of trehalose and glycogen biosynthesis genes. Porphyrin biosynthesis may also be compromised by inactivation of the redox-sensitive cytosolic enzymes Hem12p (uroporphyrinogen decarboxylase) and Sam1p (S-adenosyl methionine synthetase) and a battery of respiratory genes sensitive to low heme levels are induced. Genes of the Aft1p-dependent iron regulon were induced specifically in the absence of Prx1p despite optimal mitochondrial Fe-S biogenesis, suggesting dysfunction of the mitochondria to the cytosol signaling pathway. Strikingly, requirement of Grx2p for these events places dithiolic Grx2 in the framework of iron metabolism.

  16. Ceruloplasmin expression by human peripheral blood lymphocytes: a new link between immunity and iron metabolism.

    PubMed

    Banha, João; Marques, Liliana; Oliveira, Rita; Martins, Maria de Fátima; Paixão, Eleonora; Pereira, Dina; Malhó, Rui; Penque, Deborah; Costa, Luciana

    2008-02-01

    Ceruloplasmin (CP) is a multicopper oxidase involved in the acute phase reaction to stress. Although the physiological role of CP is uncertain, its role in iron (Fe) homeostasis and protection against free radical-initiated cell injury has been widely documented. Previous studies showed the existence of two molecular isoforms of CP: secreted CP (sCP) and a membrane glycosylphosphatidylinositol (GPI)-anchored form of CP (GPI-CP). sCP is produced mainly by the liver and is abundant in human serum whereas GPI-CP is expressed in mammalian astrocytes, rat leptomeningeal cells, and Sertolli cells. Herein, we show using RT-PCR that human peripheral blood lymphocytes (huPBL) constitutively express the transcripts for both CP molecular isoforms previously reported. Also, expression of CP in huPBL is demonstrated by immunofluorescence with confocal microscopy and flow cytometry analysis using cells isolated from healthy blood donors with normal Fe status. Importantly, the results obtained show that natural killer cells have a significantly higher CP expression compared to all other major lymphocyte subsets. In this context, the involvement of lymphocyte-derived CP on host defense processes via its anti/prooxidant properties is proposed, giving further support for a close functional interaction between the immune system and the Fe metabolism.

  17. Growth of Rhodococcus sp. strain BCP1 on gaseous n-alkanes: new metabolic insights and transcriptional analysis of two soluble di-iron monooxygenase genes

    PubMed Central

    Cappelletti, Martina; Presentato, Alessandro; Milazzo, Giorgio; Turner, Raymond J.; Fedi, Stefano; Frascari, Dario; Zannoni, Davide

    2015-01-01

    Rhodococcus sp. strain BCP1 was initially isolated for its ability to grow on gaseous n-alkanes, which act as inducers for the co-metabolic degradation of low-chlorinated compounds. Here, both molecular and metabolic features of BCP1 cells grown on gaseous and short-chain n-alkanes (up to n-heptane) were examined in detail. We show that propane metabolism generated terminal and sub-terminal oxidation products such as 1- and 2-propanol, whereas 1-butanol was the only terminal oxidation product detected from n-butane metabolism. Two gene clusters, prmABCD and smoABCD—coding for Soluble Di-Iron Monooxgenases (SDIMOs) involved in gaseous n-alkanes oxidation—were detected in the BCP1 genome. By means of Reverse Transcriptase-quantitative PCR (RT-qPCR) analysis, a set of substrates inducing the expression of the sdimo genes in BCP1 were assessed as well as their transcriptional repression in the presence of sugars, organic acids, or during the cell growth on rich medium (Luria–Bertani broth). The transcriptional start sites of both the sdimo gene clusters were identified by means of primer extension experiments. Finally, proteomic studies revealed changes in the protein pattern induced by growth on gaseous- (n-butane) and/or liquid (n-hexane) short-chain n-alkanes as compared to growth on succinate. Among the differently expressed protein spots, two chaperonins and an isocytrate lyase were identified along with oxidoreductases involved in oxidation reactions downstream of the initial monooxygenase reaction step. PMID:26029173

  18. Differential Role of Ferritins in Iron Metabolism and Virulence of the Plant-Pathogenic Bacterium Erwinia chrysanthemi 3937▿

    PubMed Central

    Boughammoura, Aïda; Matzanke, Berthold F.; Böttger, Lars; Reverchon, Sylvie; Lesuisse, Emmanuel; Expert, Dominique; Franza, Thierry

    2008-01-01

    During infection, the phytopathogenic enterobacterium Erwinia chrysanthemi has to cope with iron-limiting conditions and the production of reactive oxygen species by plant cells. Previous studies have shown that a tight control of the bacterial intracellular iron content is necessary for full virulence. The E. chrysanthemi genome possesses two loci that could be devoted to iron storage: the bfr gene, encoding a heme-containing bacterioferritin, and the ftnA gene, coding for a paradigmatic ferritin. To assess the role of these proteins in the physiology of this pathogen, we constructed ferritin-deficient mutants by reverse genetics. Unlike the bfr mutant, the ftnA mutant had increased sensitivity to iron deficiency and to redox stress conditions. Interestingly, the bfr ftnA mutant displayed an intermediate phenotype for sensitivity to these stresses. Whole-cell analysis by Mössbauer spectroscopy showed that the main iron storage protein is FtnA and that there is an increase in the ferrous iron/ferric iron ratio in the ftnA and bfr ftnA mutants. We found that ftnA gene expression is positively controlled by iron and the transcriptional repressor Fur via the small antisense RNA RyhB. bfr gene expression is induced at the stationary phase of growth. The σS transcriptional factor is necessary for this control. Pathogenicity tests showed that FtnA and the Bfr contribute differentially to the virulence of E. chrysanthemi depending on the host, indicating the importance of a perfect control of iron homeostasis in this bacterial species during infection. PMID:18165304

  19. Trivalent Iron Induced Gelation in Lambda-Carrageenan

    PubMed Central

    Running, Cordelia A.; Falshaw, Ruth; Janaswamy, Srinivas

    2012-01-01

    This communication reports gelation of lambda-carrageenan, for the first time, in the presence of trivalent iron ions. Kappa-, iota- and lambda-carrageenans are sulfated polysaccharides used extensively in food, pharmaceutical and medical applications. Kappa- and iota-carrageenans show gelation in the presence of mono- and di-valent ions, but lambda-carrageenan yields only viscous solutions. Our results show that gelation in lambda-carrageenan indeed is possible, but with trivalent ions. X-ray fiber diffraction patterns of iron (III)-lambda-carrageenan are characteristic of highly oriented and polycrystalline fibers containing well resolved Bragg reflections. The elastic modulus (G') of the product is far greater than the loss modulus (G") indicating the thermal stability of lambda-carrageenan in the presence of iron (III) ions. This novel finding has potential to expand lambda-carrageenan’s current utility beyond a viscosifying agent. PMID:22408280

  20. Trivalent iron induced gelation in lambda-carrageenan

    SciTech Connect

    Running, Cordelia A.; Falshaw, Ruth; Janaswamy, Srinivas

    2012-05-24

    This communication reports gelation of lambda-carrageenan, for the first time, in the presence of trivalent iron ions. Kappa-, iota- and lambda-carrageenans are sulfated polysaccharides used extensively in food, pharmaceutical and medical applications. Kappa- and iota-carrageenans show gelation in the presence of mono- and di-valent ions, but lambda-carrageenan yields only viscous solutions. Our results show that gelation in lambda-carrageenan indeed is possible, but with trivalent ions. X-ray fiber diffraction patterns of iron (III)-lambda-carrageenan are characteristic of highly oriented and polycrystalline fibers containing well resolved Bragg reflections. The elastic modulus (G*) of the product is far greater than the loss modulus (G*) indicating the thermal stability of lambda-carrageenan in the presence of iron (III) ions. This novel finding has potential to expand lambda-carrageenan's current utility beyond a viscosifying agent.

  1. Effects of nitrogen monoxide and carbon monoxide on molecular and cellular iron metabolism: mirror-image effector molecules that target iron.

    PubMed Central

    Watts, Ralph N; Ponka, Prem; Richardson, Des R

    2003-01-01

    Many effector functions of nitrogen monoxide (NO) and carbon monoxide (CO) are mediated through their high-affinity for iron (Fe). In this review, the roles of NO and CO are examined in terms of their effects on the molecular and cellular mechanisms involved in Fe metabolism. Both NO and CO avidly form complexes with a plethora of Fe-containing molecules. The generation of NO and CO is mediated by the nitric oxide synthase and haem oxygenase (HO) families of enzymes respectively. The effects of NO on Fe metabolism have been well characterized, whereas knowledge of the effects of CO remains within its infancy. In terms of the role of NO in Fe metabolism, one of the best characterized interactions includes its effect on the iron regulatory proteins. These molecules are mRNA-binding proteins that control the expression of the transferrin receptor 1 and ferritin, molecules that are involved in Fe uptake and storage respectively. Apart from this, activated macrophages impart their cytotoxic activity by generating NO, which results in marked Fe mobilization from tumour-cell targets. This deprives the cell of the Fe that is required for DNA synthesis and energy production. Considering that HO degrades haem, resulting in the release of CO, Fe(II) and biliverdin, it is suggested that a CO-Fe complex will form. This may account for the rapid Fe mobilization observed from macrophages after haemoglobin catabolism. Intriguingly, overexpression of HO results in cellular Fe mobilization, suggesting that CO has a similar effect to NO on Fe trafficking. Preliminary evidence suggests that, like NO, CO plays important roles in Fe metabolism. PMID:12423201

  2. Black reefs: iron-induced phase shifts on coral reefs.

    PubMed

    Kelly, Linda Wegley; Barott, Katie L; Dinsdale, Elizabeth; Friedlander, Alan M; Nosrat, Bahador; Obura, David; Sala, Enric; Sandin, Stuart A; Smith, Jennifer E; Vermeij, Mark J A; Williams, Gareth J; Willner, Dana; Rohwer, Forest

    2012-03-01

    The Line Islands are calcium carbonate coral reef platforms located in iron-poor regions of the central Pacific. Natural terrestrial run-off of iron is non-existent and aerial deposition is extremely low. However, a number of ship groundings have occurred on these atolls. The reefs surrounding the shipwreck debris are characterized by high benthic cover of turf algae, macroalgae, cyanobacterial mats and corallimorphs, as well as particulate-laden, cloudy water. These sites also have very low coral and crustose coralline algal cover and are call black reefs because of the dark-colored benthic community and reduced clarity of the overlying water column. Here we use a combination of benthic surveys, chemistry, metagenomics and microcosms to investigate if and how shipwrecks initiate and maintain black reefs. Comparative surveys show that the live coral cover was reduced from 40 to 60% to <10% on black reefs on Millennium, Tabuaeran and Kingman. These three sites are relatively large (>0.75 km(2)). The phase shift occurs rapidly; the Kingman black reef formed within 3 years of the ship grounding. Iron concentrations in algae tissue from the Millennium black reef site were six times higher than in algae collected from reference sites. Metagenomic sequencing of the Millennium Atoll black reef-associated microbial community was enriched in iron-associated virulence genes and known pathogens. Microcosm experiments showed that corals were killed by black reef rubble through microbial activity. Together these results demonstrate that shipwrecks and their associated iron pose significant threats to coral reefs in iron-limited regions. PMID:21881615

  3. Black reefs: iron-induced phase shifts on coral reefs

    PubMed Central

    Kelly, Linda Wegley; Barott, Katie L; Dinsdale, Elizabeth; Friedlander, Alan M; Nosrat, Bahador; Obura, David; Sala, Enric; Sandin, Stuart A; Smith, Jennifer E; Vermeij, Mark J A; Williams, Gareth J; Willner, Dana; Rohwer, Forest

    2012-01-01

    The Line Islands are calcium carbonate coral reef platforms located in iron-poor regions of the central Pacific. Natural terrestrial run-off of iron is non-existent and aerial deposition is extremely low. However, a number of ship groundings have occurred on these atolls. The reefs surrounding the shipwreck debris are characterized by high benthic cover of turf algae, macroalgae, cyanobacterial mats and corallimorphs, as well as particulate-laden, cloudy water. These sites also have very low coral and crustose coralline algal cover and are call black reefs because of the dark-colored benthic community and reduced clarity of the overlying water column. Here we use a combination of benthic surveys, chemistry, metagenomics and microcosms to investigate if and how shipwrecks initiate and maintain black reefs. Comparative surveys show that the live coral cover was reduced from 40 to 60% to <10% on black reefs on Millennium, Tabuaeran and Kingman. These three sites are relatively large (>0.75 km2). The phase shift occurs rapidly; the Kingman black reef formed within 3 years of the ship grounding. Iron concentrations in algae tissue from the Millennium black reef site were six times higher than in algae collected from reference sites. Metagenomic sequencing of the Millennium Atoll black reef-associated microbial community was enriched in iron-associated virulence genes and known pathogens. Microcosm experiments showed that corals were killed by black reef rubble through microbial activity. Together these results demonstrate that shipwrecks and their associated iron pose significant threats to coral reefs in iron-limited regions. PMID:21881615

  4. Black reefs: iron-induced phase shifts on coral reefs.

    PubMed

    Kelly, Linda Wegley; Barott, Katie L; Dinsdale, Elizabeth; Friedlander, Alan M; Nosrat, Bahador; Obura, David; Sala, Enric; Sandin, Stuart A; Smith, Jennifer E; Vermeij, Mark J A; Williams, Gareth J; Willner, Dana; Rohwer, Forest

    2012-03-01

    The Line Islands are calcium carbonate coral reef platforms located in iron-poor regions of the central Pacific. Natural terrestrial run-off of iron is non-existent and aerial deposition is extremely low. However, a number of ship groundings have occurred on these atolls. The reefs surrounding the shipwreck debris are characterized by high benthic cover of turf algae, macroalgae, cyanobacterial mats and corallimorphs, as well as particulate-laden, cloudy water. These sites also have very low coral and crustose coralline algal cover and are call black reefs because of the dark-colored benthic community and reduced clarity of the overlying water column. Here we use a combination of benthic surveys, chemistry, metagenomics and microcosms to investigate if and how shipwrecks initiate and maintain black reefs. Comparative surveys show that the live coral cover was reduced from 40 to 60% to <10% on black reefs on Millennium, Tabuaeran and Kingman. These three sites are relatively large (>0.75 km(2)). The phase shift occurs rapidly; the Kingman black reef formed within 3 years of the ship grounding. Iron concentrations in algae tissue from the Millennium black reef site were six times higher than in algae collected from reference sites. Metagenomic sequencing of the Millennium Atoll black reef-associated microbial community was enriched in iron-associated virulence genes and known pathogens. Microcosm experiments showed that corals were killed by black reef rubble through microbial activity. Together these results demonstrate that shipwrecks and their associated iron pose significant threats to coral reefs in iron-limited regions.

  5. Molecular and cellular aspects of iron-induced hepatic cirrhosis in rodents.

    PubMed Central

    Pietrangelo, A; Gualdi, R; Casalgrandi, G; Montosi, G; Ventura, E

    1995-01-01

    Hepatic fibrosis and cirrhosis are common findings in humans with hemochromatosis. In this study we investigated the molecular pathways of iron-induced hepatic fibrosis and evaluated the anti-fibrogenic effect of vitamin E. Male gerbils were treated with iron-dextran and fed a standard diet or a alpha-tocopherol enriched diet (250 mg/Kg diet). In gerbils on the standard diet at 6 wk after dosing with iron, in situ hybridization analysis documented a dramatic increase of signal for collagen mRNA around iron foci onto liver fat storing cells (FSC), as identified by immunocytochemistry with desmin antibody. After 4 mo, micronodular cirrhosis developed in these animals, with nonparenchymal cells surrounding hepatocyte nodules and expressing high level of TGF beta mRNA. In this group, in vivo labeling with [3H]-thymidine showed a marked proliferation of nonparenchymal cells, including FSC. In iron-dosed gerbils on the vitamin E-enriched diet for 4 mo, in spite of a severe liver iron burden, a normal lobular architecture was found, with a dramatic decrease of collagen mRNA accumulation and collagen deposition. At the molecular level, a total suppression of nonparenchymal cell proliferation was appreciable, although expression of collagen and TGF beta mRNAs was still present into microscopic iron-filled nonparenchymal cell aggregates scattered throughout the hepatic lobule. In conclusion, our study shows that anti-oxidant treatment during experimental hepatic fibrosis arrests fibrogenesis and completely prevents iron induced hepatic cirrhosis mainly through inhibition of nonparenchymal cell proliferation induced by iron. Images PMID:7706489

  6. Abscisic acid is involved in the iron-induced synthesis of maize ferritin.

    PubMed

    Lobréaux, S; Hardy, T; Briat, J F

    1993-02-01

    The ubiquitous iron storage protein ferritin has a highly conserved structure in plants and animals, but a distinct cytological location and a different level of control in response to iron excess. Plant ferritins are plastid-localized and transcriptionally regulated in response to iron, while animal ferritins are found in the cytoplasm and have their expression mainly controlled at the translational level. In order to understand the basis of these differences, we developed hydroponic cultures of maize plantlets which allowed an increase in the intracellular iron concentration, leading to a transient accumulation of ferritin mRNA and protein (Lobréaux,S., Massenet,O. and Briat,J.F., 1992, Plant Mol. Biol., 19, 563-575). Here, it is shown that iron induces ferritin and RAB (Responsive to Abscisic Acid) mRNA accumulation relatively with abscisic acid (ABA) accumulation. Ferritin mRNA also accumulates in response to exogenous ABA. Synergistic experiments demonstrate that the ABA and iron responses are linked, although full expression of the ferritin genes cannot be entirely explained by an increase in ABA concentration. Inducibility of ferritin mRNA accumulation by iron is dramatically decreased in the maize ABA-deficient mutant vp2 and can be rescued by addition of exogenous ABA, confirming the involvement of ABA in the iron response in plants. Therefore, it is concluded that a major part of the iron-induced biosynthesis of ferritin is achieved through a pathway involving an increase in the level of the plant hormone ABA. The general conclusion of this work is that the synthesis of the same protein in response to the same environmental signal can be controlled by separate and distinct mechanisms in plants and animals.

  7. Differential expression of stress-inducible proteins in chronic hepatic iron overload

    SciTech Connect

    Brown, Kyle E. Broadhurst, Kimberly A.; Mathahs, M. Meleah; Weydert, Jamie

    2007-09-01

    Introduction:: Oxidative stress can trigger a cellular stress response characterized by induction of antioxidants, acute phase reactants (APRs) and heat shock proteins (HSPs), which are presumed to play a role in limiting tissue damage. In rodents, hepatic iron overload causes oxidative stress that results in upregulation of antioxidant defenses with minimal progressive liver injury. The aim of this study was to determine whether iron overload modulates expression of other stress-responsive proteins such as APRs and HSPs that may confer protection against iron-induced damage in rodent liver. Methods:: Male rats received repeated injections of iron dextran or dextran alone over a 6-month period. Hepatic transcript levels for a panel of APRs and HSPs were quantitated by real-time PCR and protein expression was evaluated by Western blot and immunohistochemistry. Results:: Hepatic iron concentrations were increased > 50-fold in the iron-loaded rats compared to controls. Iron loading resulted in striking increases in mRNAs for Hsp32 (heme oxygenase-1; 12-fold increase vs. controls) and metallothionein-1 and -2 (both increased {approx} 6-fold). Transcripts for {alpha}1-acid glycoprotein, the major rat APR, were increased {approx} 3-fold, while expression of other classical APRs was unaltered. Surprisingly, although mRNA levels for the HSPs were not altered by iron, the abundance of Hsp25, Hsp70 and Hsp90 proteins was uniformly reduced in the iron-loaded livers, as were levels of NAD(P)H:quinone oxidoreductase 1, an Hsp70 client protein. Conclusions:: Chronic iron administration elicits a unique pattern of stress protein expression. These alterations may modulate hepatic responses to iron overload, as well as other injury processes.

  8. Exacerbation of Alcohol-Induced Oxidative Stress in Rats by Polyunsaturated Fatty Acids and Iron Load

    PubMed Central

    Patere, S. N.; Majumdar, A. S.; Saraf, M. N.

    2011-01-01

    The hypothesis that excessive intake of vegetable oil containing polyunsaturated fatty acids and iron load precipitate alcohol-induced liver damage was investigated in a rat model. In order to elucidate the mechanism underlying this synergism, the serum levels of iron, total protein, serum glutamate pyruvate transaminase, liver thiobarbituric acid reactive substances, and activities of antioxidant enzymes superoxide dismutase, catalase in liver of rats treated with alcohol, polyunsaturated fatty acids and iron per se and in combination were examined. Alcohol was fed to the rats at a level of 10-30% (blood alcohol was maintained between 150-350 mg/dl by using head space gas chromatography), polyunsaturated fatty acids at a level of 15% of diet and carbonyl iron 1.5-2% of diet per se and in combination to different groups for 30 days. Hepatotoxicity was assessed by measuring serum glutamate pyruvate transaminase, which was elevated and serum total protein, which was decreased significantly in rats fed with a combination of alcohol, polyunsaturated fatty acids and iron. It was also associated with increased lipid peroxidation and disruption of antioxidant defense in combination fed rats as compared to rats fed with alcohol or polyunsaturated fatty acids or iron. The present study revealed significant exacerbation of the alcohol-induced oxidative stress in presence of polyunsaturated fatty acids and iron. PMID:22303057

  9. Macronutrient and trace-metal geochemistry of an in situ iron-induced Southern Ocean bloom

    NASA Astrophysics Data System (ADS)

    Frew, Russell; Bowie, Andrew; Croot, Peter; Pickmere, Stuart

    We have investigated the effect of iron supply and increased phytoplankton growth on the cycling of the macronutrients phosphate, nitrate and silicic acid as well as the micronutrients copper (Cu), nickel (Ni), zinc (Zn) and cadmium (Cd). Nutrient levels were measured in situ in an iron-induced phytoplankton bloom at 61°S 140°E in the Southern Ocean Iron Release experiment (SOIREE). Nutrient ratios upon arrival at the study site indicate that much of the seasonal phytoplankton productivity was by iron-limited diatoms growing at low mean light levels. The addition of iron (Fe) induced a bloom that led to a draw-down in the macronutrients in ratios consistent with the growth of diatoms under iron-replete conditions. None of the bioutilised trace metals Cu, Ni, Zn or Cd showed any indication of co-limitation, with Fe, of phytoplankton growth. Zn concentrations did not decrease by algal uptake as expected. Cd was partitioned to the particulate phase indicating consumption by the algae. Cd was preferentially utilised with respect to P with a αCd/P=5.8. Interpretation of the Cd/Ca data from the sedimentary record using this higher induced αCd/P value would imply even higher Southern Ocean surface water P during the last glacial maximum.

  10. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements

    PubMed Central

    Swithers, Susan E.

    2013-01-01

    The negative impact of consuming sugar-sweetened beverages on weight and other health outcomes has been increasingly recognized; therefore, many people have turned to high-intensity sweeteners like aspartame, sucralose, and saccharin as a way to reduce the risk of these consequences. However, accumulating evidence suggests that frequent consumers of these sugar substitutes may also be at increased risk of excessive weight gain, metabolic syndrome, type 2 diabetes, and cardiovascular disease. This paper discusses these findings and considers the hypothesis that consuming sweet-tasting but noncaloric or reduced-calorie food and beverages interferes with learned responses that normally contribute to glucose and energy homeostasis. Because of this interference, frequent consumption of high-intensity sweeteners may have the counterintuitive effect of inducing metabolic derangements. PMID:23850261

  11. Alcohol induced changes of carbohydrate metabolism [author's transl].

    PubMed

    Ishii, H; Okuno, F; Joly, J G; Tsuchiya, M

    1978-10-01

    It is evident that ethanol by itself or one of its metabolites produces alterations in transport, metabolism and disposition of carbohydrates. Ethanol acts via changes in the redox state of co-factors; e.g. ethanol-induced hypoglycemia is due, partly, to the inhibition of hepatic gluconeogenesis by ethanol as a consequence of the increased NADH2/NAD ratio in patients whose glycogen stores are already depleted. On the other hand, hyperglycemia has also been described in patients with alcoholism. Although its mechanism is still obscure, abnormal hormonal secretion of insulin, catecholamines and glucocorticoids has been incriminated. Finally, structural changes of the liver and pancreas such as cirrhosis and pancreatitis produced by chronic alcohol consumption should also be considered as pathogenetic factors in a variety of clinical states involving deranged carbohydrate metabolism.

  12. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements.

    PubMed

    Swithers, Susan E

    2013-09-01

    The negative impact of consuming sugar-sweetened beverages on weight and other health outcomes has been increasingly recognized; therefore, many people have turned to high-intensity sweeteners like aspartame, sucralose, and saccharin as a way to reduce the risk of these consequences. However, accumulating evidence suggests that frequent consumers of these sugar substitutes may also be at increased risk of excessive weight gain, metabolic syndrome, type 2 diabetes, and cardiovascular disease. This paper discusses these findings and considers the hypothesis that consuming sweet-tasting but noncaloric or reduced-calorie food and beverages interferes with learned responses that normally contribute to glucose and energy homeostasis. Because of this interference, frequent consumption of high-intensity sweeteners may have the counterintuitive effect of inducing metabolic derangements.

  13. Iron-induced remodeling in cultured rat pulmonary artery endothelial cells.

    PubMed

    Gorbunov, Nikolai V; Atkins, James L; Gurusamy, Narasimman; Pitt, Bruce R

    2012-02-01

    Although iron is known to be a component of the pathogenesis and/or maintenance of acute lung injury (ALI) in experimental animals and human subjects, the majority of these studies have focused on disturbances in iron homeostasis in the airways resulting from exposure to noxious gases and particles. Considerably less is known about the effect of increased plasma levels of redox-reactive non-transferrin bound iron (NTBI) and its impact on pulmonary endothelium. Plasma levels of NTBI can increase under various pathophysiological conditions, including those associated with ALI, and multiple mechanisms are in place to affect the [Fe(2+)]/[Fe(3+)] redox steady state. It is well accepted, however, that intracellular transport of NTBI occurs after reduction of [Fe(3+)] to [Fe(2+)] (and is mediated by divalent metal transporters). Accordingly, as an experimental model to investigate mechanisms mediating vascular effects of redox reactive iron, rat pulmonary artery endothelial cells (RPAECs) were subjected to pulse treatment (10 min) with [Fe(2+)] nitriloacetate (30 μM) in the presence of pyrithione, an iron ionophore, to acutely increase intracellular labile pool of iron. Cellular iron influx and cell shape profile were monitored with time-lapse imaging techniques. Exposure of RPAECs to [Fe(2+)] resulted in: (i) an increase in intracellular iron as detected by the iron sensitive fluorophore, PhenGreen; (ii) depletion of cell glutathione; and (iii) nuclear translocation of stress-response transcriptional factors Nrf2 and NFkB (p65). The resulting iron-induced cell alterations were characterized by cell polarization and formation of membrane cuplike and microvilli-like projections abundant with ICAM-1, caveolin-1, and F-actin. The iron-induced re-arrangements in cytoskeleton, alterations in focal cell-cell interactions, and cell buckling were accompanied by decrease in electrical resistance of RPAEC monolayer. These effects were partially eliminated in the presence of N

  14. Iron and cancer: more ore to be mined

    PubMed Central

    Torti, Suzy V.; Torti, Frank M.

    2014-01-01

    Iron is an essential nutrient that facilitates cell proliferation and growth. However, iron also has the capacity to engage in redox cycling and free radical formation. Therefore, iron can contribute to both tumour initiation and tumour growth; recent work has also shown that iron has a role in the tumour microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumour cell survival. Signalling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy. PMID:23594855

  15. High Fat Diet Subverts Hepatocellular Iron Uptake Determining Dysmetabolic Iron Overload

    PubMed Central

    Dongiovanni, Paola; Lanti, Claudia; Gatti, Stefano; Rametta, Raffaela; Recalcati, Stefania; Maggioni, Marco; Fracanzani, Anna Ludovica; Riso, Patrizia; Cairo, Gaetano; Fargion, Silvia; Valenti, Luca

    2015-01-01

    Increased serum ferritin associated with mild hepatic iron accumulation, despite preserved upregulation of the iron hormone hepcidin, is frequently observed in patients with dysmetabolic overload syndrome (DIOS). Genetic factors and Western diet represent predisposing conditions, but the mechanisms favoring iron accumulation in DIOS are still unclear. Aims of this study were to assess the effect a high-fat diet (HFD) on hepatic iron metabolism in an experimental model in rats, to further characterize the effect of free fatty acids on iron metabolism in HepG2 hepatocytes in vitro, and to assess the translational relevance in patients with fatty liver with and without iron accumulation. Despite decreased uptake of dietary iron, rats fed HFD accumulated more hepatic iron than those fed regular diet, which was associated with steatosis development. Hepatic iron accumulation was paralleled by induction of ferritin, in the presence of preserved upregulation of hepcidin, recapitulating the features of DIOS. HFD was associated with increased expression of the major iron uptake protein Transferrin receptor-1 (TfR-1), consistently with upregulation of the intracellular iron sensor Iron regulated protein-1 (IRP1). Supplementation with fatty acids induced TfR-1 and IRP1 in HepG2 hepatocytes, favoring intracellular iron accumulation following exposure to iron salts. IRP1 silencing completely abrogated TfR-1 induction and the facilitation of intracellular iron accumulation induced by fatty acids. Hepatic TfR-1 mRNA levels were upregulated in patients with fatty liver and DIOS, whereas they were not associated with liver fat nor with inflammation. In conclusion, increased exposure to fatty acids subverts hepatic iron metabolism, favoring the induction of an iron uptake program despite hepatocellular iron accumulation. PMID:25647178

  16. Bicarbonate blocks iron translocation from cotyledons inducing iron stress responses in Citrus roots.

    PubMed

    Martínez-Cuenca, Mary-Rus; Legaz, Francisco; Forner-Giner, M Ángeles; Primo-Millo, Eduardo; Iglesias, Domingo J

    2013-07-01

    The effect of bicarbonate ion (HCO3(-)) on the mobilization of iron (Fe) reserves from cotyledons to roots during early growth of citrus seedlings and its influence on the components of the iron acquisition system were studied. Monoembryonic seeds of Citrus limon (L.) were germinated "in vitro" on two iron-deprived media, supplemented or not with 10mM HCO3(-) (-Fe+Bic and -Fe, respectively). After 21d of culture, Fe concentration in seedling organs was measured, as well as gene expression and enzymatic activities. Finally, the effect of Fe resupply on the above responses was tested in the presence and absence of HCO3(-) (+Fe+Bic or +Fe, respectively). -Fe+Bic seedlings exhibited lower Fe concentration in shoots and roots than -Fe ones but higher in cotyledons, associated to a significative inhibition of NRAMP3 expression. HCO3(-) upregulated Strategy I related genes (FRO1, FRO2, HA1 and IRT1) and FC-R and H(+)-ATPase activities in roots of Fe-starved seedlings. PEPC1 expression and PEPCase activity were also increased. When -Fe+Bic pre-treated seedlings were transferred to Fe-containing media for 15d, Fe content in shoots and roots increased, although to a lower extent in the +Fe+Bic medium. Consequently, the above-described root responses became markedly repressed, however, this effect was less pronounced in +Fe+Bic seedlings. In conclusion, it appears that HCO3(-) prevents Fe translocation from cotyledons to shoot and root, therefore reducing their Fe levels. This triggers Fe-stress responses in the root, enhancing the expression of genes related with Fe uptake and the corresponding enzymatic activities. PMID:23465471

  17. Relation between iron metabolism and antioxidants enzymes and δ-ALA-D activity in rats experimentally infected by Fasciola hepatica.

    PubMed

    Bottari, Nathieli B; Mendes, Ricardo E; Baldissera, Matheus D; Bochi, Guilherme V; Moresco, Rafael N; Leal, Marta L R; Morsch, Vera M; Schetinger, Maria R C; Christ, Ricardo; Gheller, Larissa; Marques, Éder J; Da Silva, Aleksandro S

    2016-06-01

    The aim of this study was to evaluate the iron metabolism in serum, as well as antioxidant enzymes, in addition to the Delta-Aminolevulinic Acid Dehydratase (δ-ALA-D) activity in the liver of rats experimentally infected by Fasciola hepatica. Thirty male adult rats (Wistar) specific pathogen free were divided into four groups: two uninfected group (CTRL 1 and CTRL 2) with five animals each and two infected groups (INF 1 and INF 2) with 10 animals each. Infection was performed orally with 20 metacercariae at day 1. On day 15 (CTRL 1 and INF 1 groups) and 87 PI (CTRL 2 and INF 2 groups) blood and bone marrow were collected and the animals were subsequently euthanized for liver sampling. Blood was allocated in tubes without anticoagulant for serum acquisition to measure iron, transferrin and unsaturated iron binding capacity (UIBC). δ-ALA-D, superoxide dismutase (SOD), and catalase (CAT) activities were measured in the liver. A decrease in iron, transferrin and UIBC levels was observed in all infected animals compared to control groups (P < 0.05). Furthermore, iron accumulation was observed in bone marrow of infected mice. Infected animals showed an increase in δ-ALA-D activity at 87 post-infection (PI) (INF 2) as well as in SOD activity at days 15 (INF 1) and 87 PI (INF 2). On the other hand, CAT activity was reduced in rats infected by F. hepatica during acute and chronic phase of fasciolosis (INF 1 and INF 2 groups), when moderate (acute) and severe necrosis in the liver histopathology were observed. These results may suggest that oxidative damage to tissues along with antioxidant mechanisms might have taken part in fasciolosis pathogenesis and are also involved in iron deficiency associated to changes in δ-ALA-D activity during chronic phase of disease.

  18. Cellular responses induced in vitro by iron (Fe) in a central nervous system cell line (U343MGa).

    PubMed

    Alcântara, D D F A; Ribeiro, H F; Matos, L A; Sousa, J M C; Burbano, R R; Bahia, M O

    2013-01-01

    Iron is the most important metallic chemical element on Earth. Poisoning caused by excessive iron in humans has been associated with pulmonary diseases including neoplasms caused by inhalation of iron oxides. The involvement of iron in neurodegenerative processes has already been described. DNA alterations are induced by iron and other chemical compounds containing this metal; however, the data are controversial and the mechanism by which iron induces mutagenesis remains unknown. This study assessed in vitro iron-induced cytotoxic and genotoxic responses in an astrocytic cell line. Short- and long-term cytotoxicity and genotoxicity were evaluated with the Cell Proliferation Kit II and micronucleus test, respectively. Results indicated that the highest concentration of iron sulfate tested was cytotoxic in long-term cytotoxic assays and increased micronucleus frequency in comparison to controls. The significant cytotoxicity observed here might be due to the intrinsic ability of iron to induce apoptosis and possible changes in cell cycle kinetics; the genotoxic effects are probably due to the oxidant properties of iron itself. This was the first study to investigate the induction of micronuclei by iron in central nervous system cells. PMID:23765962

  19. Characterization of lacustrine iron sulfide particles with proton-induced X-ray emission

    SciTech Connect

    Davison, W. ); Grime, G.W. ); Woof, C. )

    1992-12-01

    Black particles, collected by filtration (1.2-[mu] pore size) from the anoxic waters of a soft-water lake, were examined by a scanning proton microprobe which permitted quantitative elemental analysis by proton-induced X-ray emission (PIXE) and Rutherford backscattering (RBS). There was a uniform distribution of sulfur across the filter, but Fe, and to a lesser extent, Mn, was localized in [approximately]5-[mu]m diameter clusters. Elemental analysis with 1-[mu]m-diameter beams revealed that the Fe clusters were mainly comprised of iron oxides. Iron sulfide material not in the Fe clusters had stoichiometric proportions of Fe[sub 1.0]S[sub 0.60]P[sub 0.60]Ca[sub 0.24]K[sub 0.14]. Although a purely biogenic origin for P, Ca, and K cannot be ruled out, the composition is consistent with the particles originating as authigenic iron oxides which react with sulfide as they sink through the water column. The iron sulfide particles are richer in Cu (4,000 ppm) and Zn (6,000 ppm) than the iron oxides, suggesting that these elements are also concentrated as their insoluble sulfides. The coexistence of iron oxides and sulfides indicates that either the supply of sulfide is limiting or that some iron oxide particles are unreactive. 20 refs., 2 figs., 1 tab.

  20. Friction-induced surface activity of some hydrocarbons with clean and oxide-covered iron

    NASA Technical Reports Server (NTRS)

    Buckley, D. H.

    1973-01-01

    Sliding friction studies were conducted on a clean and oxide-covered iron surface with exposure of that surface to various hydrocarbons. The hydrocarbons included ethane, ethylene ethyl chloride, methyl chloride, and vinyl chloride. Auger cylindrical mirror analysis was used to follow interactions of the hydrocarbon with the iron surface. Results with vinyl chloride indicate friction induced surface reactivity, adsorption to surface oxides, friction sensitivity to concentration and polymerization. Variation in the loads employed influence adsorption and accordingly friction. In contrast with ethyl and vinyl chloride, friction induced surface reactivity was not observed with ethane and ethylene.

  1. Induced Clustered Nanoconfinement of Superparamagnetic Iron Oxide in Biodegradable Nanoparticles Enhances Transverse Relaxivity for Targeted Theranostics

    PubMed Central

    Ragheb, Ragy R. T.; Kim, Dongin; Bandyopadhyay, Arunima; Chahboune, Halima; Bulutoglu, Beyza; Ezaldein, Harib; Criscione, Jason M.; Fahmy, Tarek M.

    2013-01-01

    Purpose Combined therapeutic and diagnostic agents, “theranostics” are emerging valuable tools for noninvasive imaging and drug delivery. Here, we report on a solid biodegradable multifunctional nanoparticle that combines both features. Methods Poly(lactide-co-glycolide) nanoparticles were engineered to confine superparamagnetic iron oxide contrast for magnetic resonance imaging while enabling controlled drug delivery and targeting to specific cells. To achieve this dual modality, fatty acids were used as anchors for surface ligands and for encapsulated iron oxide in the polymer matrix. Results We demonstrate that fatty acid modified iron oxide prolonged retention of the contrast agent in the polymer matrix during degradative release of drug. Antibody-fatty acid surface modification facilitated cellular targeting and subsequent internalization in cells while inducing clustering of encapsulated fatty-acid modified superparamagnetic iron oxide during particle formulation. This induced clustered confinement led to an aggregation within the nanoparticle and, hence, higher transverse relaxivity, r2, (294 mM−1 s−1) compared with nanoparticles without fatty-acid ligands (160 mM−1 s−1) and higher than commercially available superparamagnetic iron oxide nanoparticles (89 mM−1 s−1). Conclusion Clustering of superparamagnetic iron oxide in poly(lactide-co-glycolide) did not affect the controlled release of encapsulated drugs such as methotrexate or clodronate and their subsequent pharmacological activity, thus highlighting the full theranostic capability of our system. PMID:23401099

  2. Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia.

    PubMed

    Armitage, Andrew E; Lim, Pei Jin; Frost, Joe N; Pasricha, Sant-Rayn; Soilleux, Elizabeth J; Evans, Emma; Morovat, Alireza; Santos, Ana; Diaz, Rebeca; Biggs, Daniel; Davies, Benjamin; Gileadi, Uzi; Robbins, Peter A; Lakhal-Littleton, Samira; Drakesmith, Hal

    2016-01-01

    Withdrawal of iron from serum (hypoferraemia) is a conserved innate immune antimicrobial strategy that can withhold this critical nutrient from invading pathogens, impairing their growth. Hepcidin (Hamp1) is the master regulator of iron and its expression is induced by inflammation. Mice lacking Hamp1 from birth rapidly accumulate iron and are susceptible to infection by blood-dwelling siderophilic bacteria such as Vibrio vulnificus. In order to study the innate immune role of hepcidin against a background of normal iron status, we developed a transgenic mouse model of tamoxifen-sensitive conditional Hamp1 deletion (termed iHamp1-KO mice). These mice attain adulthood with an iron status indistinguishable from littermate controls. Hamp1 disruption and the consequent decline of serum hepcidin concentrations occurred within hours of a single tamoxifen dose. We found that the TLR ligands LPS and Pam3CSK4 and heat-killed Brucella abortus caused an equivalent induction of inflammation in control and iHamp1-KO mice. Pam3CSK4 and B. abortus only caused a drop in serum iron in control mice, while hypoferraemia due to LPS was evident but substantially blunted in iHamp1-KO mice. Our results characterise a powerful new model of rapidly inducible hepcidin disruption, and demonstrate the critical contribution of hepcidin to the hypoferraemia of inflammation. PMID:27423740

  3. Drug-Induced Hepatotoxicity: Metabolic, Genetic and Immunological Basis

    PubMed Central

    Njoku, Dolores B.

    2014-01-01

    Drug-induced hepatotoxicity is a significant cause of acute liver failure and is usually the primary reason that therapeutic drugs are removed from the commercial market. Multiple mechanisms can culminate in drug hepatotoxicity. Metabolism, genetics and immunology separately and in concert play distinct and overlapping roles in this process. This review will cover papers we feel have addressed these mechanisms of drug-induced hepatotoxicity in adults following the consumption of commonly used medications. The aim is to generate discussion around “trigger point” papers where the investigators generated new science or provided additional contribution to existing science. Hopefully these discussions will assist in uncovering key areas that need further attention. PMID:24758937

  4. An insight into the metabolic responses of ultra-small superparamagnetic particles of iron oxide using metabonomic analysis of biofluids

    NASA Astrophysics Data System (ADS)

    Feng, Jianghua; Liu, Huili; Zhang, Limin; Bhakoo, Kishore; Lu, Lehui

    2010-10-01

    Ultra-small superparamagnetic particles of iron oxides (USPIO) have been developed as intravenous organ/tissue-targeted contrast agents to improve magnetic resonance imaging (MRI) in vivo. However, their potential toxicity and effects on metabolism have attracted particular attention. In the present study, uncoated and dextran-coated USPIO were investigated by analyzing both rat urine and plasma metabonomes using high-resolution NMR-based metabonomic analysis in combination with multivariate statistical analysis. The wealth of information gathered on the metabolic profiles from rat urine and plasma has revealed subtle metabolic changes in response to USPIO administration. The metabolic changes include the elevation of urinary α-hydroxy-n-valerate, o- and p-HPA, PAG, nicotinate and hippurate accompanied by decreases in the levels of urinary α-ketoglutarate, succinate, citrate, N-methylnicotinamide, NAG, DMA, allantoin and acetate following USPIO administration. The changes associated with USPIO administration included a gradual increase in plasma glucose, N-acetyl glycoprotein, saturated fatty acid, citrate, succinate, acetate, GPC, ketone bodies (β-hydroxybutyrate, acetone and acetoacetate) and individual amino acids, such as phenylalanine, lysine, isoleucine, glycine, glutamine and glutamate and a gradual decrease of myo-inositol, unsaturated fatty acid and triacylglycerol. Hence USPIO administration effects are reflected in changes in a number of metabolic pathways including energy, lipid, glucose and amino acid metabolism. The size- and surface chemistry-dependent metabolic responses and possible toxicity were observed using NMR analysis of biofluids. These changes may be attributed to the disturbances of hepatic, renal and cardiac functions following USPIO administrations. The potential biotoxicity can be derived from metabonomic analysis and serum biochemistry analysis. Metabonomic strategy offers a promising approach for the detection of subtle

  5. An update on the transport and metabolism of iron in Listeria monocytogenes: the role of proteins involved in pathogenicity.

    PubMed

    Lechowicz, Justyna; Krawczyk-Balska, Agata

    2015-08-01

    Listeria monocytogenes is a Gram-positive bacterium that causes a rare but severe human disease with high mortality rate. The microorganism is widespread in the natural environment where it shows a saprophytic lifestyle. In the human body it infects many different cell types, where it lives intracellularly, however it may also temporarily live extracellularly. The ability to survive and grow in such diverse niches suggests that this bacterium has a wide range of mechanisms for both the acquisition of various sources of iron and effective management of this microelement. In this review, data about the mechanisms of transport, metabolism and regulation of iron, including recent findings in these areas, are summarized with focus on the importance of these mechanisms for the virulence of L. monocytogenes. These data indicate the key role of haem transport and maintenance of intracellular iron homeostasis for the pathogenesis of L. monocytogenes. Furthermore, some of the proteins involved in iron homeostasis like Fri and FrvA seem to deserve special attention due to their potential use in the development of new therapeutic antilisterial strategies. PMID:25820385

  6. Iron Metabolism Dysregulation and Cognitive Dysfunction in Pediatric Obesity: Is There a Connection?

    PubMed Central

    Grandone, Anna; Marzuillo, Pierluigi; Perrone, Laura; Miraglia del Giudice, Emanuele

    2015-01-01

    Obesity and iron deficiency (ID) are two of the most common nutritional disorders in the world. In children both conditions deserve particular attention. Several studies revealed an association between obesity and iron deficiency in children and, in some cases, a reduced response to oral supplementation. The connecting mechanism, however, is not completely known. This review is focused on: (1) iron deficiency in obese children and the role of hepcidin in the connection between body fat and poor iron status; (2) iron status and consequences on health, in particular on cognitive function; (3) cognitive function and obesity; (4) suggestion of a possible link between cognitive dysfunction and ID in pediatric obesity; and implications for therapy and future research. PMID:26561830

  7. Iron Metabolism Dysregulation and Cognitive Dysfunction in Pediatric Obesity: Is There a Connection?

    PubMed

    Grandone, Anna; Marzuillo, Pierluigi; Perrone, Laura; Del Giudice, Emanuele Miraglia

    2015-11-06

    Obesity and iron deficiency (ID) are two of the most common nutritional disorders in the world. In children both conditions deserve particular attention. Several studies revealed an association between obesity and iron deficiency in children and, in some cases, a reduced response to oral supplementation. The connecting mechanism, however, is not completely known. This review is focused on: (1) iron deficiency in obese children and the role of hepcidin in the connection between body fat and poor iron status; (2) iron status and consequences on health, in particular on cognitive function; (3) cognitive function and obesity; (4) suggestion of a possible link between cognitive dysfunction and ID in pediatric obesity; and implications for therapy and future research.

  8. Local auxin metabolism regulates environment-induced hypocotyl elongation.

    PubMed

    Zheng, Zuyu; Guo, Yongxia; Novák, Ondřej; Chen, William; Ljung, Karin; Noel, Joseph P; Chory, Joanne

    2016-01-01

    A hallmark of plants is their adaptability of size and form in response to widely fluctuating environments. The metabolism and redistribution of the phytohormone auxin play pivotal roles in establishing active auxin gradients and resulting cellular differentiation. In Arabidopsis thaliana, cotyledons and leaves synthesize indole-3-acetic acid (IAA) from tryptophan through indole-3-pyruvic acid (3-IPA) in response to vegetational shade. This newly synthesized auxin moves to the hypocotyl where it induces elongation of hypocotyl cells. Here we show that loss of function of VAS2 (IAA-amido synthetase Gretchen Hagen 3 (GH3).17) leads to increases in free IAA at the expense of IAA-Glu (IAA-glutamate) in the hypocotyl epidermis. This active IAA elicits shade- and high temperature-induced hypocotyl elongation largely independently of 3-IPA-mediated IAA biosynthesis in cotyledons. Our results reveal an unexpected capacity of local auxin metabolism to modulate the homeostasis and spatial distribution of free auxin in specialized organs such as hypocotyls in response to shade and high temperature. PMID:27249562

  9. Local auxin metabolism regulates environment-induced hypocotyl elongation

    PubMed Central

    Zheng, Zuyu; Guo, Yongxia; Novák, Ondřej; Chen, William; Ljung, Karin; Noel, Joseph P.; Chory, Joanne

    2016-01-01

    A hallmark of plants is their adaptability of size and form in response to widely fluctuating environments. The metabolism and redistribution of the phytohormone auxin play pivotal roles in establishing active auxin gradients and resulting cellular differentiation. In Arabidopsis thaliana, cotyledons and leaves synthesize indole-3-acetic acid (IAA) from tryptophan through indole-3-pyruvic acid (3-IPA) in response to vegetational shade. This newly synthesized auxin moves to the hypocotyl where it induces elongation of hypocotyl cells. Here we show that loss of function of VAS2 (IAA-amido synthetase Gretchen Hagen 3 (GH3).17) leads to increases in free IAA at the expense of IAA-Glu (IAA-glutamate) in the hypocotyl epidermis. This active IAA elicits shade- and high temperature-induced hypocotyl elongation largely independently of 3-IPA-mediated IAA biosynthesis in cotyledons. Our results reveal an unexpected capacity of local auxin metabolism to modulate the homeostasis and spatial distribution of free auxin in specialized organs such as hypocotyls in response to shade and high temperature. PMID:27249562

  10. Iron-induced neuronal damage in a rat model of post-traumatic stress disorder.

    PubMed

    Zhao, Ming; Yu, Zhibo; Zhang, Yang; Huang, Xueling; Hou, Jingming; Zhao, YanGang; Luo, Wei; Chen, Lin; Ou, Lan; Li, Haitao; Zhang, Jiqiang

    2016-08-25

    Previous studies have shown that iron redistribution and deposition in the brain occurs in some neurodegenerative diseases, and oxidative damage due to abnormal iron level is a primary cause of neuronal death. In the present study, we used the single prolonged stress (SPS) model to mimic post-traumatic stress disorder (PTSD), and examined whether iron was involved in the progression of PTSD. The anxiety-like behaviors of the SPS group were assessed by the elevated plus maze (EPM) and open field tests, and iron levels were measured by inductively coupled plasma optical emission spectrometer (ICP-OES). Expression of glucocorticoid receptors and transferrin receptor 1 (TfR1) and ferritin (Fn) was detected by Western blot and immunohistochemistry in selected brain areas; TfR1 and Fn mRNA expression were detected by quantitative-polymerase chain reaction (Q-PCR). Ultrastructures of the hippocampus were observed under a transmission electron microscope. Our results showed that SPS exposure induced anxiety-like symptoms and increased the level of serum cortisol and the concentration of iron in key brain areas such as the hippocampus, prefrontal cortex, and striatum. The stress induced region-specific changes in both protein and mRNA levels of TfR1 and Fn. Moreover, swelling mitochondria and cell apoptosis were observed in neurons in brain regions with iron accumulation. We concluded that SPS stress increased iron in some cognition-related brain regions and subsequently cause neuronal injury, indicating that the iron may function in the pathology of PTSD.

  11. Sulforaphane rescues memory dysfunction and synaptic and mitochondrial alterations induced by brain iron accumulation.

    PubMed

    Lavich, I C; de Freitas, B S; Kist, L W; Falavigna, L; Dargél, V A; Köbe, L M; Aguzzoli, C; Piffero, B; Florian, P Z; Bogo, M R; de Lima, M N M; Schröder, N

    2015-08-20

    Iron overload contributes to the development of neurodegeneration and the exacerbation of normal apoptosis rates, largely due to its participation in the Fenton reaction and production of reactive oxygen species (ROS). Mitochondria constitute the major intracellular source of ROS and the main target of attack by free radicals. They are dynamic organelles that bind (fusion) and divide (fission) in response to environmental stimuli, developmental status, and energy needs of the cells. Sulforaphane (SFN) is a natural compound that displays antioxidant and anti-inflammatory activities. This study aims to investigate the effects of SFN on memory deficits and changes in markers of mitochondrial function, DNM1L and OPA1, and the synaptic marker, synaptophysin, induced by neonatal iron treatment. Male rats received vehicle or carbonyl iron (30mg/kg) from the 12th to the 14th postnatal day. In adulthood, they were treated with saline or SFN (0.5 or 5mg/kg) for 14days every other day. Memory deficits were assessed using the object recognition task. DNM1L, OPA1, and synaptophysin levels in the hippocampus were quantified by Western blotting. Results showed that SFN was able to reverse iron-induced decreases in mitochondrial fission protein, DNM1L, as well as synaptophysin levels in the hippocampus, leading to a recovery of recognition memory impairment induced by iron. These findings suggest that SFN may be further investigated as potential agent for the treatment of cognitive deficits associated with neurodegenerative disorders.

  12. Low Dose Iron Treatments Induce a DNA Damage Response in Human Endothelial Cells within Minutes

    PubMed Central

    Mollet, Inês G.; Giess, Adam; Paschalaki, Koralia; Periyasamy, Manikandan; Lidington, Elaine C.; Mason, Justin C.; Jones, Michael D.; Game, Laurence; Ali, Simak; Shovlin, Claire L.

    2016-01-01

    Background Spontaneous reports from patients able to report vascular sequelae in real time, and recognition that serum non transferrin bound iron may reach or exceed 10μmol/L in the blood stream after iron tablets or infusions, led us to hypothesize that conventional iron treatments may provoke acute vascular injury. This prompted us to examine whether a phenotype could be observed in normal human endothelial cells treated with low dose iron. Methodology Confluent primary human endothelial cells (EC) were treated with filter-sterilized iron (II) citrate or fresh media for RNA sequencing and validation studies. RNA transcript profiles were evaluated using directional RNA sequencing with no pre-specification of target sequences. Alignments were counted for exons and junctions of the gene strand only, blinded to treatment types. Principal Findings Rapid changes in RNA transcript profiles were observed in endothelial cells treated with 10μmol/L iron (II) citrate, compared to media-treated cells. Clustering for Gene Ontology (GO) performed on all differentially expressed genes revealed significant differences in biological process terms between iron and media-treated EC, whereas 10 sets of an equivalent number of randomly selected genes from the respective EC gene datasets showed no significant differences in any GO terms. After 1 hour, differentially expressed genes clustered to vesicle mediated transport, protein catabolism, and cell cycle (Benjamini p = 0.0016, 0.0024 and 0.0032 respectively), and by 6 hours, to cellular response to DNA damage stimulus most significantly through DNA repair genes FANCG, BLM, and H2AFX. Comet assays demonstrated that 10μM iron treatment elicited DNA damage within 1 hour. This was accompanied by a brisk DNA damage response pulse, as ascertained by the development of DNA damage response (DDR) foci, and p53 stabilization. Significance These data suggest that low dose iron treatments are sufficient to modify the vascular endothelium

  13. Fetal iron deficiency induces chromatin remodeling at the Bdnf locus in adult rat hippocampus.

    PubMed

    Tran, Phu V; Kennedy, Bruce C; Lien, Yu-Chin; Simmons, Rebecca A; Georgieff, Michael K

    2015-02-15

    Fetal and subsequent early postnatal iron deficiency causes persistent impairments in cognitive and affective behaviors despite prompt postnatal iron repletion. The long-term cognitive impacts are accompanied by persistent downregulation of brain-derived neurotrophic factor (BDNF), a factor critical for hippocampal plasticity across the life span. This study determined whether early-life iron deficiency epigenetically modifies the Bdnf locus and whether dietary choline supplementation during late gestation reverses these modifications. DNA methylation and histone modifications were assessed at the Bdnf-IV promoter in the hippocampus of rats [at postnatal day (PND) 65] that were iron-deficient (ID) during the fetal-neonatal period. Iron deficiency was induced in rat pups by providing pregnant and nursing dams an ID diet (4 mg/kg Fe) from gestational day (G) 2 through PND7, after which iron deficiency was treated with an iron-sufficient (IS) diet (200 mg/kg Fe). This paradigm resulted in about 60% hippocampal iron loss on PND15 with complete recovery by PND65. For choline supplementation, pregnant rat dams were given dietary choline (5 g/kg) from G11 through G18. DNA methylation was determined by quantitative sequencing of bisulfite-treated DNA, revealing a small alteration at the Bdnf-IV promoter. Chromatin immunoprecipitation analysis showed increased HDAC1 binding accompanied by reduced binding of RNA polymerase II and USF1 at the Bdnf-IV promoter in formerly ID rats. These changes were correlated with altered histone methylations. Prenatal choline supplementation reverses these epigenetic modifications. Collectively, the findings identify epigenetic modifications as a potential mechanism to explicate the long-term repression of Bdnf following fetal and early postnatal iron deficiency.

  14. The Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes - the EPIC-InterAct Study

    PubMed Central

    Podmore, Clara; Meidtner, Karina; Schulze, Matthias B; Scott, Robert A; Ramond, Anna; Butterworth, Adam S; Di Angelantonio, Emanuele; Danesh, John; Arriola, Larraitz; Barricarte, Aurelio; Boeing, Heiner; Clavel-Chapelon, Françoise; Cross, Amanda J; Dahm, Christina C; Fagherazzi, Guy; Franks, Paul W; Gavrila, Diana; Grioni, Sara; Gunter, Marc J; Gusto, Gaelle; Jakszyn, Paula; Katzke, Verena; Key, Timothy J; Kühn, Tilman; Mattiello, Amalia; Nilsson, Peter M; Olsen, Anja; Overvad, Kim; Palli, Domenico; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Sánchez-Cantalejo, Emilio; Slimani, Nadia; Sluijs, Ivonne; Spijkerman, Annemieke MW; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; Feskens, Edith JM; Forouhi, Nita G; Sharp, Stephen J; Riboli, Elio; Langenberg, Claudia; Wareham, Nicholas J

    2016-01-01

    Objective Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores for T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigate associations of ferritin, transferrin saturation (TSAT), serum iron and transferrin with T2D incidence, to clarify the role of iron in the pathogenesis of T2D. Research and Design Methods The EPIC-InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron and transferrin with incident T2D in 11,052 cases and a random sub-cohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population. Results Higher levels of ferritin and transferrin were associated with a higher risk of T2D [HR in men and women, respectively: 1.07 (95% CI: 1.01; 1.12) and 1.12 (1.05; 1.19) per 100 μg/L higher ferritin level; 1.11 (1.00; 1.24) and 1.22 (1.12; 1.33) per 0.5 g/L higher transferrin level] after adjustment for age, centre, BMI, physical activity, smoking status, education, hsCRP, ALT and GGT. Elevated TSAT (≥45% versus <45%) was associated with a lower risk of T2D in women [0.68 (0.54; 0.86)] but was not statistically significantly associated in men [0.90 (0.75; 1.08)]. Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (pinteraction<0.01). Conclusions The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D. PMID:26861925

  15. Anaerobic oxidation of ferrous iron by purple bacteria, a new type of phototrophic metabolism.

    PubMed Central

    Ehrenreich, A; Widdel, F

    1994-01-01

    Anoxic iron-rich sediment samples that had been stored in the light showed development of brown, rusty patches. Subcultures in defined mineral media with ferrous iron (10 mmol/liter, mostly precipitated as FeCO3) yielded enrichments of anoxygenic phototrophic bacteria which used ferrous iron as the sole electron donor for photosynthesis. Two different types of purple bacteria, represented by strains L7 and SW2, were isolated which oxidized colorless ferrous iron under anoxic conditions in the light to brown ferric iron. Strain L7 had rod-shaped, nonmotile cells (1.3 by 2 to 3 microns) which frequently formed gas vesicles. In addition to ferrous iron, strain L7 used H2 + CO2, acetate, pyruvate, and glucose as substrate for phototrophic growth. Strain SW2 had small rod-shaped, nonmotile cells (0.5 by 1 to 1.5 microns). Besides ferrous iron, strain SW2 utilized H2 + CO2, monocarboxylic acids, glucose, and fructose. Neither strain utilized free sulfide; however, both strains grew on black ferrous sulfide (FeS) which was converted to ferric iron and sulfate. Strains L7 and SW2 grown photoheterotrophically without ferrous iron were purple to brownish red and yellowish brown, respectively; absorption spectra revealed peaks characteristic of bacteriochlorophyll a. The closest phototrophic relatives of strains L7 and SW2 so far examined on the basis of 16S rRNA sequences were species of the genera Chromatium (gamma subclass of proteobacteria) and Rhodobacter (alpha subclass), respectively. In mineral medium, the new isolates formed 7.6 g of cell dry mass per mol of Fe(II) oxidized, which is in good agreement with a photoautotrophic utilization of ferrous iron as electron donor for CO2 fixation. Dependence of ferrous iron oxidation on light and CO2 was also demonstrated in dense cell suspensions. In media containing both ferrous iron and an organic substrate (e.g., acetate, glucose), strain L7 utilized ferrous iron and the organic compound simultaneously; in contrast, strain

  16. Influence of Iron Chlorosis on Pigment and Protein Metabolism in Leaves of Nicotiana tabacum L. 1

    PubMed Central

    Shetty, A. S.; Miller, G. W.

    1966-01-01

    Experiments were conducted on Nicotiana tabacum, L. to study the relation in the grana among chlorophylls, carotenoids, and proteins. The effect of iron chlorosis on protein and pigment synthesis was studied at different stages of chlorosis using glycine-U-C14. Pigments were separated by thin layer chromatography. Chlorophyll a, chlorophyll b, carotenoid, and protein contents of chloroplasts from chlorotic tissue were less than those of normal tissues. A 25% decrease in protein labeling and a 45% decrease in chlorophyll labeling was noted in deficient tissue compared to normal tissue even before chlorosis was perceptible. Both normal and iron deficient leaf discs which received iron in the incubation medium incorporated higher amounts of radioactive glycine into chlorophyll a and chlorophyll b at all stages of development than their respective counterparts not supplied with iron in the incubation medium. The presence of iron in the incubation medium reduced the amount of glycine incorporated into carotenes and xanthophylls, except where the tissue was severely chlorotic. This may be attributed to active competition for glycine between the iron-dependent- (chlorophyll) and iron-independent-(carotenoid) biosynthetic pathways. Incorporation of glycine into chloroplast pigments was lowest at severe chlorosis, probably due to a reduction in the overall enzyme activity. PMID:16656270

  17. Iron and FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR-dependent regulation of proteins and genes in Arabidopsis thaliana roots.

    PubMed

    Mai, Hans-Jörg; Lindermayr, Christian; von Toerne, Christine; Fink-Straube, Claudia; Durner, Jörg; Bauer, Petra

    2015-09-01

    Iron is an essential micronutrient for plants, and iron deficiency requires a variety of physiological adaptations. FIT (FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR) is essential for the regulation of iron uptake in Arabidopsis thaliana roots. FIT is transcriptionally as well as posttranscriptionally regulated in response to iron supply. To investigate to which extent posttranscriptional regulation upon iron deficiency applies to proteins and to determine the dependency on FIT, we performed a parallel proteomic and transcriptomic study with wild-type, a fit knock-out mutant, and a FIT overexpressing Arabidopsis line. Among 92 proteins differentially regulated by iron and/or FIT, we identified 30 proteins, which displayed differential regulation at the transcriptional level. Eleven protein spots were regulated in at least one of the data points even contrary to the respective genes dependent on FIT. We found ten proteins in at least two forms. The analysis of functional classification showed enriched GO terms among the posttranscriptionally regulated genes and of proteins, that were downregulated or absent in the fit knock-out mutant. Taken together, we provide evidence for iron and FIT-dependent posttranscriptional regulation in iron homeostasis in A. thaliana.

  18. The role of S-methylisothiourea hemisulfate as inducible nitric oxide synthase inhibitor against kidney iron deposition in iron overload rats

    PubMed Central

    Maleki, Maryam; Samadi, Melika; Khanmoradi, Mehrangiz; Nematbakhsh, Mehdi; Talebi, Ardeshir; Nasri, Hamid

    2016-01-01

    Background: Iron dextran is in common use to maintain iron stores. However, it is potentially toxic and may lead to iron deposition (ID) and impair functions of organs. Iron overload can regulate the expression of inducible nitric oxide synthase (iNOS) in some cells that has an important role in tissue destruction. S-methylisothiourea hemisulfate (SMT) is a direct inhibitor of iNOS, and this study was designed to investigate the effect of SMT against kidney ID in iron overload rats. Materials and Methods: 24 Wistar rats (male and female) were randomly assigned to two groups. Iron overloading was performed by iron dextran 100 mg/kg/day every other day for 2 weeks. In addition, during the study, groups 1 and 2 received vehicle and SMT (10 mg/kg, ip), respectively. Finally, blood samples were obtained, and the kidneys were prepared for histopathological procedures. Results: SMT significantly reduced the serum levels of creatinine and blood urea nitrogen. However, SMT did not alter the serum levels of iron and nitrite, and the kidney tissue level of nitrite. Co-administration of SMT with iron dextran did not attenuate the ID in the kidney. Conclusion: SMT, as a specific iNOS inhibitor, could not protect the kidney from ID while it attenuated the serum levels of kidney function biomarkers. PMID:27308268

  19. Iron metabolism and resistance to infection by invasive bacteria in the social amoeba Dictyostelium discoideum.

    PubMed

    Bozzaro, Salvatore; Buracco, Simona; Peracino, Barbara

    2013-01-01

    Dictyostelium cells are forest soil amoebae, which feed on bacteria and proliferate as solitary cells until bacteria are consumed. Starvation triggers a change in life style, forcing cells to gather into aggregates to form multicellular organisms capable of cell differentiation and morphogenesis. As a soil amoeba and a phagocyte that grazes on bacteria as the obligate source of food, Dictyostelium could be a natural host of pathogenic bacteria. Indeed, many pathogens that occasionally infect humans are hosted for most of their time in protozoa or free-living amoebae, where evolution of their virulence traits occurs. Due to these features and its amenability to genetic manipulation, Dictyostelium has become a valuable model organism for studying strategies of both the host to resist infection and the pathogen to escape the defense mechanisms. Similarly to higher eukaryotes, iron homeostasis is crucial for Dictyostelium resistance to invasive bacteria. Iron is essential for Dictyostelium, as both iron deficiency or overload inhibit cell growth. The Dictyostelium genome shares with mammals many genes regulating iron homeostasis. Iron transporters of the Nramp (Slc11A) family are represented with two genes, encoding Nramp1 and Nramp2. Like the mammalian ortholog, Nramp1 is recruited to phagosomes and macropinosomes, whereas Nramp2 is a membrane protein of the contractile vacuole network, which regulates osmolarity. Nramp1 and Nramp2 localization in distinct compartments suggests that both proteins synergistically regulate iron homeostasis. Rather than by absorption via membrane transporters, iron is likely gained by degradation of ingested bacteria and efflux via Nramp1 from phagosomes to the cytosol. Nramp gene disruption increases Dictyostelium sensitivity to infection, enhancing intracellular growth of Legionella or Mycobacteria. Generation of mutants in other "iron genes" will help identify genes essential for iron homeostasis and resistance to pathogens.

  20. Iron metabolism and resistance to infection by invasive bacteria in the social amoeba Dictyostelium discoideum

    PubMed Central

    Bozzaro, Salvatore; Buracco, Simona; Peracino, Barbara

    2013-01-01

    Dictyostelium cells are forest soil amoebae, which feed on bacteria and proliferate as solitary cells until bacteria are consumed. Starvation triggers a change in life style, forcing cells to gather into aggregates to form multicellular organisms capable of cell differentiation and morphogenesis. As a soil amoeba and a phagocyte that grazes on bacteria as the obligate source of food, Dictyostelium could be a natural host of pathogenic bacteria. Indeed, many pathogens that occasionally infect humans are hosted for most of their time in protozoa or free-living amoebae, where evolution of their virulence traits occurs. Due to these features and its amenability to genetic manipulation, Dictyostelium has become a valuable model organism for studying strategies of both the host to resist infection and the pathogen to escape the defense mechanisms. Similarly to higher eukaryotes, iron homeostasis is crucial for Dictyostelium resistance to invasive bacteria. Iron is essential for Dictyostelium, as both iron deficiency or overload inhibit cell growth. The Dictyostelium genome shares with mammals many genes regulating iron homeostasis. Iron transporters of the Nramp (Slc11A) family are represented with two genes, encoding Nramp1 and Nramp2. Like the mammalian ortholog, Nramp1 is recruited to phagosomes and macropinosomes, whereas Nramp2 is a membrane protein of the contractile vacuole network, which regulates osmolarity. Nramp1 and Nramp2 localization in distinct compartments suggests that both proteins synergistically regulate iron homeostasis. Rather than by absorption via membrane transporters, iron is likely gained by degradation of ingested bacteria and efflux via Nramp1 from phagosomes to the cytosol. Nramp gene disruption increases Dictyostelium sensitivity to infection, enhancing intracellular growth of Legionella or Mycobacteria. Generation of mutants in other “iron genes” will help identify genes essential for iron homeostasis and resistance to pathogens. PMID

  1. Neutron-induced hydrogen and helium production in iron

    SciTech Connect

    Haight, Robert C.

    2004-01-01

    In support of the Advanced Fuel Cycle Initiative, cross sections for hydrogen and helium production by neutrons are being investigated on structural materials from threshold to 100 MeV with the continuous-in-energy spallation neutron source at the Los Alamos Neutron Science Center (LANSCE). The present measurements are for elemental iron. The results are compared with values from the ENDF/B-VI library and its extension with LA150 evaluations. For designs in the Advanced Fuel Cycle Initiative, structural materials will be subjected to very large fluences of neutrons, and the selection of these materials will be guided by their resistance to radiation damage. The macroscopic effects of radiation damage result both from displacement of atoms in the materials as well as nuclear transmutation. We are studying the production of hydrogen and helium by neutrons, because these gases can lead to significant changes in materials properties such as embrittlement and swelling. Our experiments span the full range from threshold to 100 MeV. The lower neutron energies are those characteristic of fission neutrons, whereas the higher energies are relevant for accelerator-based irradiation test facilities. Results for the nickel isotopes, {sup 58,60}Ni, have been reported previously. The present studies are on natural iron.

  2. Higher concentrations of nanoscale zero-valent iron (nZVI) in soil induced rice chlorosis due to inhibited active iron transportation.

    PubMed

    Wang, Jie; Fang, Zhanqiang; Cheng, Wen; Yan, Xiaomin; Tsang, Pokeung Eric; Zhao, Dongye

    2016-03-01

    In this study, the effects of concentrations 0, 100, 250, 500, 750 and 1000 mg kg(-1) of nanoscale zero-valent iron (nZVI) on germination, seedlings growth, physiology and toxicity mechanisms were investigated. The results showed that nZVI had no effect on germination, but inhibited the rice seedlings growth in higher concentrations (>500 mg kg(-1) nZVI). The highest suppression rate of the length of roots and shoots reached 46.9% and 57.5%, respectively. The 1000mg kg(-1) nZVI caused the highest suppression rates for chlorophyll and carotenoids, at 91.6% and 85.2%, respectively. In addition, the activity of antioxidant enzymes was altered by the translocation of nanoparticles and changes in active iron content. Visible symptoms of iron deficiency were observed at higher concentrations, at which the active iron content decreased 61.02% in the shoots, but the active iron content not decreased in roots. Interestingly, the total and available amounts of iron in the soil were not less than those in the control. Therefore, the plants iron deficiency was not caused by (i) deficiency of available iron in the soil and (ii) restraint of the absorption that plant takes in the available iron, while induced by (ⅲ) the transport of active iron from the root to the shoot was blocked. The cortex tissues were seriously damaged by nZVI which was transported from soil to the root, these were proved by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). This current study shows that the mechanism of iron deficiency in rice seedling was due to transport of active iron from the root to the shoot blocked, which was caused by the uptake of nZVI.

  3. Higher concentrations of nanoscale zero-valent iron (nZVI) in soil induced rice chlorosis due to inhibited active iron transportation.

    PubMed

    Wang, Jie; Fang, Zhanqiang; Cheng, Wen; Yan, Xiaomin; Tsang, Pokeung Eric; Zhao, Dongye

    2016-03-01

    In this study, the effects of concentrations 0, 100, 250, 500, 750 and 1000 mg kg(-1) of nanoscale zero-valent iron (nZVI) on germination, seedlings growth, physiology and toxicity mechanisms were investigated. The results showed that nZVI had no effect on germination, but inhibited the rice seedlings growth in higher concentrations (>500 mg kg(-1) nZVI). The highest suppression rate of the length of roots and shoots reached 46.9% and 57.5%, respectively. The 1000mg kg(-1) nZVI caused the highest suppression rates for chlorophyll and carotenoids, at 91.6% and 85.2%, respectively. In addition, the activity of antioxidant enzymes was altered by the translocation of nanoparticles and changes in active iron content. Visible symptoms of iron deficiency were observed at higher concentrations, at which the active iron content decreased 61.02% in the shoots, but the active iron content not decreased in roots. Interestingly, the total and available amounts of iron in the soil were not less than those in the control. Therefore, the plants iron deficiency was not caused by (i) deficiency of available iron in the soil and (ii) restraint of the absorption that plant takes in the available iron, while induced by (ⅲ) the transport of active iron from the root to the shoot was blocked. The cortex tissues were seriously damaged by nZVI which was transported from soil to the root, these were proved by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). This current study shows that the mechanism of iron deficiency in rice seedling was due to transport of active iron from the root to the shoot blocked, which was caused by the uptake of nZVI. PMID:26803790

  4. Body iron stores and glucose intolerance in premenopausal women: role of hyperandrogenism, insulin resistance, and genomic variants related to inflammation, oxidative stress, and iron metabolism.

    PubMed

    Martínez-García, M Angeles; Luque-Ramírez, Manuel; San-Millán, José L; Escobar-Morreale, Héctor F

    2009-08-01

    OBJECTIVE Increased serum ferritin levels and iron stores may be involved in the development of abnormal glucose tolerance in women presenting with obesity and/or polycystic ovary syndrome (PCOS). We aimed to study the determinants of serum ferritin levels in premenopausal women among indexes of insulin resistance, adiposity, hyperandrogenism, and genotypes pertaining to inflammation, oxidative stress, and iron metabolism. RESEARCH DESIGN AND METHODS A total of 257 premenopausal women, classified depending on the presence or absence of PCOS, obesity, and/or abnormal glucose tolerance, underwent a complete metabolic evaluation, serum ferritin, haptoglobin, and C-reactive protein (CRP) measurements, and genotyping for proinflammatory and prooxidant variants and mutations in the HFE gene. RESULTS Serum ferritin concentrations were increased in women presenting with PCOS and/or abnormal glucose tolerance, independent of obesity. A stepwise multivariate linear regression analysis (R(2) = 0.18, P < 0.0001) retained menstrual dysfunction (beta = 0.14, P = 0.035), free testosterone (beta = 0.14, P = 0.052), insulin sensitivity index (beta = -0.12, P = 0.012), the His63Asp variant in HFE (beta = 0.16, P = 0.008), and abnormal glucose tolerance (beta = 0.15, P = 0.015) as significant predictors of the logarithm of ferritin levels, whereas CRP, haptoglobin, waist-to-hip ratio, or variants in the TNFalpha, TNFRSF1B, IL6, IL6ST, IL6Ralpha, PON1, and HFE Cys282Tyr mutation exerted no influence. CONCLUSIONS Androgen excess (partly because of hyperandrogenemia and partly because of menstrual dysfunction), insulin resistance, abnormal glucose tolerance, and the HFE His63Asp variant correlate with ferritin levels in premenopausal women.

  5. SUNLIGHT AND IRON(III)-INDUCED PHOTOCHEMICAL PRODUCTION OF DISSOLVED GASEOUS MERCURY IN FRESHWATER. (R827632)

    EPA Science Inventory

    Mechanistic understanding of sunlight-induced natural processes for
    production of dissolved gaseous mercury (DGM) in freshwaters has remained
    limited, and few direct field tests of the mechanistic hypotheses are available.
    We exposed ferric iron salt-spiked fresh s...

  6. Use of iron colloid-enhanced MRI for study of acute radiation-induced hepatic injury

    SciTech Connect

    Suto, Yuji; Ametani, Masaki; Kato, Takashi; Hashimoto, Masayuki; Kamba, Masayuki; Sugihara, Syuji; Ohta, Yoshio

    1996-03-01

    We present a case with acute radiation-induced hepatic injury using chondroitin sulfate iron colloid (CSIC)-enhanced MRI. Uptake of CSIC was decreased in the irradiated portion of the liver. CSIC-enhanced MRI is useful for obtaining information on the function of the reticuloendothelial system and demarcates between irradiated and nonirradiated zones. 18 refs., 3 figs

  7. ARE MACROPHAGES ACTIVATED AND INDUCE PULMONARY INJURY BY INTRACELLULARLY BIOAVAILABLE IRON?

    EPA Science Inventory

    ARE MACROPHAGES ACTIVATED AND INDUCE PULMONARY INJURY BY INTRACELLULARLY BIOAVAILABLE IRON? UP Kodavanti1, MCJ Schladweiler1, S Becker2, DL Costa1, P Mayer3, A Ziesenis3, WG Kreyling3, 1ETD, 2HSDivision, NHEERL, USEPA, Research Triangle Park, NC, USA, and 3GSF, Inhalation Biology...

  8. The Role of Iron and Iron Overload in Chronic Liver Disease

    PubMed Central

    Milic, Sandra; Mikolasevic, Ivana; Orlic, Lidija; Devcic, Edita; Starcevic-Cizmarevic, Nada; Stimac, Davor; Kapovic, Miljenko; Ristic, Smiljana

    2016-01-01

    The liver plays a major role in iron homeostasis; thus, in patients with chronic liver disease, iron regulation may be disturbed. Higher iron levels are present not only in patients with hereditary hemochromatosis, but also in those with alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C viral infection. Chronic liver disease decreases the synthetic functions of the liver, including the production of hepcidin, a key protein in iron metabolism. Lower levels of hepcidin result in iron overload, which leads to iron deposits in the liver and higher levels of non-transferrin-bound iron in the bloodstream. Iron combined with reactive oxygen species leads to an increase in hydroxyl radicals, which are responsible for phospholipid peroxidation, oxidation of amino acid side chains, DNA strain breaks, and protein fragmentation. Iron-induced cellular damage may be prevented by regulating the production of hepcidin or by administering hepcidin agonists. Both of these methods have yielded successful results in mouse models. PMID:27332079

  9. Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome.

    PubMed

    Ariza, Jeanelle; Steward, Craig; Rueckert, Flora; Widdison, Matt; Coffman, Robert; Afjei, Atiyeh; Noctor, Stephen C; Hagerman, Randi; Hagerman, Paul; Martínez-Cerdeño, Verónica

    2015-02-19

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene that is characterized by progressive action tremor, gait ataxia, and cognitive decline. Recent studies of mitochondrial dysfunction in FXTAS have suggested that iron dysregulation may be one component of disease pathogenesis. We tested the hypothesis that iron dysregulation is part of the pathogenic process in FXTAS. We analyzed postmortem choroid plexus from FXTAS and control subjects, and found that in FXTAS iron accumulated in the stroma, transferrin levels were decreased in the epithelial cells, and transferrin receptor 1 distribution was shifted from the basolateral membrane (control) to a predominantly intracellular location (FXTAS). In addition, ferroportin and ceruloplasmin were markedly decreased within the epithelial cells. These alterations have implications not only for understanding the pathophysiology of FXTAS, but also for the development of new clinical treatments that may incorporate selective iron chelation.

  10. Iron stimulates plasma-activated medium-induced A549 cell injury

    PubMed Central

    Adachi, Tetsuo; Nonomura, Saho; Horiba, Minori; Hirayama, Tasuku; Kamiya, Tetsuro; Nagasawa, Hideko; Hara, Hirokazu

    2016-01-01

    Non-thermal atmospheric pressure plasma is applicable to living cells and has emerged as a novel technology for cancer therapy. Plasma has recently been shown to affect cells not only by direct irradiation, but also by indirect treatments with previously prepared plasma-activated medium (PAM). Iron is an indispensable element but is also potentially toxic because it generates the hydroxyl radical (•OH) in the presence of hydrogen peroxide (H2O2) via the Fenton reaction. The aim of the present study was to demonstrate the contribution of iron to PAM-induced A549 adenocarcinoma cell apoptosis. We detected the generation of •OH and elevation of intracellular ferrous ions in PAM-treated cells and found that they were inhibited by iron chelator. The elevations observed in ferrous ions may have been due to their release from the intracellular iron store, ferritin. Hydroxyl radical-induced DNA injury was followed by the activation of poly(ADP-ribose) polymerase-1, depletion of NAD+ and ATP, and elevations in intracellular Ca2+. The sensitivities of normal cells such as smooth muscle cells and keratinocytes to PAM were less than that of A549 cells. These results demonstrated that H2O2 in PAM and/or •OH generated in the presence of iron ions disturbed the mitochondrial-nuclear network in cancer cells. PMID:26865334

  11. Early iron-deficiency-induced transcriptional changes in Arabidopsis roots as revealed by microarray analyses

    PubMed Central

    Buckhout, Thomas J; Yang, Thomas JW; Schmidt, Wolfgang

    2009-01-01

    Background Iron (Fe) is an essential nutrient in plants and animals, and Fe deficiency results in decreased vitality and performance. Due to limited bio-availability of Fe, plants have evolved sophisticated adaptive alterations in development, biochemistry and metabolism that are mainly regulated at the transcriptional level. We have investigated the early transcriptional response to Fe deficiency in roots of the model plant Arabidopsis, using a hydroponic system that permitted removal of Fe from the nutrient solution within seconds and transferring large numbers of plants with little or no mechanical damage to the root systems. We feel that this experimental approach offers significant advantages over previous and recent DNA microarray investigations of the Fe-deficiency response by increasing the resolution of the temporal response and by decreasing non-Fe deficiency-induced transcriptional changes, which are common in microarray analyses. Results The expression of sixty genes were changed after 6 h of Fe deficiency and 65% of these were found to overlap with a group of seventy-nine genes that were altered after 24 h. A disproportionally high number of transcripts encoding ion transport proteins were found, which function to increase the Fe concentration and decrease the zinc (Zn) concentration in the cytosol. Analysis of global changes in gene expression revealed that changes in Fe availability were associated with the differential expression of genes that encode transporters with presumed function in uptake and distribution of transition metals other than Fe. It appeared that under conditions of Fe deficiency, the capacity for Zn uptake increased, most probably the result of low specificity of the Fe transporter IRT1 that was induced upon Fe deficiency. The transcriptional regulation of several Zn transports under Fe deficiency led presumably to the homeostatic regulation of the cytosolic concentration of Zn and of other transition metal ions such as Mn to

  12. Soybean Ferritin Expression in Saccharomyces cerevisiae Modulates Iron Accumulation and Resistance to Elevated Iron Concentrations

    PubMed Central

    de Llanos, Rosa; Martínez-Garay, Carlos Andrés; Fita-Torró, Josep; Romero, Antonia María; Martínez-Pastor, María Teresa

    2016-01-01

    ABSTRACT Fungi, including the yeast Saccharomyces cerevisiae, lack ferritin and use vacuoles as iron storage organelles. This work explored how plant ferritin expression influenced baker's yeast iron metabolism. Soybean seed ferritin H1 (SFerH1) and SFerH2 genes were cloned and expressed in yeast cells. Both soybean ferritins assembled as multimeric complexes, which bound yeast intracellular iron in vivo and, consequently, induced the activation of the genes expressed during iron scarcity. Soybean ferritin protected yeast cells that lacked the Ccc1 vacuolar iron detoxification transporter from toxic iron levels by reducing cellular oxidation, thus allowing growth at high iron concentrations. Interestingly, when simultaneously expressed in ccc1Δ cells, SFerH1 and SFerH2 assembled as heteropolymers, which further increased iron resistance and reduced the oxidative stress produced by excess iron compared to ferritin homopolymer complexes. Finally, soybean ferritin expression led to increased iron accumulation in both wild-type and ccc1Δ yeast cells at certain environmental iron concentrations. IMPORTANCE Iron deficiency is a worldwide nutritional disorder to which women and children are especially vulnerable. A common strategy to combat iron deficiency consists of dietary supplementation with inorganic iron salts, whose bioavailability is very low. Iron-enriched yeasts and cereals are alternative strategies to diminish iron deficiency. Animals and plants possess large ferritin complexes that accumulate, detoxify, or buffer excess cellular iron. However, the yeast Saccharomyces cerevisiae lacks ferritin and uses vacuoles as iron storage organelles. Here, we explored how soybean ferritin expression influenced yeast iron metabolism, confirming that yeasts that express soybean seed ferritin could be explored as a novel strategy to increase dietary iron absorption. PMID:26969708

  13. Photo-induced spin transition of Iron(III) compounds with pi-pi intermolecular interactions.

    PubMed

    Hayami, Shinya; Hiki, Kenji; Kawahara, Takayoshi; Maeda, Yonezo; Urakami, Daisuke; Inoue, Katsuya; Ohama, Mitsuo; Kawata, Satoshi; Sato, Osamu

    2009-01-01

    Iron(III) spin-crossover compounds [Fe(pap)(2)]ClO(4) (1), [Fe(pap)(2)]BF(4) (2), [Fe(pap)(2)]PF(6) (3), [Fe(qsal)(2)]NCS (4), and [Fe(qsal)(2)]NCSe (5) (Hpap=2-(2-pyridylmethyleneamino)phenol and Hqsal=2-[(8-quinolinylimino)methyl]phenol) were prepared and their spin-transition properties investigated by magnetic susceptibility and Mössbauer spectroscopy measurements. The iron(III) compounds exhibited spin transition with thermal hysteresis. Single crystals of the iron(III) compounds were obtained as suitable solvent adducts for X-ray analysis, and structures in high-spin (HS) and low-spin (LS) states were revealed. Light-induced excited-spin-state trapping (LIESST) effects of the iron(III) compounds were induced by light irradiation at 532 nm for 1-3 and at 800 nm for 4 and 5. The activation energy E(a) and the low-temperature tunneling rate k(HL)(T-->0) of iron(III) LIESST compound 1 were estimated to be 1079 cm(-1) and 2.4x10(-8) s(-1), respectively, by HS-->LS relaxation experiments. The Huang-Rhys factor S of 1 was also estimated to be 50, which was similar to that expected for iron(II) complexes. It is thought that the slow relaxation in iron(III) systems is achieved by the large structural distortion between HS and LS states. Introduction of strong intermolecular interactions, such as pi-pi stacking, can also play an important role in the relaxation behavior, because it can enhance the structural distortion of the LIESST complex. PMID:19191246

  14. Testosterone alters iron metabolism and stimulates red blood cell production independently of dihydrotestosterone

    PubMed Central

    Beggs, Luke A.; Yarrow, Joshua F.; Conover, Christine F.; Meuleman, John R.; Beck, Darren T.; Morrow, Matthew; Zou, Baiming; Shuster, Jonathan J.

    2014-01-01

    Testosterone (T) stimulates erythropoiesis and regulates iron homeostasis. However, it remains unknown whether the (type II) 5α-reduction of T to dihydrotestosterone (DHT) mediates these androgenic effects, as it does in some other tissues. Our purpose was to determine whether inhibition of type II 5α-reductase (via finasteride) alters red blood cell (RBC) production and serum markers of iron homeostasis subsequent to testosterone-enanthate (TE) administration in older hypogonadal men. Sixty men aged ≥60 yr with serum T <300 ng/dl or bioavailable T <70 ng/dl received treatment with TE (125 mg/wk) vs. vehicle paired with finasteride (5 mg/day) vs. placebo using a 2 × 2 factorial design. Over the course of 12 mo, TE increased RBC count 9%, hematocrit 4%, and hemoglobin 8% while suppressing serum hepcidin 57% (P < 0.001 for all measurements). Most of the aforementioned changes occurred in the first 3 mo of treatment, and finasteride coadministration did not significantly alter any of these effects. TE also reduced serum ferritin 32% (P = 0.002) within 3 mo of treatment initiation without altering iron, transferrin, or transferrin saturation. We conclude that TE stimulates erythropoiesis and alters iron homeostasis independently of the type II 5α-reductase enzyme. These results demonstrate that elevated DHT is not required for androgen-mediated erythropoiesis or for alterations in iron homeostasis that would appear to support iron incorporation into RBCs. PMID:25074984

  15. NMR relaxation induced by iron oxide particles: testing theoretical models

    NASA Astrophysics Data System (ADS)

    Gossuin, Y.; Orlando, T.; Basini, M.; Henrard, D.; Lascialfari, A.; Mattea, C.; Stapf, S.; Vuong, Q. L.

    2016-04-01

    Superparamagnetic iron oxide particles find their main application as contrast agents for cellular and molecular magnetic resonance imaging. The contrast they bring is due to the shortening of the transverse relaxation time T 2 of water protons. In order to understand their influence on proton relaxation, different theoretical relaxation models have been developed, each of them presenting a certain validity domain, which depends on the particle characteristics and proton dynamics. The validation of these models is crucial since they allow for predicting the ideal particle characteristics for obtaining the best contrast but also because the fitting of T 1 experimental data by the theory constitutes an interesting tool for the characterization of the nanoparticles. In this work, T 2 of suspensions of iron oxide particles in different solvents and at different temperatures, corresponding to different proton diffusion properties, were measured and were compared to the three main theoretical models (the motional averaging regime, the static dephasing regime, and the partial refocusing model) with good qualitative agreement. However, a real quantitative agreement was not observed, probably because of the complexity of these nanoparticulate systems. The Roch theory, developed in the motional averaging regime (MAR), was also successfully used to fit T 1 nuclear magnetic relaxation dispersion (NMRD) profiles, even outside the MAR validity range, and provided a good estimate of the particle size. On the other hand, the simultaneous fitting of T 1 and T 2 NMRD profiles by the theory was impossible, and this occurrence constitutes a clear limitation of the Roch model. Finally, the theory was shown to satisfactorily fit the deuterium T 1 NMRD profile of superparamagnetic particle suspensions in heavy water.

  16. NMR relaxation induced by iron oxide particles: testing theoretical models.

    PubMed

    Gossuin, Y; Orlando, T; Basini, M; Henrard, D; Lascialfari, A; Mattea, C; Stapf, S; Vuong, Q L

    2016-04-15

    Superparamagnetic iron oxide particles find their main application as contrast agents for cellular and molecular magnetic resonance imaging. The contrast they bring is due to the shortening of the transverse relaxation time T 2 of water protons. In order to understand their influence on proton relaxation, different theoretical relaxation models have been developed, each of them presenting a certain validity domain, which depends on the particle characteristics and proton dynamics. The validation of these models is crucial since they allow for predicting the ideal particle characteristics for obtaining the best contrast but also because the fitting of T 1 experimental data by the theory constitutes an interesting tool for the characterization of the nanoparticles. In this work, T 2 of suspensions of iron oxide particles in different solvents and at different temperatures, corresponding to different proton diffusion properties, were measured and were compared to the three main theoretical models (the motional averaging regime, the static dephasing regime, and the partial refocusing model) with good qualitative agreement. However, a real quantitative agreement was not observed, probably because of the complexity of these nanoparticulate systems. The Roch theory, developed in the motional averaging regime (MAR), was also successfully used to fit T 1 nuclear magnetic relaxation dispersion (NMRD) profiles, even outside the MAR validity range, and provided a good estimate of the particle size. On the other hand, the simultaneous fitting of T 1 and T 2 NMRD profiles by the theory was impossible, and this occurrence constitutes a clear limitation of the Roch model. Finally, the theory was shown to satisfactorily fit the deuterium T 1 NMRD profile of superparamagnetic particle suspensions in heavy water.

  17. NMR relaxation induced by iron oxide particles: testing theoretical models.

    PubMed

    Gossuin, Y; Orlando, T; Basini, M; Henrard, D; Lascialfari, A; Mattea, C; Stapf, S; Vuong, Q L

    2016-04-15

    Superparamagnetic iron oxide particles find their main application as contrast agents for cellular and molecular magnetic resonance imaging. The contrast they bring is due to the shortening of the transverse relaxation time T 2 of water protons. In order to understand their influence on proton relaxation, different theoretical relaxation models have been developed, each of them presenting a certain validity domain, which depends on the particle characteristics and proton dynamics. The validation of these models is crucial since they allow for predicting the ideal particle characteristics for obtaining the best contrast but also because the fitting of T 1 experimental data by the theory constitutes an interesting tool for the characterization of the nanoparticles. In this work, T 2 of suspensions of iron oxide particles in different solvents and at different temperatures, corresponding to different proton diffusion properties, were measured and were compared to the three main theoretical models (the motional averaging regime, the static dephasing regime, and the partial refocusing model) with good qualitative agreement. However, a real quantitative agreement was not observed, probably because of the complexity of these nanoparticulate systems. The Roch theory, developed in the motional averaging regime (MAR), was also successfully used to fit T 1 nuclear magnetic relaxation dispersion (NMRD) profiles, even outside the MAR validity range, and provided a good estimate of the particle size. On the other hand, the simultaneous fitting of T 1 and T 2 NMRD profiles by the theory was impossible, and this occurrence constitutes a clear limitation of the Roch model. Finally, the theory was shown to satisfactorily fit the deuterium T 1 NMRD profile of superparamagnetic particle suspensions in heavy water. PMID:26933908

  18. Copper and zinc metabolism in aminonucleoside-induced nephrotic syndrome.

    PubMed

    Pedraza-Chaverrí, J; Torres-Rodríguez, G A; Cruz, C; Mainero, A; Tapia, E; Ibarra-Rubio, M E; Silencio, J L

    1994-01-01

    Copper (Cu) and zinc (Zn) were measured in urine, serum and tissues from rats with nephrotic syndrome (NS) induced with a single subcutaneous dose of puromycin aminonucleoside (PAN; 15 mg/100 g BW). Control animals were pair-fed. Urine was collected daily, and the rats were sacrificed on day 10. PAN-nephrotic rats had proteinuria (days 3-10), high urinary Cu (days 1, 2, 4-10) and Zn (days 3-10) excretion. On day 10, nephrotic rats had: (a) albuminuria, hypoalbuminemia, hypoproteinemia, high urine and low serum levels of ceruloplasmin; (b) low Cu and Zn serum levels; (c) high clearance and fractional excretion of Cu and Zn, and (d) low kidney and liver Cu content and essentially normal tissue Zn levels. The alterations in Cu metabolism were more intense than those in Zn metabolism. Urine Cu and Zn showed a positive correlation with urine total protein on days 3-10 which suggests that high urinary excretion of Cu and Zn may be due to the excretion of its carrier proteins. In conclusion, these rats did not show a typical Zn deficiency but a clear decrease in Cu in the liver and kidney.

  19. Cadmium Toxicity Induced Alterations in the Root Proteome of Green Gram in Contrasting Response towards Iron Supplement

    PubMed Central

    Muneer, Sowbiya; Hakeem, Khalid Rehman; Mohamed, Rozi; Lee, Jeong Hyun

    2014-01-01

    Cadmium signifies a severe threat to crop productivity and green gram is a notably iron sensitive plant which shows considerable variation towards cadmium stress. A gel-based proteomics analysis was performed with the roots of green gram exposed to iron and cadmium combined treatments. The resulting data show that twenty three proteins were down-regulated in iron-deprived roots either in the absence (−Fe/−Cd) or presence (−Fe/+Cd) of cadmium. These down-regulated proteins were however well expressed in roots under iron sufficient conditions, even in the presence of cadmium (+Fe/+Cd). The functional classification of these proteins determined that 21% of the proteins are associated with nutrient metabolism. The other proteins in higher quantities are involved in either transcription or translation regulation, and the rest are involved in biosynthesis metabolism, antioxidant pathways, molecular chaperones and stress response. On the other hand, several protein spots were also absent in roots in response to iron deprivation either in absence (−Fe/−Cd) or presence (−Fe/+Cd) of cadmium but were well expressed in the presence of iron (+Fe/+Cd). Results suggest that green gram plants exposed to cadmium stress are able to change the nutrient metabolic balance in roots, but in the mean time regulate cadmium toxicity through iron supplements. PMID:24739807

  20. Protective effect of Clerodendrum colebrookianum leaves against iron-induced oxidative stress and hepatotoxicity in Swiss albino mice.

    PubMed

    Das, Abhishek; Chaudhuri, Dipankar; Ghate, Nikhil Baban; Panja, Sourav; Chatterjee, Anupam; Mandal, Nripendranath

    2015-05-01

    Liver toxicity due to iron overload leads to oxidative damage of proteins, lipids and nucleic acids which in turn manifests several human diseases. Here, we evaluated the improving effect of Clerodendrum colebrookianum leaf on iron overload induced liver injury along with in vitro iron chelation and the protection of Fenton reaction induced DNA damage was conducted. Iron overload was induced by intraperitoneal administration of iron-dextran into mice. Post oral administration of different doses of the extract (50, 100 and 200 mg/kg body weight) showed significant decrease in different biochemical markers such as liver iron, serum ferritin and serum enzyme levels, along with decreased lipid peroxidation, protein oxidation and collagen content. In addition, the extract effectively enhanced the antioxidant enzyme levels and also exhibited the potential activity of the reductive release of ferritin iron. The protective effect of C. colebrookianum extract on injured liver was furthermore supported by the histopathological studies that showed improvement histologically. In conclusion, the present results demonstrated the hepatoprotective efficiency of C. colebrookianum leaf in iron overloaded mice, and hence, a potential iron chelating drug for iron overload diseases. PMID:26040025

  1. Tucum-Do-Cerrado (Bactris setosa Mart.) Consumption Modulates Iron Homeostasis and Prevents Iron-Induced Oxidative Stress in the Rat Liver

    PubMed Central

    Fustinoni-Reis, Adriana M.; Arruda, Sandra F.; Dourado, Lívia P. S.; da Cunha, Marcela S. B.; Siqueira, Egle M. A.

    2016-01-01

    This study investigated the effect of tucum-do-cerrado consumption in the oxidative status of iron-supplemented rats. Four groups of rats were treated: Control (AIN-93G), Tuc (AIN-93G added of tucum-do-cerrado), Fe (AIN-93G iron-enriched), or TucFe (AIN-93G with tucum-do-cerrado and iron-enriched) diet, for 30 days. Iron-enriched diet increased serum, liver, spleen, and intestine iron levels; transferrin saturation; liver lipid oxidation; mRNA levels of hepatic Hamp and Bmp6, and Nrf2 in the intestine. Tucum-do-cerrado consumption reduced spleen lipid and protein oxidation; mRNA levels of hepatic Hamp and Ftl, and increased serum antioxidant capacity and hepatic mRNA levels of Bmp6, Hmox1, Nqo1, and Nrf2. TucFe diet consumption abrogated the liver Hamp iron-induced up-regulation, prevented intestinal iron accumulation; hepatic lipid peroxidation; splenic protein damage, and the increase of catalase, glutathione reductase, and glutathione peroxidase activity in some tissues. These results suggest that tucum-do-cerrado protects tissues against oxidative damage, by reducing iron availability in liver and consequently inhibiting liver Hamp expression. PMID:26901220

  2. Application of Electric Gun for Shock Induced Phase Transition Experiments in Iron

    NASA Astrophysics Data System (ADS)

    Li, Tao; Zhu, Wenjun; Chen, Hong; Li, Qiang

    2011-06-01

    Electric gun can be applied in experiments for shock induced phase. The thickness of sample is comparable to the grain size of real matter. In this paper, the propagation of small distance in iron sample of about 1mm thickness is investigated to distinguish wave structure evolution of the shock induced phase transition. In the experiment, an aluminum foil is discharged into plasma to drive a 0.25 mm thickness Mylar flyer through a 10 mm diameter gun barrel, and the Mylar flyer is then accelerated to impact a 1 mm thickness iron sample. The signal of the free-surface of the iron sample is captured by a high precision DPS interferometer. The obtained three-wave structure velocity profile in nanosecond time-scale clearly provides evidence of shock induced phase transition in the thin iron sample. This research was supported by Grant No. 2007A01004 from the Science and Technology Foundation of China Academy of Engineering Physics. The authors would like to thank Yulin Gui for helpful discussions.

  3. Sodium Ascorbate induces apoptosis in neuroblastoma cell lines by interfering with iron uptake

    PubMed Central

    Carosio, Roberta; Zuccari, Guendalina; Orienti, Isabella; Mangraviti, Salvatore; Montaldo, Paolo G

    2007-01-01

    Background Neuroblastoma (NB) is an extra-cranial solid tumour of childhood. In spite of the good clinical response to first-line therapy, complete eradication of NB cells is rarely achieved. Thus, new therapeutic strategies are needed to eradicate surviving NB cells and prevent relapse. Sodium ascorbate has been recently reported to induce apoptosis of B16 melanoma cells through down-regulation of the transferrin receptor, CD71. Since NB and melanoma share the same embryologic neuroectodermal origin, we used different human NB cell lines to assess whether the same findings occurred. Results We could observe dose- and time-dependent induction of apoptosis in all NB cell lines. Sodium ascorbate decreased the expression of CD71 and caused cell death within 24 h. An increase in the global and specific caspase activity took place, as well as an early loss of the mitochondrial transmembrane potential. Moreover, intracellular iron was significantly decreased after exposure to sodium ascorbate. Apoptotic markers were reverted when the cells were pretreated with the iron donor ferric ammonium citrate (FAC), further confirming that iron depletion is responsible for the ascorbate-induced cell death in NB cells. Conclusion Sodium ascorbate is highly toxic to neuroblastoma cell lines and the specific mechanism of vitamin C-induced apoptosis is due to a perturbation of intracellular iron levels ensuing TfR-downregulation. PMID:17760959

  4. Pleiotropic actions of iron balance in diabetes mellitus.

    PubMed

    Wang, Xinhui; Fang, Xuexian; Wang, Fudi

    2015-03-01

    As an essential element, iron plays a central role in many physiological processes, including redox balance, inflammation, energy metabolism, and environment sensing. Perturbations in iron homeostasis are associated with several conditions, including hyperglycemia and diabetes, both of which have been studied in patients and animal models. To clarify the pleiotropic role of iron homeostasis in diabetes development, the early studies on diseases with iron-overload, studies on clinical iron depletion therapies, associations between iron-related genetic polymorphisms and diabetes, and etiological mechanisms underlying iron perturbations-impaired insulin secretion and insulin sensitivity were carefully reviewed and discussed. Hereditary hemochromatosis, transfusion-dependent thalassemia, and excess heme iron intake can increase the risk of developing diabetes. Genetically modified mice and mice fed a high-iron diet present with discrepant phenotypes due to differences in tissue iron distribution. Moreover, several genetic polymorphisms related to iron homeostasis have been associated with the risk of developing diabetes. Tightly controlled iron metabolism is essential for insulin secretion and insulin sensitivity, and iron overload in pancreatic islets alters reactive oxygen species (ROS) generation, as well as hypoxia-inducible factor-1α (HIF-1α) stability and adenosine triphosphate (ATP) synthesis, thereby impairing the function and viability of β-cells. Decreased levels of adiponectin, macrophage-mediated inflammation, and ROS-mediated liver kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) activation can contribute to iron overload-induced insulin resistance, whereas iron deficiency could also participate in obesity-related inflammation, hypoxia, and insulin resistance. Because iron homeostasis is closely correlated with many metabolic processes, future studies are needed in order to elucidate the finely tuned network among iron

  5. Role of a Fur homolog in iron metabolism in Nitrosomonas europaea

    PubMed Central

    2011-01-01

    Background In response to environmental iron concentrations, many bacteria coordinately regulate transcription of genes involved in iron acquisition via the ferric uptake regulation (Fur) system. The genome of Nitrosomonas europaea, an ammonia-oxidizing bacterium, carries three genes (NE0616, NE0730 and NE1722) encoding proteins belonging to Fur family. Results Of the three N. europaea fur homologs, only the Fur homolog encoded by gene NE0616 complemented the Escherichia coli H1780 fur mutant. A N. europaea fur:kanP mutant strain was created by insertion of kanamycin-resistance cassette in the promoter region of NE0616 fur homolog. The total cellular iron contents of the fur:kanP mutant strain increased by 1.5-fold compared to wild type when grown in Fe-replete media. Relative to the wild type, the fur:kanP mutant exhibited increased sensitivity to iron at or above 500 μM concentrations. Unlike the wild type, the fur:kanP mutant was capable of utilizing iron-bound ferrioxamine without any lag phase and showed over expression of several outer membrane TonB-dependent receptor proteins irrespective of Fe availability. Conclusions Our studies have clearly indicated a role in Fe regulation by the Fur protein encoded by N. europaea NE0616 gene. Additional studies are required to fully delineate role of this fur homolog. PMID:21338516

  6. Anaerobic Sulfur Metabolism Coupled to Dissimilatory Iron Reduction in the Extremophile Acidithiobacillus ferrooxidans

    PubMed Central

    Osorio, Héctor; Mangold, Stefanie; Denis, Yann; Ñancucheo, Ivan; Esparza, Mario; Johnson, D. Barrie; Bonnefoy, Violaine; Dopson, Mark

    2013-01-01

    Gene transcription (microarrays) and protein levels (proteomics) were compared in cultures of the acidophilic chemolithotroph Acidithiobacillus ferrooxidans grown on elemental sulfur as the electron donor under aerobic and anaerobic conditions, using either molecular oxygen or ferric iron as the electron acceptor, respectively. No evidence supporting the role of either tetrathionate hydrolase or arsenic reductase in mediating the transfer of electrons to ferric iron (as suggested by previous studies) was obtained. In addition, no novel ferric iron reductase was identified. However, data suggested that sulfur was disproportionated under anaerobic conditions, forming hydrogen sulfide via sulfur reductase and sulfate via heterodisulfide reductase and ATP sulfurylase. Supporting physiological evidence for H2S production came from the observation that soluble Cu2+ included in anaerobically incubated cultures was precipitated (seemingly as CuS). Since H2S reduces ferric iron to ferrous in acidic medium, its production under anaerobic conditions indicates that anaerobic iron reduction is mediated, at least in part, by an indirect mechanism. Evidence was obtained for an alternative model implicating the transfer of electrons from S0 to Fe3+ via a respiratory chain that includes a bc1 complex and a cytochrome c. Central carbon pathways were upregulated under aerobic conditions, correlating with higher growth rates, while many Calvin-Benson-Bassham cycle components were upregulated during anaerobic growth, probably as a result of more limited access to carbon dioxide. These results are important for understanding the role of A. ferrooxidans in environmental biogeochemical metal cycling and in industrial bioleaching operations. PMID:23354702

  7. Acidithiobacillus ferriphilus sp. nov., a facultatively anaerobic iron- and sulfur-metabolizing extreme acidophile.

    PubMed

    Falagán, Carmen; Johnson, D Barrie

    2016-01-01

    The genus Acidithiobacillus includes three species that conserve energy from the oxidation of ferrous iron, as well as reduced sulfur, to support their growth. Previous work, based on multi-locus sequence analysis, identified a fourth group of iron- and sulfur-oxidizing acidithiobacilli as a potential distinct species. Eleven strains of 'Group IV' acidithiobacilli, isolated from different global locations, have been studied. These were all shown to be obligate chemolithotrophs, growing aerobically by coupling the oxidation of ferrous iron or reduced sulfur (but not hydrogen) to molecular oxygen, or anaerobically by the oxidation of reduced sulfur coupled to ferric iron reduction. All strains were mesophilic, although some were also psychrotolerant. Strain variation was also noted in terms of tolerance to extremely low pH and to elevated concentrations of transition metals. One strain was noted to display far greater tolerance to chloride than reported for other iron-oxidizing acidithiobacilli. All of the strains were able to catalyse the oxidative dissolution of pyrite and, on the basis of some of the combined traits of some of the strains examined, it is proposed that these may have niche roles in commercial mineral bioprocessing operations, such as for low temperature bioleaching of polysulfide ores in brackish waters. The name Acidithiobacillus ferriphilus sp. nov. is proposed to accommodate the strains described, with the type strain being M20T ( = DSM 100412T = JCM 30830T).

  8. Effect of entF deletion on iron acquisition and erythritol metabolism by Brucella abortus 2308.

    PubMed

    Jain, Neeta; Rodriguez, Araceli C; Kimsawatde, Gade; Seleem, Mohamed N; Boyle, Stephen M; Sriranganathan, Nammalwar

    2011-03-01

    Brucella abortus has been shown to produce two siderophores: 2,3-dihydroxybenzoic acid (2,3-DHBA) and brucebactin. Previous studies on Brucella have shown that 2,3-DHBA is associated with erythritol utilization and virulence in pregnant ruminants. The biosynthetic pathway and role of brucebactin are not known and the only gene shown to be involved so far is entF. Using cre-lox methodology, an entF mutant was created in wild-type B. abortus 2308. Compared with the wild-type strain, the ΔentF strain showed significant growth inhibition in iron minimal media that became exacerbated in the presence of an iron chelator. For the first time, we have demonstrated the death of the ΔentF strain under iron-limiting conditions in the presence of erythritol. Addition of FeCl(3) restored the growth of the ΔentF strain, suggesting a significant role in iron acquisition. Further, complementation of the ΔentF strain using a plasmid containing an entF gene suggested the absence of any polar effects. In contrast, there was no significant difference in survival and growth between the ΔentF and wild-type strains grown in the murine macrophage cell line J774A.1, suggesting that an alternate iron acquisition pathway is present in Brucella when grown intracellulary.

  9. Acidithiobacillus ferriphilus sp. nov., a facultatively anaerobic iron- and sulfur-metabolizing extreme acidophile.

    PubMed

    Falagán, Carmen; Johnson, D Barrie

    2016-01-01

    The genus Acidithiobacillus includes three species that conserve energy from the oxidation of ferrous iron, as well as reduced sulfur, to support their growth. Previous work, based on multi-locus sequence analysis, identified a fourth group of iron- and sulfur-oxidizing acidithiobacilli as a potential distinct species. Eleven strains of 'Group IV' acidithiobacilli, isolated from different global locations, have been studied. These were all shown to be obligate chemolithotrophs, growing aerobically by coupling the oxidation of ferrous iron or reduced sulfur (but not hydrogen) to molecular oxygen, or anaerobically by the oxidation of reduced sulfur coupled to ferric iron reduction. All strains were mesophilic, although some were also psychrotolerant. Strain variation was also noted in terms of tolerance to extremely low pH and to elevated concentrations of transition metals. One strain was noted to display far greater tolerance to chloride than reported for other iron-oxidizing acidithiobacilli. All of the strains were able to catalyse the oxidative dissolution of pyrite and, on the basis of some of the combined traits of some of the strains examined, it is proposed that these may have niche roles in commercial mineral bioprocessing operations, such as for low temperature bioleaching of polysulfide ores in brackish waters. The name Acidithiobacillus ferriphilus sp. nov. is proposed to accommodate the strains described, with the type strain being M20T ( = DSM 100412T = JCM 30830T). PMID:26498321

  10. Reduced-dimensionality-induced helimagnetism in iron nanoislands.

    PubMed

    Phark, S-H; Fischer, J A; Corbetta, M; Sander, D; Nakamura, K; Kirschner, J

    2014-01-01

    Low-dimensionality in magnetic materials often leads to noncollinear magnetic order, such as a helical spin order and skyrmions, which have received much attention because of envisioned applications in spin transport and in future data storage. Up to now, however, the real-space observation of the noncollinear magnetic order has been limited mostly to systems involving a strong spin-orbit interaction. Here we report a noncollinear magnetic order in individual nanostructures of a prototypical magnetic material, bilayer iron islands on Cu (111). Spin-polarized scanning tunnelling microscopy reveals a magnetic stripe phase with a period of 1.28 nm, which is identified as a one-dimensional helical spin order. Ab initio calculations identify reduced-dimensionality-enhanced long-range antiferromagnetic interactions as the driving force of this spin order. Our findings point at the potential of nanostructured magnets as a new experimental arena of noncollinear magnetic order stabilized in a nanostructure, magnetically decoupled from the substrate. PMID:25336303

  11. Deciphering the iron response in Acinetobacter baumannii: a proteomics approach

    PubMed Central

    Nwugo, Chika; Gaddy, Jennifer A.; Zimbler, Daniel L.; Actis, Luis A.

    2010-01-01

    Iron is an essential nutrient that plays a role in bacterial differential gene expression and protein production. Accordingly, the comparative analysis of total lysate and outer membrane fractions isolated from A. baumannii ATCC 19606T cells cultured under iron-rich and -chelated conditions using 2-D gel electrophoresis-mass spectrometry resulted in the identification of 58 protein spots differentially produced. While 19 and 35 of them represent iron-repressed and iron-induced protein spots, respectively, four other spots represent a metal chelation response unrelated to iron. Most of the iron-repressed protein spots represent outer membrane siderophore receptors, some of which could be involved in the utilization of siderophores produced by other bacteria. The iron-induced protein spots represent a wide range of proteins including those involved in iron storage, such as Bfr, metabolic and energy processes, such as AcnA, AcnB, GlyA, SdhA, and SodB, as well as lipid biosynthesis. The detection of an iron-regulated Hfq ortholog indicates that iron regulation in this bacterium could be mediated by Fur and small RNAs as described in other bacteria. The iron-induced production of OmpA suggests this protein plays a role in iron metabolism as shown by the diminished ability of an OmpA isogenic deficient derivative to grow under iron-chelated conditions. PMID:20692388

  12. The influence of oxidative stress induced by iron on telomere length.

    PubMed

    Kepinska, Marta; Szyller, Jakub; Milnerowicz, Halina

    2015-11-01

    Oxidative stress can be induced by increased concentrations of iron in the body and consequently can cause shortening of telomeres. Telomeres, called mitotic clocks, are non-coding fragments at the end of chromosomes. During the replication of genetic material they are shortened, playing the role of ageing biomarkers in eukaryotes. In human endothelial cells, oxidative stress causes a decrease in telomerase activity. Shortening of chromosomes in telomeric parts was found in patients with primary hemochromatosis and in patients taking supplements containing iron. Increased level of transferrin saturation is associated with the presence of shorter telomeres in the chromosomes of leukocytes. The relationship between iron status and telomere length is still not fully understood.

  13. The correlation between swelling and radiation-induced segregation in iron-chromium-nickel alloys.

    SciTech Connect

    Allen, T. R.; Busby, J. T.; Kenik, E. A.; Was, G. S.

    1998-03-05

    The magnitudes of both void swelling and radiation-induced segregation (RIS) in iron-chromium-nickel alloys are dependent on bulk alloy composition. Because the diffusivity of nickel via the vacancy flux is slow relative to chromium, nickel enriches and chromium depletes at void surfaces during irradiation. This local composition change reduces the subsequent vacancy flux to the void, thereby reducing void swelling. In this work, the resistance to swelling from major element segregation is estimated using diffusivities derived from grain boundary segregation measurements in irradiated iron-chromium-nickel alloys. The resistance to void swelling in iron- and nickel-base alloys correlates with the segregation and both are functions of bulk alloy composition. Alloys that display the greatest amount of nickel enrichment and chromium depletion are found to be most resistant to void swelling, as predicted. Additionally, swelling is shown to be greater in alloys in which the RIS profiles are slow to develop.

  14. Iron dextran increases hepatic oxidative stress and alters expression of genes related to lipid metabolism contributing to hyperlipidaemia in murine model.

    PubMed

    Silva, Maísa; da Costa Guerra, Joyce Ferreira; Sampaio, Ana Flávia Santos; de Lima, Wanderson Geraldo; Silva, Marcelo Eustáquio; Pedrosa, Maria Lucia

    2015-01-01

    The objective of this study was to investigate the effects of iron dextran on lipid metabolism and to determine the involvement of oxidative stress. Fischer rats were divided into two groups: the standard group (S), which was fed the AIN-93M diet, and the standard plus iron group (SI), which was fed the same diet but also received iron dextran injections. Serum cholesterol and triacylglycerol levels were higher in the SI group than in the S group. Iron dextran was associated with decreased mRNA levels of pparα, and its downstream gene cpt1a, which is involved in lipid oxidation. Iron dextran also increased mRNA levels of apoB-100, MTP, and L-FABP indicating alterations in lipid secretion. Carbonyl protein and TBARS were consistently higher in the liver of the iron-treated rats. Moreover, a significant positive correlation was found between oxidative stress products, lfabp expression, and iron stores. In addition, a negative correlation was found between pparα expression, TBARS, carbonyl protein, and iron stores. In conclusion, our results suggest that the increase observed in the transport of lipids in the bloodstream and the decreased fatty acid oxidation in rats, which was promoted by iron dextran, might be attributed to increased oxidative stress. PMID:25685776

  15. Changes in metabolic profile, iron and ferritin levels during the treatment of metastatic renal cancer - A new potential biomarker?

    PubMed

    Golčić, Marin; Petković, Marija

    2016-09-01

    Metastatic renal cell carcinoma (mRCC) develops in approximately 33% of all renal cancer patients. First line treatment of mRCC includes drugs such as sunitinib, temsirolimus and pazopanib, with overall survival now reaching up to 43,6months in patients with favorable-risk metastatic disease. Several side-effects in mRCC treatment, such as hypothyroidism, can be used as positive prognostic factors and indicate good response to therapy. Hypercholesterolemia and hypertriglyceridemia independent of hypothyroidism are reported as side-effects in temsirolimus treatment and recently in sunitinib treatment, but the exact mechanism and significance of the changes remains elusive. Most likely, metabolic changes are caused by inhibition of mechanistic target of rapamycin (mTOR), a positive target of tumor growth suppression, but also a regulator of iron homeostasis. There are no clinical studies reporting changes in iron and ferritin levels during mRCC biotherapy, but we hypothesize that inhibition of mTOR will also affect iron and ferritin levels. If both lipid and iron changes correlate, there is a high possibility that both changes are primarily caused by mTOR inhibition and the level of change should correlate with the inhibition of mTOR pathway and hence the efficacy of targeted treatment. We lastly hypothesize that mRCC biotherapy causes hypercholesterolemia with a possibly improved cholesterol profile due to increase HDL/LDL ratio, so statins might not have a role as supplementary treatment, whereas a sharp rise in triglyceride levels seems to be the primary target for additional therapy. PMID:27515221

  16. Surface iron inhibits quartz-induced cytotoxic and inflammatory responses in alveolar macrophages.

    PubMed

    Ghiazza, Mara; Scherbart, Agnes M; Fenoglio, Ivana; Grendene, Francesca; Turci, Francesco; Martra, Gianmario; Albrecht, Catrin; Schins, Roel P F; Fubini, Bice

    2011-01-14

    The mechanism of enhancement/inhibition of quartz toxicity induced by iron is still unclear. Here the amount of iron on a fibrogenic quartz (Qz) was increased by wet impregnation (Fe(NO(3))(3) 0.67 and 6.7 wt %). X-ray diffraction (XRD), XRF diffuse reflectance, UV-vis, and infrared (IR) spectroscopies revealed dispersed ferric ions, and hematite aggregates at the higher loading. Surface features relevant to pathogenicity and cell responses were compared not only to the original quartz but also to reference quartz DQ12. Surface charge (ζ-potential) was more negative on the original and low-loaded specimen than on the high-loaded one. DQ12 had a less negative ζ-potential than Qz, ascribed to the absence of aluminium present in Qz (1.7 wt %). All quartz specimens were able to generate HO(•) radicals, iron-loaded samples being more reactive than original quartz. Iron deposition inhibited the rupture of a C-H bond. All quartzes were phagocytized by alveolar macrophages (AMΦ cell line NR8383) to the same extent, irrespective of their surface state. Conversely, iron loading increased AMΦ viability (evaluated by cytotoxicity and induction of apoptosis). Qz was found to be much less cytotoxic than DQ12. The induction of oxidative stress and inflammatory responses (evaluated by HO-1 mRNA expression and TNF-α mRNA and protein expression) revealed a reduction in inflammogenicity upon iron loading and a more inflammogenic potency of DQ12 ascribed to undissociated SiOH interacting via H-bonding with cell membrane components. The results suggest that besides aluminium also iron at the quartz surface may have an inhibitory effect on adverse health responses.

  17. Iron induces protection and necrosis in cultured cardiomyocytes: Role of reactive oxygen species and nitric oxide.

    PubMed

    Munoz, Juan Pablo; Chiong, Mario; García, Lorena; Troncoso, Rodrigo; Toro, Barbra; Pedrozo, Zully; Diaz-Elizondo, Jessica; Salas, Daniela; Parra, Valentina; Núñez, Marco T; Hidalgo, Cecilia; Lavandero, Sergio

    2010-02-15

    We investigate here the role of reactive oxygen species and nitric oxide in iron-induced cardiomyocyte hypertrophy or cell death. Cultured rat cardiomyocytes incubated with 20 microM iron (added as FeCl(3)-Na nitrilotriacetate, Fe-NTA) displayed hypertrophy features that included increased protein synthesis and cell size, plus realignment of F-actin filaments along with sarcomeres and activation of the atrial natriuretic factor gene promoter. Incubation with higher Fe-NTA concentrations (100 microM) produced cardiomyocyte death by necrosis. Incubation for 24 h with Fe-NTA (20-40 microM) or the nitric oxide donor Delta-nonoate increased iNOS mRNA but decreased iNOS protein levels; under these conditions, iron stimulated the activity and the dimerization of iNOS. Fe-NTA (20 microM) promoted short- and long-term generation of reactive oxygen species, whereas preincubation with l-arginine suppressed this response. Preincubation with 20 microM Fe-NTA also attenuated the necrotic cell death triggered by 100 microM Fe-NTA, suggesting that these preincubation conditions have cardioprotective effects. Inhibition of iNOS activity with 1400 W enhanced iron-induced ROS generation and prevented both iron-dependent cardiomyocyte hypertrophy and cardioprotection. In conclusion, we propose that Fe-NTA (20 microM) stimulates iNOS activity and that the enhanced NO production, by promoting hypertrophy and enhancing survival mechanisms through ROS reduction, is beneficial to cardiomyocytes. At higher concentrations, however, iron triggers cardiomyocyte death by necrosis. PMID:19969068

  18. Baking soda induced severe metabolic alkalosis in a haemodialysis patient.

    PubMed

    Solak, Yalcin; Turkmen, Kultigin; Atalay, Huseyin; Turk, Suleyman

    2009-08-01

    Metabolic alkalosis is a rare occurence in hemodialysis population compared to metabolic acidosis unless some precipitating factors such as nasogastric suction, vomiting and alkali ingestion or infusion are present. When metabolic alkalosis develops, it may cause serious clinical consequences among them are sleep apnea, resistent hypertension, dysrhythmia and seizures. Here, we present a 54-year-old female hemodialysis patient who developed a severe metabolic alkalosis due to baking soda ingestion to relieve dyspepsia. She had sleep apnea, volume overload and uncontrolled hypertension due to metabolic alkalosis. Metabolic alkalosis was corrected and the patient's clinical condition was relieved with negative-bicarbonate hemodialysis. PMID:25984015

  19. Baking soda induced severe metabolic alkalosis in a haemodialysis patient.

    PubMed

    Solak, Yalcin; Turkmen, Kultigin; Atalay, Huseyin; Turk, Suleyman

    2009-08-01

    Metabolic alkalosis is a rare occurence in hemodialysis population compared to metabolic acidosis unless some precipitating factors such as nasogastric suction, vomiting and alkali ingestion or infusion are present. When metabolic alkalosis develops, it may cause serious clinical consequences among them are sleep apnea, resistent hypertension, dysrhythmia and seizures. Here, we present a 54-year-old female hemodialysis patient who developed a severe metabolic alkalosis due to baking soda ingestion to relieve dyspepsia. She had sleep apnea, volume overload and uncontrolled hypertension due to metabolic alkalosis. Metabolic alkalosis was corrected and the patient's clinical condition was relieved with negative-bicarbonate hemodialysis.

  20. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects are Diminished in Adrenalectomized Rats

    EPA Science Inventory

    Acute ozone exposure increases circulating stress hormones and induces peripheral metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for ozone-induced systemic metabolic effects and lung injury. Male Wis...

  1. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects are Diminished in Adrenalectomized Rats#

    EPA Science Inventory

    Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats ...

  2. Iron Mediates N-Methyl-d-aspartate Receptor-dependent Stimulation of Calcium-induced Pathways and Hippocampal Synaptic Plasticity*

    PubMed Central

    Muñoz, Pablo; Humeres, Alexis; Elgueta, Claudio; Kirkwood, Alfredo; Hidalgo, Cecilia; Núñez, Marco T.

    2011-01-01

    Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist N-methyl-d-aspartate (NMDA), and the effects of iron addition/chelation on hippocampal basal synaptic transmission and long-term potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodine-reduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N-acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP. PMID:21296883

  3. Iron oxide nanoparticles induce Pseudomonas aeruginosa growth, induce biofilm formation, and inhibit antimicrobial peptide function.

    PubMed

    Borcherding, Jennifer; Baltrusaitis, Jonas; Chen, Haihan; Stebounova, Larissa; Wu, Chia-Ming; Rubasinghege, Gayan; Mudunkotuwa, Imali A; Caraballo, Juan Carlos; Zabner, Joseph; Grassian, Vicki H; Comellas, Alejandro P

    2014-04-01

    Given the increased use of iron-containing nanoparticles in a number of applications, it is important to understand any effects that iron-containing nanoparticles can have on the environment and human health. Since iron concentrations are extremely low in body fluids, there is potential that iron-containing nanoparticles may influence the ability of bacteria to scavenge iron for growth, affect virulence and inhibit antimicrobial peptide (AMP) function. In this study, Pseudomonas aeruginosa (PA01) and AMPs were exposed to iron oxide nanoparticles, hematite (α-Fe2O3), of different sizes ranging from 2 to 540 nm (2 ± 1, 43 ± 6, 85 ± 25 and 540 ± 90 nm) in diameter. Here we show that the greatest effect on bacterial growth, biofilm formation, and AMP function impairment is found when exposed to the smallest particles. These results are attributed in large part to enhanced dissolution observed for the smallest particles and an increase in the amount of bioavailable iron. Furthermore, AMP function can be additionally impaired by adsorption onto nanoparticle surfaces. In particular, lysozyme readily adsorbs onto the nanoparticle surface which can lead to loss of peptide activity. Thus, this current study shows that co-exposure of nanoparticles and known pathogens can impact host innate immunity. Therefore, it is important that future studies be designed to further understand these types of impacts. PMID:25221673

  4. Exercise-induced albuminuria is related to metabolic syndrome.

    PubMed

    Greenberg, Sharon; Shenhar-Tsarfaty, Shani; Rogowski, Ori; Shapira, Itzhak; Zeltser, David; Weinstein, Talia; Lahav, Dror; Vered, Jaffa; Tovia-Brodie, Oholi; Arbel, Yaron; Berliner, Shlomo; Milwidsky, Assi

    2016-06-01

    Microalbuminuria (MA) is a known marker for endothelial dysfunction and future cardiovascular events. Exercise-induced albuminuria (EiA) may precede the appearance of MA. Associations between EiA and metabolic syndrome (MS) have not been assessed so far. Our aim was to investigate this association in a large sample of apparently healthy individuals with no baseline albuminuria. This was a cross-sectional study of 2,027 adults with no overt cardiovascular diseases who took part in a health survey program and had no baseline MA. Diagnosis of MS was based on harmonized criteria. All patients underwent an exercise test (Bruce protocol), and urinary albumin was measured before and after the examination. Urinary albumin-to-creatinine ratio (ACR) values before and after exercise were 0.40 (0.21-0.89) and 1.06 (0.43-2.69) mg/g for median (interquartile range) respectively. A total of 394 (20%) subjects had EiA; ACR rose from normal rest values (0.79 mg/g) to 52.28 mg/g after exercise (P < 0.001); this effect was not shown for the rest of the study population. EiA was related to higher prevalence of MS (13.8% vs. 27.1%, P < 0.001), higher metabolic equivalents (P < 0.001), higher baseline blood pressure (P < 0.001), and higher levels of fasting plasma glucose, triglycerides, and body mass index (P < 0.001). Multivariate binary logistic regression model showed that subjects with MS were 98% more likely to have EiA (95% confidence interval: 1.13-3.46, P = 0.016). In conclusion, EiA in the absence of baseline MA is independently related to MS.

  5. The lysine biosynthetic enzyme Lys4 influences iron metabolism, mitochondrial function and virulence in Cryptococcus neoformans.

    PubMed

    Do, Eunsoo; Park, Minji; Hu, Guanggan; Caza, Mélissa; Kronstad, James W; Jung, Won Hee

    2016-09-01

    The lysine biosynthesis pathway via α-aminoadipate in fungi is considered an attractive target for antifungal drugs due to its absence in mammalian hosts. The iron-sulfur cluster-containing enzyme homoaconitase converts homocitrate to homoisocitrate in the lysine biosynthetic pathway, and is encoded by LYS4 in the model yeast Saccharomyces cerevisiae. In this study, we identified the ortholog of LYS4 in the human fungal pathogen, Cryptococcus neoformans, and found that LYS4 expression is regulated by iron levels and by the iron-related transcription factors Hap3 and HapX. Deletion of the LYS4 gene resulted in lysine auxotrophy suggesting that Lys4 is essential for lysine biosynthesis. Our study also revealed that lysine uptake was mediated by two amino acid permeases, Aap2 and Aap3, and influenced by nitrogen catabolite repression (NCR). Furthermore, the lys4 mutant showed increased sensitivity to oxidative stress, agents that challenge cell wall/membrane integrity, and azole antifungal drugs. We showed that these phenotypes were due in part to impaired mitochondrial function as a result of LYS4 deletion, which we propose disrupts iron homeostasis in the organelle. The combination of defects are consistent with our observation that the lys4 mutant was attenuated virulence in a mouse inhalation model of cryptococcosis. PMID:27353379

  6. Isolation of acetogenic bacteria that induce biocorrosion by utilizing metallic iron as the sole electron donor.

    PubMed

    Kato, Souichiro; Yumoto, Isao; Kamagata, Yoichi

    2015-01-01

    Corrosion of iron occurring under anoxic conditions, which is termed microbiologically influenced corrosion (MIC) or biocorrosion, is mostly caused by microbial activities. Microbial activity that enhances corrosion via uptake of electrons from metallic iron [Fe(0)] has been regarded as one of the major causative factors. In addition to sulfate-reducing bacteria and methanogenic archaea in marine environments, acetogenic bacteria in freshwater environments have recently been suggested to cause MIC under anoxic conditions. However, no microorganisms that perform acetogenesis-dependent MIC have been isolated or had their MIC-inducing mechanisms characterized. Here, we enriched and isolated acetogenic bacteria that induce iron corrosion by utilizing Fe(0) as the sole electron donor under freshwater, sulfate-free, and anoxic conditions. The enriched communities produced significantly larger amounts of Fe(II) than the abiotic controls and produced acetate coupled with Fe(0) oxidation prior to CH4 production. Microbial community analysis revealed that Sporomusa sp. and Desulfovibrio sp. dominated in the enrichments. Strain GT1, which is closely related to the acetogen Sporomusa sphaeroides, was eventually isolated from the enrichment. Strain GT1 grew acetogenetically with Fe(0) as the sole electron donor and enhanced iron corrosion, which is the first demonstration of MIC mediated by a pure culture of an acetogen. Other well-known acetogenic bacteria, including Sporomusa ovata and Acetobacterium spp., did not grow well on Fe(0). These results indicate that very few species of acetogens have specific mechanisms to efficiently utilize cathodic electrons derived from Fe(0) oxidation and induce iron corrosion.

  7. Carbon and iron ion radiation-induced cytotoxicity and transformation in vitro

    PubMed Central

    Zhou, Zhaozong; Ware, Jeffrey H.; Kennedy, Ann R.

    2011-01-01

    The present study was undertaken to characterize carbon and iron ion radiation-induced adverse biological effects in terms of toxicity and transformation in vitro. HTori-3 human thyroid epithelial cells were irradiated with 0.3-GeV/n (13.6 KeV/µm) carbon ions and 1-GeV/n (150 KeV/µm) iron ions, both of which represent high-mass, high atomic number (Z) and high-energy particles known as HZE particles, as well as γ-rays. The survival of the irradiated cells was determined by a clonogenic survival assay. The yield of colonies growing in soft agar was used as a surrogate endpoint biomarker for transformation in vitro. The results showed that HZE particles and γ-ray radiations are effective in increasing the yield of anchorage-independent colonies. Based on the relative biological effectiveness (RBE) values in the clonogenic survival assays, 0.3-GeV/n carbon ions and 1-GeV/n iron ions were 2.9 and 2.4 times, respectively, as effective as γ-rays at killing the irradiated HTori-3 cells. At a dose of 200 cGy, 0.3-GeV/n carbon ions and 1-GeV/n iron ions were found to be 3.5 and 7.3 times, respectively, as effective as γ-rays at inducing anchorage-independent growth. These results suggest that the carcinogenic potential of 0.3-GeV/n carbon ions, as represented by the ability to induce anchorage-independent growth, may be lower than that of 1-GeV/n iron ions. PMID:22866150

  8. Protective effects of acerola juice on genotoxicity induced by iron in vivo.

    PubMed

    Horta, Roberta Nunes; Kahl, Vivian Francilia Silva; Sarmento, Merielen da Silva; Nunes, Marisa Fernanda Silva; Porto, Carem Rejane Maglione; Andrade, Vanessa Moraes de; Ferraz, Alexandre de Barros Falcão; Silva, Juliana Da

    2016-03-01

    Metal ions such as iron can induce DNA damage by inducing reactive oxygen species (ROS) and oxidative stress. Vitamin C is one of the most widely consumed antioxidants worldwide, present in many fruits and vegetables, especially inMalpighia glabra L., popularly known as acerola, native to Brazil. Acerola is considered a functional fruit due to its high antioxidant properties and phenolic contents, and therefore is consumed to prevent diseases or as adjuvant in treatment strategies. Here, the influence of ripe and unripe acerola juices on iron genotoxicity was analyzed in vivo using the comet assay and micronucleus test. The comet assay results showed that acerola juice exerted no genotoxic or antigenotoxic activity. Neither ripe nor unripe acerola juices were mutagenic to animals treated with juices, in micronucleus test. However, when compared to iron group, the pre-treatment with acerola juices exerted antimutagenic activity, decreasing significantly micronucleus mean values in bone marrow. Stage of ripeness did not influence the interaction of acerola compounds with DNA, and both ripe and unripe acerola juices exerted protective effect over DNA damage generated by iron.

  9. Protective effects of acerola juice on genotoxicity induced by iron in vivo

    PubMed Central

    Horta, Roberta Nunes; Kahl, Vivian Francilia Silva; Sarmento, Merielen da Silva; Nunes, Marisa Fernanda Silva; Porto, Carem Rejane Maglione; de Andrade, Vanessa Moraes; Ferraz, Alexandre de Barros Falcão; Silva, Juliana Da

    2016-01-01

    Abstract Metal ions such as iron can induce DNA damage by inducing reactive oxygen species (ROS) and oxidative stress. Vitamin C is one of the most widely consumed antioxidants worldwide, present in many fruits and vegetables, especially inMalpighia glabra L., popularly known as acerola, native to Brazil. Acerola is considered a functional fruit due to its high antioxidant properties and phenolic contents, and therefore is consumed to prevent diseases or as adjuvant in treatment strategies. Here, the influence of ripe and unripe acerola juices on iron genotoxicity was analyzed in vivo using the comet assay and micronucleus test. The comet assay results showed that acerola juice exerted no genotoxic or antigenotoxic activity. Neither ripe nor unripe acerola juices were mutagenic to animals treated with juices, in micronucleus test. However, when compared to iron group, the pre-treatment with acerola juices exerted antimutagenic activity, decreasing significantly micronucleus mean values in bone marrow. Stage of ripeness did not influence the interaction of acerola compounds with DNA, and both ripe and unripe acerola juices exerted protective effect over DNA damage generated by iron. PMID:27007905

  10. Protective effects of acerola juice on genotoxicity induced by iron in vivo.

    PubMed

    Horta, Roberta Nunes; Kahl, Vivian Francilia Silva; Sarmento, Merielen da Silva; Nunes, Marisa Fernanda Silva; Porto, Carem Rejane Maglione; Andrade, Vanessa Moraes de; Ferraz, Alexandre de Barros Falcão; Silva, Juliana Da

    2016-03-01

    Metal ions such as iron can induce DNA damage by inducing reactive oxygen species (ROS) and oxidative stress. Vitamin C is one of the most widely consumed antioxidants worldwide, present in many fruits and vegetables, especially inMalpighia glabra L., popularly known as acerola, native to Brazil. Acerola is considered a functional fruit due to its high antioxidant properties and phenolic contents, and therefore is consumed to prevent diseases or as adjuvant in treatment strategies. Here, the influence of ripe and unripe acerola juices on iron genotoxicity was analyzed in vivo using the comet assay and micronucleus test. The comet assay results showed that acerola juice exerted no genotoxic or antigenotoxic activity. Neither ripe nor unripe acerola juices were mutagenic to animals treated with juices, in micronucleus test. However, when compared to iron group, the pre-treatment with acerola juices exerted antimutagenic activity, decreasing significantly micronucleus mean values in bone marrow. Stage of ripeness did not influence the interaction of acerola compounds with DNA, and both ripe and unripe acerola juices exerted protective effect over DNA damage generated by iron. PMID:27007905

  11. Calorie Restriction Down-Regulates Expression of the Iron Regulatory Hormone Hepcidin in Normal and d-Galactose–Induced Aging Mouse Brain

    PubMed Central

    Shi, Wenli; Li, Man; Gao, Qian

    2014-01-01

    Abstract It has been shown that iron progressively accumulates in the brain with age. Calorie restriction (CR) may allay many of the adverse effects of aging on the brain, yet the underlying mechanisms, in particular in relation to brain iron metabolism, remain unclear. This study aimed to investigate the role of CR in the regulation of cerebral cellular iron homeostasis. C57BL/6 mice were randomly divided into four groups of eight. The control group was fed a conventional diet ad libitum; the CR group received 70% of the calories of the control mouse intake per day; the d-galactose (d-gal) group received subcutaneous injection of d-gal at a dose of 100 mg/kg once daily to produce mouse model of aging; the d-gal plus CR group received both of the two interventions for 14 weeks. The Morris water maze (MWM) was employed to test the cognitive performance of all animals, and the expression of iron regulatory genes, ferroportin and hepcidin, in the cortex and hippocampus were detected by quantitative real-time PCR. Compared to the controls, the d-gal group mice showed significant spatial reference memory deficits in the MWM test, whereas the d-gal-CR group mice exhibited almost normal cognitive function, indicating that CR protects against d-gal–induced learning and memory impairment. Hepcidin mRNA expression was increased in the d-gal group, decreased in the CR group, and was basically unchanged in the d-gal-CR group. There was no statistical difference in the transmembrane iron exporter ferroportin expression between control and any of the experimental groups. The results suggest that the anti-aging effects of CR might partially lie in its capacity to reduce or avoid age-related iron accumulation in the brain through down-regulating expression of brain hepcidin—the key negative regulator for intracellular iron efflux—and that facilitating the balance of brain iron metabolism may be a promising anti-aging measure. PMID:24044515

  12. Hepatocyte Nuclear Factor 4α Controls Iron Metabolism and Regulates Transferrin Receptor 2 in Mouse Liver*

    PubMed Central

    Matsuo, Shunsuke; Ogawa, Masayuki; Muckenthaler, Martina U.; Mizui, Yumiko; Sasaki, Shota; Fujimura, Takafumi; Takizawa, Masayuki; Ariga, Nagayuki; Ozaki, Hiroaki; Sakaguchi, Masakiyo; Gonzalez, Frank J.; Inoue, Yusuke

    2015-01-01

    Iron is an essential element in biological systems, but excess iron promotes the formation of reactive oxygen species, resulting in cellular toxicity. Several iron-related genes are highly expressed in the liver, a tissue in which hepatocyte nuclear factor 4α (HNF4α) plays a critical role in controlling gene expression. Therefore, the role of hepatic HNF4α in iron homeostasis was examined using liver-specific HNF4α-null mice (Hnf4aΔH mice). Hnf4aΔH mice exhibit hypoferremia and a significant change in hepatic gene expression. Notably, the expression of transferrin receptor 2 (Tfr2) mRNA was markedly decreased in Hnf4aΔH mice. Promoter analysis of the Tfr2 gene showed that the basal promoter was located at a GC-rich region upstream of the transcription start site, a region that can be transactivated in an HNF4α-independent manner. HNF4α-dependent expression of Tfr2 was mediated by a proximal promoter containing two HNF4α-binding sites located between the transcription start site and the translation start site. Both the GC-rich region of the basal promoter and the HNF4α-binding sites were required for maximal transactivation. Moreover, siRNA knockdown of HNF4α suppressed TFR2 expression in human HCC cells. These results suggest that Tfr2 is a novel target gene for HNF4α, and hepatic HNF4α plays a critical role in iron homeostasis. PMID:26527688

  13. Hepatocyte Nuclear Factor 4α Controls Iron Metabolism and Regulates Transferrin Receptor 2 in Mouse Liver.

    PubMed

    Matsuo, Shunsuke; Ogawa, Masayuki; Muckenthaler, Martina U; Mizui, Yumiko; Sasaki, Shota; Fujimura, Takafumi; Takizawa, Masayuki; Ariga, Nagayuki; Ozaki, Hiroaki; Sakaguchi, Masakiyo; Gonzalez, Frank J; Inoue, Yusuke

    2015-12-25

    Iron is an essential element in biological systems, but excess iron promotes the formation of reactive oxygen species, resulting in cellular toxicity. Several iron-related genes are highly expressed in the liver, a tissue in which hepatocyte nuclear factor 4α (HNF4α) plays a critical role in controlling gene expression. Therefore, the role of hepatic HNF4α in iron homeostasis was examined using liver-specific HNF4α-null mice (Hnf4a(ΔH) mice). Hnf4a(ΔH) mice exhibit hypoferremia and a significant change in hepatic gene expression. Notably, the expression of transferrin receptor 2 (Tfr2) mRNA was markedly decreased in Hnf4a(ΔH) mice. Promoter analysis of the Tfr2 gene showed that the basal promoter was located at a GC-rich region upstream of the transcription start site, a region that can be transactivated in an HNF4α-independent manner. HNF4α-dependent expression of Tfr2 was mediated by a proximal promoter containing two HNF4α-binding sites located between the transcription start site and the translation start site. Both the GC-rich region of the basal promoter and the HNF4α-binding sites were required for maximal transactivation. Moreover, siRNA knockdown of HNF4α suppressed TFR2 expression in human HCC cells. These results suggest that Tfr2 is a novel target gene for HNF4α, and hepatic HNF4α plays a critical role in iron homeostasis.

  14. Hepcidin and Iron Metabolism in Pregnancy: Correlation with Smoking and Birth Weight and Length.

    PubMed

    Chełchowska, Magdalena; Ambroszkiewicz, Jadwiga; Gajewska, Joanna; Jabłońska-Głąb, Ewa; Maciejewski, Tomasz M; Ołtarzewski, Mariusz

    2016-09-01

    To estimate the effect of tobacco smoking on iron homeostasis and the possible association between hepcidin and the neonatal birth weight and length, concentrations of serum hepcidin and selected iron markers were measured in 81 healthy pregnant women (41 smokers and 40 nonsmokers). The smoking mothers had significantly lower concentrations of serum hepcidin (p < 0.001), iron (p < 0.001), and hemoglobin (p < 0.05), but higher erythropoietin (p < 0.05) levels compared with non-smoking pregnant women. Logistic regression analysis showed the highest negative impact of the number of cigarettes smoked per day (β = -0.46; p < 0.01) and positive impact of ferritin level (β = 0.47; p < 0.001) on serum hepcidin concentration. The birth weight and the body length of smoking mothers' infants were significantly lower than in tobacco abstinent group (p < 0.001). In multiple regression analysis, birth body weight (β = 0.56; p < 0.001) and length (β = 0.50; p < 0.001) were significantly related to maternal hepcidin values. Tobacco smoking affected hepcidin level in serum of pregnant women in a dose-dependent manner. Low concentrations of iron and hemoglobin in maternal serum coexisting with high level of erythropoietin suggest that smoking could lead to subclinical iron deficiency and chronic hypoxia not only in mothers but also in fetus. Low serum hepcidin concentration in smoking pregnant women might be associated with lower fetal birth weight and length. PMID:26785641

  15. Oral administration of iron-saturated bovine lactoferrin–loaded ceramic nanocapsules for breast cancer therapy and influence on iron and calcium metabolism

    PubMed Central

    Mahidhara, Ganesh; Kanwar, Rupinder K; Roy, Kislay; Kanwar, Jagat R

    2015-01-01

    We determined the anticancer efficacy and internalization mechanism of our polymeric–ceramic nanoparticle system (calcium phosphate nanocores, enclosed in biodegradable polymers chitosan and alginate nanocapsules/nanocarriers [ACSC NCs]) loaded with iron-saturated bovine lactoferrin (Fe-bLf) in a breast cancer xenograft model. ACSC-Fe-bLf NCs with an overall size of 322±27.2 nm were synthesized. In vitro internalization and anticancer efficacy were evaluated in the MDA-MB-231 cells using multicellular tumor spheroids, CyQUANT and MTT assays. These NCs were orally delivered in a breast cancer xenograft mice model, and their internalization, cytotoxicity, biodistribution, and anticancer efficacy were evaluated. Chitosan-coated calcium phosphate Fe-bLf NCs effectively (59%, P≤0.005) internalized in a 1-hour period using clathrin-mediated endocytosis (P≤0.05) and energy-mediated pathways (P≤0.05) for internalization; 3.3 mg/mL of ACSC-Fe-bLf NCs completely disintegrated (~130-fold reduction, P≤0.0005) the tumor spheroids in 72 hours and 96 hours. The IC50 values determined for ACSC-Fe-bLf NCs were 1.69 mg/mL at 10 hours and 1.62 mg/mL after 20 hours. We found that Fe-bLf-NCs effectively (P≤0.05) decreased the tumor size (4.8-fold) compared to the void NCs diet and prevented tumor recurrence when compared to intraperitoneal injection of Taxol and Doxorubicin. Receptor gene expression and micro-RNA analysis confirmed upregulation of low-density lipoprotein receptor and transferrin receptor (liver, intestine, and brain). Several micro-RNAs responsible for iron metabolism upregulated with NCs were identified. Taken together, orally delivered Fe-bLf NCs offer enhanced antitumor activity in breast cancer by internalizing via low-density lipoprotein receptor and transferrin receptor and regulating the micro-RNA expression. These NCs also restored the body iron and calcium levels and increased the hematologic counts. PMID:26124661

  16. Iron deficiency.

    PubMed

    Scrimshaw, N S

    1991-10-01

    The world's leading nutritional problem is iron deficiency. 66% of children and women aged 15-44 years in developing countries have it. Further, 10-20% of women of childbearing age in developed countries are anemic. Iron deficiency is identified with often irreversible impairment of a child's learning ability. It is also associated with low capacity for adults to work which reduces productivity. In addition, it impairs the immune system which reduces the body's ability to fight infection. Iron deficiency also lowers the metabolic rate and the body temperature when exposed to cold. Hemoglobin contains nearly 73% of the body's iron. This iron is always being recycled as more red blood cells are made. The rest of the needed iron does important tasks for the body, such as binds to molecules that are reservoirs of oxygen for muscle cells. This iron comes from our diet, especially meat. Even though some plants, such as spinach, are high in iron, the body can only absorb 1.4-7% of the iron in plants whereas it can absorb 20% of the iron in red meat. In many developing countries, the common vegetarian diets contribute to high rates of iron deficiency. Parasitic diseases and abnormal uterine bleeding also promote iron deficiency. Iron therapy in anemic children can often, but not always, improve behavior and cognitive performance. Iron deficiency during pregnancy often contributes to maternal and perinatal mortality. Yet treatment, if given to a child in time, can lead to normal growth and hinder infections. However, excess iron can be damaging. Too much supplemental iron in a malnourished child promotes fatal infections since the excess iron is available for the pathogens use. Many countries do not have an effective system for diagnosing, treating, and preventing iron deficiency. Therefore a concerted international effort is needed to eliminate iron deficiency in the world.

  17. Beneficial effect of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine-induced metabolic disorders.

    PubMed

    Literáti-Nagy, B; Péterfai, E; Kulcsár, E; Literáti-Nagy, Zs; Buday, B; Tory, K; Mandl, J; Sümegi, B; Fleming, A; Roth, J; Korányi, L

    2010-11-20

    Olanzapine is a widely used atypical antipsychotic, with well known metabolic side effects such as weight gain, insulin resistance and blood glucose abnormalities. It has been previously shown in a phase II clinical trial that BGP-15, an amidoxim derivative has insulin-sensitizing effects. The aim of this study was to investigate the efficacy of BGP-15 for the treatment of olanzapine-induced metabolic side effects, in healthy volunteers. Thirty-seven (37) subjects (ages 18-55 years) with normal glucose metabolism were randomly assigned to 17 days of once-daily treatment with 400mg of BGP-15 or placebo and 5mg of olanzapine for 3 days followed by 10mg for 14 days. Total body and muscle tissue glucose utilization was determined by hyperinsulinemic-euglycemic clamp technique. As expected the 17-day olanzapine treatment provoked insulin resistance and body weight gain (p<0.05) in both groups. Administration of BGP-15 significantly reduced olanzapine-induced insulin resistance. The protective effect of BGP-15 on insulin stimulated glucose utilization had the highest magnitude in the values calculated for the muscle tissue (p=0.002). In healthy individuals BGP-15 was safe and well tolerated during the whole study period. It is suggested that BGP-15 can be a successful insulin sensitizer agent to prevent side effects of olanzapine treatment.

  18. Shotgun proteome analysis of Bordetella pertussis reveals a distinct influence of iron availability on the bacterial metabolism, virulence, and defense response.

    PubMed

    Alvarez Hayes, Jimena; Lamberti, Yanina; Surmann, Kristin; Schmidt, Frank; Völker, Uwe; Rodriguez, Maria Eugenia

    2015-07-01

    One of the mechanisms involved in host immunity is the limitation of iron accessibility to pathogens, which in turn provokes the corresponding physiological adaptation of pathogens. This study reports a gel-free nanoLC-MS/MS-based comparative proteome analysis of Bordetella pertussis grown under iron-excess and iron-depleted conditions. Out of the 926 proteins covered 98 displayed a shift in their abundance in response to low iron availability. Forty-seven of them were found to be increased in level while 58 were found with decreased protein levels under iron starvation. In addition to proteins previously reported to be influenced by iron in B. pertussis, we observed changes in metabolic proteins involved in fatty acid utilization and poly-hydroxybutyrate production. Additionally, many bacterial virulence factors regulated by the BvgAS two-component system were found at decreased levels in response to iron limitation. These results, together with the increased production of proteins potentially involved in oxidative stress resistance, seem to indicate that iron starvation provokes changes in B. pertussis phenotype that might shape host-pathogen interaction.

  19. Metabolic flexibility of the Fe(II)-oxidizing phototropic strain Rhodopseudomonas palustris TIE1 and its potential role in microbial iron cycling

    NASA Astrophysics Data System (ADS)

    Schmidt, C.; Oswald, K.; Melton, E. D.; Kappler, A.

    2012-04-01

    The biogeochemical conversion of iron(II) and iron(III) is widespread in many aquatic and terrestrial environments. In the anoxic regime of soils and sediments the conversion and alternation of the iron redox state is predominantly run by microorganisms that are thought to gain life-sustaining energy by the oxidation and/or reduction of ferrous/ferric components. The spatial arrangement of microbial iron(II) oxidation and iron(III) reduction is largely controlled by the availability of the required electron acceptor and electron donor, as well as the essential source of energy (i.e. light or chemical energy). The physico-chemical patterns of many microbial environments undergo dynamic variations (i.e. diurnal and seasonal changes) as a function of natural external forces (i.e. seasonality, storm events, algae blooms) which strongly affects the local budget of organic carbon and nutrients, as well as the day light penetration. Such fluctuations force microorganisms either to follow the flow of substrate or to switch their metabolism to alternative electron acceptors and/or donors. Different photoferrotrophic bacteria have been shown to be able to grow either on organic (heterotrophic) or inorganic (autotrophic) substrates while exploiting light as their energy source. Within the frame of this study the preference for organic substrates (lactate and acetate) and/or ferrous iron (in simultaneous presence) for photo(ferro)trophic growth of Rhodopseudomonas palustris TIE1 has been investigated in detail. Rates of iron oxidation, acetate/lactate consumption and growth have been followed over time as a function of different lactate to acetate to iron(II) ratios. Additional experiments have been designed to evaluate the potential of Rhodopseudomonas palustris TIE1 to contribute to the redox cycling of iron. TIE1 has been grown in a batch set-up in which the iron(III)-reducing strain Shewanella oneidensis MR1 has been incubated at different ferrihydrite concentrations in

  20. Iron yoke eddy current induced losses with application to the ALS septum magnets

    SciTech Connect

    Schlueter, R.D.

    1991-08-16

    The theoretical development of relations governing the eddy current induced losses in iron electromagnet yokes is reviewed. A baseline laminated electromagnet design is analyzed and a parametric study illustrates the sensitivity of core losses to perturbations of various geometrical, material, and excitation parameters. Core losses and field gradients for the ALS septum magnets are calculated. Design modifications capable of eliminating transverse and longitudinal field gradients are discussed.

  1. New insights into the human body iron metabolism analyzed by a Petri net based approach.

    PubMed

    Sackmann, Andrea; Formanowicz, Dorota; Formanowicz, Piotr; Blazewicz, Jacek

    2009-04-01

    Iron homeostasis is one of the most important biochemical processes in the human body. Despite this fact, the process is not fully understood and until recently only rough descriptions of parts of the process could be found in the literature. Here, an extension of the recently published formal model of the main part of the process is presented. This extension consists in including all known mechanisms of hepcidin regulation. Hepcidin is a hormone synthesized in the liver which is mainly responsible for an inhibition of iron absorption in the small intestine during an inflammatory process. The model is expressed in the language of Petri net theory which allows for its relatively easy analysis and simulation.

  2. Iron-Induced Virulence of Salmonella enterica Serovar Typhimurium at the Intestinal Epithelial Interface Can Be Suppressed by Carvacrol

    PubMed Central

    Kortman, Guus A. M.; Roelofs, Rian W. H. M.; Swinkels, Dorine W.; de Jonge, Marien I.; Burt, Sara A.

    2014-01-01

    Oral iron therapy can increase the abundance of bacterial pathogens, e.g., Salmonella spp., in the large intestine of African children. Carvacrol is a natural compound with antimicrobial activity against various intestinal bacterial pathogens, among which is the highly prevalent Salmonella enterica serovar Typhimurium. This study aimed to explore a presumed interaction between carvacrol and bacterial iron handling and to assess the potential of carvacrol in preventing the increase of bacterial pathogenicity during high iron availability. S. Typhimurium was cultured with increasing concentrations of iron and carvacrol to study the effects of these combined interventions on growth, adhesion to intestinal epithelial cells, and iron uptake/influx in both bacterial and epithelial cells. In addition, the ability of carvacrol to remove iron from the high-affinity ligand transferrin and an Fe-dye complex was examined. Carvacrol retarded growth of S. Typhimurium at all iron conditions. Furthermore, iron-induced epithelial adhesion was effectively reduced by carvacrol at high iron concentrations. The reduction of growth and virulence by carvacrol was not paralleled by a change in iron uptake or influx into S. Typhimurium. In contrast, bioavailability of iron for epithelial cells was moderately decreased under these conditions. Further, carvacrol was shown to lack the properties of an iron binding molecule; however, it was able to weaken iron-ligand interactions by which it may possibly interfere with bacterial virulence. In conclusion, our in vitro data suggest that carvacrol has the potential to serve as a novel dietary supplement to prevent pathogenic overgrowth and colonization in the large intestine during oral iron therapy. PMID:24379194

  3. Induced phenylpropanoid metabolism during suberization and lignification: a comparative analysis

    NASA Technical Reports Server (NTRS)

    Bernards, M. A.; Susag, L. M.; Bedgar, D. L.; Anterola, A. M.; Lewis, N. G.

    2000-01-01

    Induction of the biosynthesis of phenylpropanoids was monitored at the enzyme level through measurement of the temporal change in the activity of two marker enzymes of phenylpropanoid metabolism, phenylalanine ammonia-lyase, (PAL, E.C. 4.1.3.5) and 4-coumaryl-CoA ligase (4-CL, E.C. 6.2.1.12) and two marker enzymes for hydroxycinnamyl alcohol biosynthesis, cinnamoyl-CoA:NADP+ oxidoreductase (CCR, E.C. 1.2.1.44) and cinnamyl alcohol dehydrogenase (CAD, E.C. 1.1.1.195) in both suberizing potato (Solanum tuberosum) tubers and lignifying loblolly pine (Pinus taeda) cell cultures. While measurable activities of PAL, 4-CL and CAD increased upon initiation of suberization in potato tubers, that of CCR did not. By contrast, all four enzymes were induced upon initiation of lignification in pine cell cultures. The lack of CCR induction in potato by wound treatment is consistent with the channelling of hydroxycinnamoyl-CoA derivatives away from monolignol formation and toward other hydroxycinnamoyl derivatives such as those that accumulate during suberization.

  4. The haemochromatosis protein HFE induces an apparent iron-deficient phenotype in H1299 cells that is not corrected by co-expression of beta 2-microglobulin.

    PubMed

    Wang, Jian; Chen, Guohua; Pantopoulos, Kostas

    2003-03-15

    HFE, an atypical MHC class I type molecule, has a critical, yet still elusive function in the regulation of systemic iron metabolism. HFE mutations are linked to hereditary haemochromatosis type 1, a common autosomal recessive disorder of iron overload. Most patients are homozygous for a C282Y point mutation that abrogates the interaction of HFE with beta(2)-microglobulin (beta(2)M) and, thus, impairs its proper processing and expression on the cell surface. An H63D substitution is also associated with disease. To investigate the function of HFE we have generated clones of human H1299 lung cancer cells that express wild-type, C282Y or H63D HFE under the control of a tetracycline-inducible promoter. Consistent with earlier observations in other cell lines, the expression of wild-type or H63D, but not C282Y, HFE induces an apparent iron-deficient phenotype, manifested in the activation of iron-regulatory protein and concomitant increase in transferrin receptor levels and decrease in ferritin content. This phenotype persists in cells expressing wild-type HFE after transfection with a beta(2)M cDNA. Whereas endogenous beta(2)M is sufficient for the presentation of at least a fraction of chimeric HFE on the cell surface, this effect is stimulated by approx. 2.8-fold in beta(2)M transfectants. The co-expression of exogenous beta(2)M does not significantly affect the half-life of HFE. These results suggest that the apparent iron-deficient phenotype elicited by HFE is not linked to beta(2)M insufficiency.

  5. Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice

    PubMed Central

    Ishimoto, Takuji; Lanaspa, Miguel A.; Le, MyPhuong T.; Garcia, Gabriela E.; Diggle, Christine P.; MacLean, Paul S.; Jackman, Matthew R.; Asipu, Aruna; Roncal-Jimenez, Carlos A.; Kosugi, Tomoki; Rivard, Christopher J.; Maruyama, Shoichi; Rodriguez-Iturbe, Bernardo; Sánchez-Lozada, Laura G.; Bonthron, David T.; Sautin, Yuri Y.; Johnson, Richard J.

    2012-01-01

    Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Fructose intake also causes features of metabolic syndrome in laboratory animals and humans. The first enzyme in fructose metabolism is fructokinase, which exists as two isoforms, A and C. Here we show that fructose-induced metabolic syndrome is prevented in mice lacking both isoforms but is exacerbated in mice lacking fructokinase A. Fructokinase C is expressed primarily in liver, intestine, and kidney and has high affinity for fructose, resulting in rapid metabolism and marked ATP depletion. In contrast, fructokinase A is widely distributed, has low affinity for fructose, and has less dramatic effects on ATP levels. By reducing the amount of fructose for metabolism in the liver, fructokinase A protects against fructokinase C-mediated metabolic syndrome. These studies provide insights into the mechanisms by which fructose causes obesity and metabolic syndrome. PMID:22371574

  6. Microbial communities from different subsystems in biological heap leaching system play different roles in iron and sulfur metabolisms.

    PubMed

    Xiao, Yunhua; Liu, Xueduan; Ma, Liyuan; Liang, Yili; Niu, Jiaojiao; Gu, Yabing; Zhang, Xian; Hao, Xiaodong; Dong, Weiling; She, Siyuan; Yin, Huaqun

    2016-08-01

    The microbial communities are important for minerals decomposition in biological heap leaching system. However, the differentiation and relationship of composition and function of microbial communities between leaching heap (LH) and leaching solution (LS) are still unclear. In this study, 16S rRNA gene sequencing was used to assess the microbial communities from the two subsystems in ZiJinShan copper mine (Fujian province, China). Results of PCoA and dissimilarity test showed that microbial communities in LH samples were significantly different from those in LS samples. The dominant genera of LH was Acidithiobacillus (57.2 ∼ 87.9 %), while Leptospirillum (48.6 ∼ 73.7 %) was predominant in LS. Environmental parameters (especially pH) were the major factors to influence the composition and structure of microbial community by analysis of Mantel tests. Results of functional test showed that microbial communities in LH utilized sodium thiosulfate more quickly and utilized ferrous sulfate more slowly than those in LS, which further indicated that the most sulfur-oxidizing processes of bioleaching took place in LH and the most iron-oxidizing processes were in LS. Further study found that microbial communities in LH had stronger pyrite leaching ability, and iron extraction efficiency was significantly positively correlated with Acidithiobacillus (dominated in LH), which suggested that higher abundance ratio of sulfur-oxidizing microbes might in favor of minerals decomposition. Finally, a conceptual model was designed through the above results to better exhibit the sulfur and iron metabolism in bioleaching systems. PMID:27094188

  7. Iron Transformations Induced by an Acid-Tolerant Desulfosporosinus Species

    PubMed Central

    Bertel, Doug; Peck, John; Quick, Thomas J.

    2012-01-01

    The mineralogical transformations of Fe phases induced by an acid-tolerant, Fe(III)- and sulfate-reducing bacterium, Desulfosporosinus sp. strain GBSRB4.2 were evaluated under geochemical conditions associated with acid mine drainage-impacted systems (i.e., low pH and high Fe concentrations). X-ray powder diffractometry coupled with magnetic analysis by first-order reversal curve diagrams were used to evaluate mineral phases produced by GBSRB4.2 in media containing different ratios of Fe(II) and Fe(III). In medium containing Fe predominately in the +II oxidation state, ferrimagnetic, single-domain greigite (Fe3S4) was formed, but the addition of Fe(III) inhibited greigite formation. In media that contained abundant Fe(III) [as schwertmannite; Fe8O8(OH)6SO4 · nH2O], the activities of strain GBSRB4.2 enhanced the transformation of schwertmannite to goethite (α-FeOOH), due to the increased pH and Fe(II) concentrations that resulted from the activities of GBSRB4.2. PMID:22038606

  8. Iron transformations induced by an acid-tolerant Desulfosporosinus species.

    PubMed

    Bertel, Doug; Peck, John; Quick, Thomas J; Senko, John M

    2012-01-01

    The mineralogical transformations of Fe phases induced by an acid-tolerant, Fe(III)- and sulfate-reducing bacterium, Desulfosporosinus sp. strain GBSRB4.2 were evaluated under geochemical conditions associated with acid mine drainage-impacted systems (i.e., low pH and high Fe concentrations). X-ray powder diffractometry coupled with magnetic analysis by first-order reversal curve diagrams were used to evaluate mineral phases produced by GBSRB4.2 in media containing different ratios of Fe(II) and Fe(III). In medium containing Fe predominately in the +II oxidation state, ferrimagnetic, single-domain greigite (Fe₃S₄) was formed, but the addition of Fe(III) inhibited greigite formation. In media that contained abundant Fe(III) [as schwertmannite; Fe₈O₈(OH)₆SO₄ · nH₂O], the activities of strain GBSRB4.2 enhanced the transformation of schwertmannite to goethite (α-FeOOH), due to the increased pH and Fe(II) concentrations that resulted from the activities of GBSRB4.2. PMID:22038606

  9. Development of a Quantitative SRM-Based Proteomics Method to Study Iron Metabolism of Synechocystis sp. PCC 6803.

    PubMed

    Vuorijoki, Linda; Isojärvi, Janne; Kallio, Pauli; Kouvonen, Petri; Aro, Eva-Mari; Corthals, Garry L; Jones, Patrik R; Muth-Pawlak, Dorota

    2016-01-01

    The cyanobacterium Synechocystis sp. PCC 6803 (S. 6803) is a well-established model species in oxygenic photosynthesis research and a potential host for biotechnological applications. Despite recent advances in genome sequencing and microarray techniques applied in systems biology, quantitative proteomics approaches with corresponding accuracy and depth are scarce for S. 6803. In this study, we developed a protocol to screen changes in the expression of 106 proteins representing central metabolic pathways in S. 6803 with a targeted mass spectrometry method, selected reaction monitoring (SRM). We evaluated the response to the exposure of both short- and long-term iron deprivation. The experimental setup enabled the relative quantification of 96 proteins, with 87 and 92 proteins showing adjusted p-values <0.01 under short- and long-term iron deficiency, respectively. The high sensitivity of the SRM method for S. 6803 was demonstrated by providing quantitative data for altogether 64 proteins that previously could not be detected with the classical data-dependent MS approach under similar conditions. This highlights the effectiveness of SRM for quantification and extends the analytical capability to low-abundance proteins in unfractionated samples of S. 6803. The SRM assays and other generated information are now publicly available via PASSEL and Panorama.

  10. Development of a Quantitative SRM-Based Proteomics Method to Study Iron Metabolism of Synechocystis sp. PCC 6803.

    PubMed

    Vuorijoki, Linda; Isojärvi, Janne; Kallio, Pauli; Kouvonen, Petri; Aro, Eva-Mari; Corthals, Garry L; Jones, Patrik R; Muth-Pawlak, Dorota

    2016-01-01

    The cyanobacterium Synechocystis sp. PCC 6803 (S. 6803) is a well-established model species in oxygenic photosynthesis research and a potential host for biotechnological applications. Despite recent advances in genome sequencing and microarray techniques applied in systems biology, quantitative proteomics approaches with corresponding accuracy and depth are scarce for S. 6803. In this study, we developed a protocol to screen changes in the expression of 106 proteins representing central metabolic pathways in S. 6803 with a targeted mass spectrometry method, selected reaction monitoring (SRM). We evaluated the response to the exposure of both short- and long-term iron deprivation. The experimental setup enabled the relative quantification of 96 proteins, with 87 and 92 proteins showing adjusted p-values <0.01 under short- and long-term iron deficiency, respectively. The high sensitivity of the SRM method for S. 6803 was demonstrated by providing quantitative data for altogether 64 proteins that previously could not be detected with the classical data-dependent MS approach under similar conditions. This highlights the effectiveness of SRM for quantification and extends the analytical capability to low-abundance proteins in unfractionated samples of S. 6803. The SRM assays and other generated information are now publicly available via PASSEL and Panorama. PMID:26652789

  11. Expression profiling reveals an unexpected growth-stimulating effect of surplus iron on the yeast Saccharomyces cerevisiae.

    PubMed

    Du, Yang; Cheng, Wang; Li, Wei-Fang

    2012-08-01

    Iron homeostasis plays a crucial role in growth and division of cells in all kingdoms of life. Although yeast iron metabolism has been extensively studied, little is known about the molecular mechanism of response to surplus iron. In this study, expression profiling of Saccharomyces cerevisiae in the presence of surplus iron revealed a dual effect at 1 and 4 h. A cluster of stress-responsive genes was upregulated via activation of the stress-resistance transcription factor Msn4, which indicated the stress effect of surplus iron on yeast metabolism. Genes involved in aerobic metabolism and several anabolic pathways are also upregulated in iron-surplus conditions, which could significantly accelerate yeast growth. This dual effect suggested that surplus iron might participate in a more complex metabolic network, in addition to serving as a stress inducer. These findings contribute to our understanding of the global response of yeast to the fluctuating availability of iron in the environment.

  12. Iron-mediated Oxidation Induces Conformational Changes within the Redox-sensing Protein HbpS*

    PubMed Central

    de Orué Lucana, Darío Ortiz; Roscher, Mareike; Honigmann, Alf; Schwarz, Julia

    2010-01-01

    HbpS is an extracellular oligomeric protein, which has been shown to act in concert with the two-component system SenS-SenR during the sensing of redox stress. HbpS can bind and degrade heme under oxidative stress conditions, leading to a free iron ion. The liberated iron is subsequently coordinated on the protein surface. Furthermore, HbpS has been shown to modulate the phosphorylation state of the sensor kinase SenS as, in the absence of oxidative stress conditions, HbpS inhibits SenS autophosphorylation whereas the presence of heme or iron ions and redox-stressing agents enhances it. Using HbpS wild type and mutants as well as different biochemical and biophysical approaches, we show that iron-mediated oxidative stress induces both secondary structure and overall intrinsic conformational changes within HbpS. We demonstrate in addition that HbpS is oxidatively modified, leading to the generation of highly reactive carbonyl groups and tyrosine-tyrosine bonds. Further examination of the crystal structure and subsequent mutational analyses allowed the identification of the tyrosine residue participating in dityrosine formation, which occurs between two monomers within the octomeric assembly. Therefore, it is proposed that oxidative modifications causing structural and conformational changes are responsible for the control of SenS and hence of the HbpS-SenS-SenR signaling cascade. PMID:20571030

  13. F2-laser-induced surface modification of iron thin films to obtain corrosion resistance

    NASA Astrophysics Data System (ADS)

    Okoshi, Masayuki; Awaihara, Yuta; Yamashita, Tsugito; Inoue, Narumi

    2014-02-01

    Rustproof, chemical-resistant pure-iron thin films were successfully fabricated by the 157 nm F2-laser-induced surface modification of 50-nm-thick iron thin films. An approximately 2-nm-thick Fe3O4 layer underneath a native Fe2O3 layer of approximately 0.6 nm in thickness was formed on the iron thin films after F2 laser irradiation, as confirmed by X-ray photoelectron spectroscopy. The anodic polarization measurement in a 3 wt % NaCl aqueous solution (quasi-seawater) was conducted; the F2-laser-irradiated samples showed high corrosion resistance to the quasi-seawater. Moreover, no rust was observed on the samples after the immersion test in quasi-seawater for 48 h and longer. The measurement also revealed that the F2-laser-irradiated samples showed high corrosion resistance to a HNO3 aqueous solution. Thus, the micropatterning of iron thin films was demonstrated by the combination of F2 laser irradiation and subsequent HNO3 chemical etching.

  14. Pomegranate juice intake attenuates the increase in oxidative stress induced by intravenous iron during hemodialysis.

    PubMed

    Shema-Didi, Lilach; Kristal, Batya; Ore, Liora; Shapiro, Galina; Geron, Ronit; Sela, Shifra

    2013-06-01

    The hemodialysis (HD) procedure induces oxidative stress (OS), which is further aggravated by intravenous (IV) iron administration, aimed at correcting anemia of patients with HD. We have recently shown that 1 year of pomegranate juice (PJ) intake attenuated OS and inflammation in patients with HD. In the current study, we hypothesized that a single dose of PJ can attenuate the enhanced OS and inflammation induced by both the dialysis procedure and IV iron administration during HD session. Twenty-seven patients with HD were randomized to receive PJ or placebo during 1 dialysis session with IV iron. Blood samples were drawn before and after the session to asses OS biomarkers such as advanced oxidation protein products and myeloperoxidase (MPO), whereas polymorphonuclear leukocyte (PMNL) counts served as an indirect measure of inflammation. At the end of the dialysis session, an increase in advanced oxidation protein products and MPO levels as well as a decrease in PMNLs counts were observed in the placebo group, whereas no significant changes occurred in the PJ group. The postdialysis increase in MPO levels in the placebo group is a direct result of PMNL degranulation, associated with postdialysis decrease in PMNL counts. Degranulation of PMNLs leads to the release of other cell moieties, such as inflammatory mediators and proteases that enhance inflammation. We conclude that PJ intake attenuated the increase in systemic OS and inflammation induced by IV iron administration during the dialysis session. These beneficial effects illuminate the previously observed attenuation in OS and inflammation in patients with HD on prolonged PJ intake.

  15. Endothelial dysfunction and inflammation induced by iron oxide nanoparticle exposure: Risk factors for early atherosclerosis.

    PubMed

    Zhu, Mo-Tao; Wang, Bing; Wang, Yun; Yuan, Lan; Wang, Hua-Jian; Wang, Meng; Ouyang, Hong; Chai, Zhi-Fang; Feng, Wei-Yue; Zhao, Yu-Liang

    2011-06-10

    More recently, the correlation between exposure to nanoparticles and cardiovascular diseases is of particular concern in nanotoxicology related fields. Nanoparticle-triggered endothelial dysfunction is hypothesized to be a dominant mechanism in the development of the diseases. To test this hypothesis, iron oxide nanoparticles (Fe₂O₃ and Fe₃O₄), as two widely used nanomaterials and the main metallic components in particulate matter, were selected to assess their potential risks on human endothelial system. The direct effects of iron oxide nanoparticles on human aortic endothelial cells (HAECs) and the possible effects mediated by monocyte (U937 cells) phagocytosis and activation were investigated. In the study, HAECs and U937 cells were exposed to 2, 20, 100 μg/mL of 22-nm-Fe₂O₃ and 43-nm-Fe₃O₄ particles. Our results indicate that cytoplasmic vacuolation, mitochondrial swelling and cell death were induced in HAEC. A significant increase in nitric oxide (NO) production was induced which coincided with the elevation of nitric oxide synthase (NOS) activity in HAECs. Adhesion of monocytes to the HAECs was significantly enhanced as a consequence of the up-regulation of intracellular cell adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8) expression, all of which are considered as early steps of atheroscelerosis. Phagocytosis and dissolution of nanoparticles by monocytes were found to simultaneously provoke oxidative stress and mediate severe endothelial toxicity. We conclude that intravascular iron oxide nanoparticles may induce endothelial system inflammation and dysfunction by three ways: (1) nanoparticles may escape from phagocytosis that interact directly with the endothelial monolayer; (2) nanoparticles are phagocytized by monocytes and then dissolved, thus impact the endothelial cells as free iron ions; or (3) nanoparticles are phagocytized by monocytes to provoke oxidative stress responses.

  16. Effects of iron on Vitamin C/copper-induced hydroxyl radical generation in bicarbonate-rich water.

    PubMed

    Jansson, Patric J; Del Castillo, Urko; Lindqvist, Christer; Nordström, Tommy

    2005-05-01

    The aim of this study was to evaluate whether iron, like copper, could support Vitamin C mediated hydroxyl radical formation in bicarbonate-rich water. By using the hydroxyl radical indicator coumarin-3-carboxylic acid, we found that iron, in contrast to copper, was not capable to support Vitamin C induced hydroxyl radical formation. However, when 0.2 mg/l iron and 0.1 mg/l copper were both added to bicarbonate supplemented Milli-Q water, the Vitamin C induced formation of 7-hydroxycoumarin, as measured by HPLC analysis, was inhibited by 47.5%. The inhibition of hydroxyl radical formation by iron was also evident in the experiments performed on copper contaminated bicarbonate-rich household drinking water samples. In the presence of 0.2 mg/l of ferric iron the ascorbic acid induced hydroxyl radical formation was inhibited by 36.0-44.6%. This inhibition was even more significant, 47.0-59.2%, when 0.8 mg/l of ferric iron was present. None of the other redox-active metals, e.g. manganese, nickel or cobalt, could support ascorbic acid induced hydroxyl radical formation and did not have any impact on the ascorbic acid/copper-induced hydroxyl radical generation. Our results show, that iron cannot by itself produce hydroxyl radicals in bicarbonate rich water but can significantly reduce Vitamin C/copper-induced hydroxyl radical formation. These findings might partly explain the mechanism for the iron-induced protective effect on various copper related degenerative disorders that earlier has been observed in animal model systems. PMID:16036332

  17. Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration

    PubMed Central

    Kurihara, Toshihide; Westenskow, Peter D; Gantner, Marin L; Usui, Yoshihiko; Schultz, Andrew; Bravo, Stephen; Aguilar, Edith; Wittgrove, Carli; Friedlander, Mollie SH; Paris, Liliana P; Chew, Emily; Siuzdak, Gary; Friedlander, Martin

    2016-01-01

    Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies. DOI: http://dx.doi.org/10.7554/eLife.14319.001 PMID:26978795

  18. Chronic cola drinking induces metabolic and cardiac alterations in rats

    PubMed Central

    Milei, José; Losada, Matilde Otero; Llambí, Hernán Gómez; Grana, Daniel R; Suárez, Daniel; Azzato, Francisco; Ambrosio, Giuseppe

    2011-01-01

    AIM: To investigate the effects of chronic drinking of cola beverages on metabolic and echocardiographic parameters in rats. METHODS: Forty-eight male Wistar rats were divided in 3 groups and allowed to drink regular cola (C), diet cola (L), or tap water (W) ad libitum during 6 mo. After this period, 50% of the animals in each group were euthanized. The remaining rats drank tap water ad libitum for an additional 6 mo and were then sacrificed. Rat weight, food, and beverage consumption were measured regularly. Biochemical, echocardiographic and systolic blood pressure data were obtained at baseline, and at 6 mo (treatment) and 12 mo (washout). A complete histopathology study was performed after sacrifice. RESULTS: After 6 mo, C rats had increased body weight (+7%, P < 0.01), increased liquid consumption (+69%, P < 0.001), and decreased food intake (-31%, P < 0.001). C rats showed mild hyperglycemia and hypertriglyceridemia. Normoglycemia (+69%, P < 0.01) and sustained hypertriglyceridemia (+69%, P < 0.01) were observed in C after washout. Both cola beverages induced an increase in left ventricular diastolic diameter (C: +9%, L: +7%, P < 0.05 vs W) and volumes (diastolic C: +26%, L: +22%, P < 0.01 vs W; systolic C: +24%, L: +24%, P < 0.05 vs W) and reduction of relative posterior wall thickness (C: -8%, L: -10%, P < 0.05 vs W). Cardiac output tended to increase (C: +25%, P < 0.05 vs W; L: +17%, not significant vs W). Heart rate was not affected. Pathology findings were scarce, related to aging rather than treatment. CONCLUSION: This experimental model may prove useful to investigate the consequences of high consumption of soft drinks. PMID:21526048

  19. Ursodeoxycholic Acid Ameliorates Fructose-Induced Metabolic Syndrome in Rats

    PubMed Central

    2014-01-01

    The metabolic syndrome (MS) is characterized by insulin resistance, dyslipidemia and hypertension. It is associated with increased risk of cardiovascular diseases and type-2 diabetes. Consumption of fructose is linked to increased prevalence of MS. Ursodeoxycholic acid (UDCA) is a steroid bile acid with antioxidant, anti-inflammatory activities and has been shown to improve insulin resistance. The current study aims to investigate the effect of UDCA (150 mg/kg) on MS induced in rats by fructose administration (10%) in drinking water for 12 weeks. The effects of UDCA were compared to fenofibrate (100 mg/kg), an agonist of PPAR-α receptors. Treatment with UDCA or fenofibrate started from the 6th week after fructose administration once daily. Fructose administration resulted in significant increase in body weight, elevations of blood glucose, serum insulin, cholesterol, triglycerides, advanced glycation end products (AGEs), uric acid levels, insulin resistance index and blood pressure compared to control rats. Moreover, fructose increased oxidative stress in aortic tissues indicated by significant increases of malondialdehyde (MDA), expression of iNOS and reduction of reduced glutathione (GSH) content. These disturbances were associated with decreased eNOS expression, increased infiltration of leukocytes and loss of aortic vascular elasticity. Treatment with UDCA successfully ameliorated the deleterious effects of fructose. The protective effect of UDCA could be attributed to its ability to decrease uric acid level, improve insulin resistance and diminish oxidative stress in vascular tissues. These results might support possible clinical application of UDCA in MS patients especially those present with liver diseases, taking into account its tolerability and safety. However, further investigations on human subjects are needed before the clinical application of UDCA for this indication. PMID:25202970

  20. Iron induces hepatocytes death via MAPK activation and mitochondria-dependent apoptotic pathway: beneficial role of glycine.

    PubMed

    Bhattacharyya, Sudip; Ghosh, Jyotirmoy; Sil, Parames C

    2012-10-01

    In the present study we investigated the beneficial role of glycine in iron (FeSO₄) induced oxidative damage in murine hepatocytes. Exposure of hepatocytes to 20 μM FeSO₄ for 3 hours enhanced reactive oxygen species (ROS) generation and induced alteration in biochemical parameters related to hepatic oxidative stress. Investigating cell signalling pathway, we observed that iron (FeSO₄) intoxication caused NF-κB activation as well as the phosphorylation of p38 and ERK MAPKs. Iron (FeSO₄) administration also disrupted Bcl-2/Bad protein balance, reduced mitochondrial membrane potential, released cytochrome c and induced the activation of caspases and cleavage of PARP protein. Flow cytometric analysis also confirmed that iron (FeSO₄) induced hepatocytes death is apoptotic in nature. Glycine (10 mM) supplementation, on the other hand, reduced all the iron (FeSO₄) induced apoptotic indices. Combining, results suggest that glycine could be a beneficial agent against iron mediated toxicity in hepatocytes. PMID:22817335

  1. Laser microdissection-assisted analysis of the functional fate of iron deficiency-induced root hairs in cucumber.

    PubMed

    Santi, Simonetta; Schmidt, Wolfgang

    2008-01-01

    Iron ranks fourth in the sequence of abundance of the elements in the Earth's crust, but its low bio-availability often limits plant growth. When present in suboptimal amounts, the acquisition of iron by plants is aided by a suite of responses, comprising molecular and developmental changes that facilitate the uptake of iron from sparingly soluble pools. The expression of genes involved in the mobilization of iron (CsHA1), the reduction of ferric chelates (CsFRO1), and in the uptake of ferrous iron (CsIRT1) was investigated in epidermal cells of Fe-sufficient and Fe-deficient cucumber (Cucumis sativum L.) roots using the Laser Microdissection and Pressure Catapulting (LMPC) method. Growing plants hydroponically in media deprived of iron induced the differentiation of almost all epidermal cells into root hairs. No root hairs were formed under iron-replete conditions. The formation of root hairs in response to Fe starvation was associated with a dramatic increase in message levels of CsFRO1, CsIRT1, and the iron-inducible H(+)-ATPase isoform CsHA1, when compared to epidermal cells of Fe-sufficient plants. On the contrary, transcripts of a housekeeping ATPase isoform, CsHA2, were not detected in root hairs, suggesting that Fe-deficiency-induced acidification is predominantly mediated by CsHA1. These data show that the formation of root hairs in response to iron deficiency is associated with cell-specific accumulation of transcripts that are involved in iron acquisition. The results also show that this includes the differential regulation of ATPase isoforms with similar function, but supposedly different characteristics, to counteract the imbalance in nutrient supply efficiently. PMID:18316319

  2. Antioxidant Activity of Caffeic Acid against Iron-Induced Free Radical Generation—A Chemical Approach

    PubMed Central

    Genaro-Mattos, Thiago C.; Maurício, Ângelo Q.; Rettori, Daniel; Alonso, Antonio; Hermes-Lima, Marcelo

    2015-01-01

    Caffeic acid (CA) is a phenolic compound widely found in coffee beans with known beneficial effects in vivo. Many studies showed that CA has anti-inflammatory, anti-mutagenic, antibacterial and anti-carcinogenic properties, which could be linked to its antioxidant activity. Taking in consideration the reported in vitro antioxidant mechanism of other polyphenols, our working hypothesis was that the CA antioxidant activity could be related to its metal-chelating property. With that in mind, we sought to investigate the chemical antioxidant mechanism of CA against in vitro iron-induced oxidative damage under different assay conditions. CA was able to prevent hydroxyl radical formation promoted by the classical Fenton reaction, as determined by 2-deoxyribose (2-DR) oxidative degradation and DMPO hydroxylation. In addition to its ability to prevent hydroxyl radical formation, CA had a great inhibition of membrane lipid peroxidation. In the lipid peroxidation assays CA acted as both metal-chelator and as hydrogen donor, preventing the deleterious action promoted by lipid-derived peroxyl and alkoxyl radicals. Our results indicate that the observed antioxidant effects were mostly due to the formation of iron-CA complexes, which are able to prevent 2-DR oxidation and DMPO hydroxylation. Noteworthy, the formation of iron-CA complexes and prevention of oxidative damage was directly related to the pH of the medium, showing better antioxidant activity at higher pH values. Moreover, in the presence of lipid membranes the antioxidant potency of CA was much higher, indicating its enhanced effectiveness in a hydrophobic environment. Overall, our results show that CA acts as an antioxidant through an iron chelating mechanism, preventing the formation of free hydroxyl radicals and, therefore, inhibiting Fenton-induced oxidative damage. The chemical properties of CA described here—in association with its reported signaling effects—could be an explanation to its beneficial effects

  3. Antioxidant Activity of Caffeic Acid against Iron-Induced Free Radical Generation--A Chemical Approach.

    PubMed

    Genaro-Mattos, Thiago C; Maurício, Ângelo Q; Rettori, Daniel; Alonso, Antonio; Hermes-Lima, Marcelo

    2015-01-01

    Caffeic acid (CA) is a phenolic compound widely found in coffee beans with known beneficial effects in vivo. Many studies showed that CA has anti-inflammatory, anti-mutagenic, antibacterial and anti-carcinogenic properties, which could be linked to its antioxidant activity. Taking in consideration the reported in vitro antioxidant mechanism of other polyphenols, our working hypothesis was that the CA antioxidant activity could be related to its metal-chelating property. With that in mind, we sought to investigate the chemical antioxidant mechanism of CA against in vitro iron-induced oxidative damage under different assay conditions. CA was able to prevent hydroxyl radical formation promoted by the classical Fenton reaction, as determined by 2-deoxyribose (2-DR) oxidative degradation and DMPO hydroxylation. In addition to its ability to prevent hydroxyl radical formation, CA had a great inhibition of membrane lipid peroxidation. In the lipid peroxidation assays CA acted as both metal-chelator and as hydrogen donor, preventing the deleterious action promoted by lipid-derived peroxyl and alkoxyl radicals. Our results indicate that the observed antioxidant effects were mostly due to the formation of iron-CA complexes, which are able to prevent 2-DR oxidation and DMPO hydroxylation. Noteworthy, the formation of iron-CA complexes and prevention of oxidative damage was directly related to the pH of the medium, showing better antioxidant activity at higher pH values. Moreover, in the presence of lipid membranes the antioxidant potency of CA was much higher, indicating its enhanced effectiveness in a hydrophobic environment. Overall, our results show that CA acts as an antioxidant through an iron chelating mechanism, preventing the formation of free hydroxyl radicals and, therefore, inhibiting Fenton-induced oxidative damage. The chemical properties of CA described here--in association with its reported signaling effects--could be an explanation to its beneficial effects

  4. Antioxidant Activity of Caffeic Acid against Iron-Induced Free Radical Generation--A Chemical Approach.

    PubMed

    Genaro-Mattos, Thiago C; Maurício, Ângelo Q; Rettori, Daniel; Alonso, Antonio; Hermes-Lima, Marcelo

    2015-01-01

    Caffeic acid (CA) is a phenolic compound widely found in coffee beans with known beneficial effects in vivo. Many studies showed that CA has anti-inflammatory, anti-mutagenic, antibacterial and anti-carcinogenic properties, which could be linked to its antioxidant activity. Taking in consideration the reported in vitro antioxidant mechanism of other polyphenols, our working hypothesis was that the CA antioxidant activity could be related to its metal-chelating property. With that in mind, we sought to investigate the chemical antioxidant mechanism of CA against in vitro iron-induced oxidative damage under different assay conditions. CA was able to prevent hydroxyl radical formation promoted by the classical Fenton reaction, as determined by 2-deoxyribose (2-DR) oxidative degradation and DMPO hydroxylation. In addition to its ability to prevent hydroxyl radical formation, CA had a great inhibition of membrane lipid peroxidation. In the lipid peroxidation assays CA acted as both metal-chelator and as hydrogen donor, preventing the deleterious action promoted by lipid-derived peroxyl and alkoxyl radicals. Our results indicate that the observed antioxidant effects were mostly due to the formation of iron-CA complexes, which are able to prevent 2-DR oxidation and DMPO hydroxylation. Noteworthy, the formation of iron-CA complexes and prevention of oxidative damage was directly related to the pH of the medium, showing better antioxidant activity at higher pH values. Moreover, in the presence of lipid membranes the antioxidant potency of CA was much higher, indicating its enhanced effectiveness in a hydrophobic environment. Overall, our results show that CA acts as an antioxidant through an iron chelating mechanism, preventing the formation of free hydroxyl radicals and, therefore, inhibiting Fenton-induced oxidative damage. The chemical properties of CA described here--in association with its reported signaling effects--could be an explanation to its beneficial effects

  5. Estrogens prevent metabolic dysfunctions induced by circadian disruptions in female mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Circadian disruption has become a significant factor contributing to the epidemics of obesity and insulin resistance. However, interventions to treat metabolic dysfunctions induced by circadian disruptions are limited. The ovarian hormone, estrogen, produces important antiobesity and antidiabetic ef...

  6. Ozone-Induced Metabolic Impairment is Attenuated in Adrenalectomized Wistar Kyoto Rats

    EPA Science Inventory

    Rationale: Air pollutants have been linked to increased incidence of metabolic syndrome however the mechanisms are poorly understood. We have recently shown that ozone exposure induces significant hyperglycemia together with elevated serum leptin and epinephrine in the Wistar Ky...

  7. Impairment of carbon metabolism induced by the herbicide glyphosate.

    PubMed

    Orcaray, Luis; Zulet, Amaia; Zabalza, Ana; Royuela, Mercedes

    2012-01-01

    The herbicide glyphosate reduces plant growth and causes plant death by inhibiting the biosynthesis of aromatic amino acids. The objective of this work was to determine whether glyphosate-treated plants show a carbon metabolism pattern comparable to that of plants treated with herbicides that inhibit branched-chain amino acid biosynthesis. Glyphosate-treated plants showed impaired carbon metabolism with an accumulation of carbohydrates in the leaves and roots. The growth inhibition detected after glyphosate treatment suggested impaired metabolism that impedes the utilization of available carbohydrates or energy at the expected rate. These effects were common to both types of amino acid biosynthesis inhibitors. Under aerobic conditions, ethanolic fermentative metabolism was enhanced in the roots of glyphosate-treated plants. This fermentative response was not related to changes in the respiratory rate or to a limitation of the energy charge. This response, which was similar for both types of herbicides, might be considered a general response to stress conditions.

  8. Iron potentiates bacterial lipopolysaccharide-induced nitric oxide formation in animal organs.

    PubMed

    Kubrina, L N; Mikoyan, V D; Mordvintcev, P I; Vanin, A F

    1993-04-16

    Administration of an Fe(2+)-citrate complex to mongrel mice pretreated with lipopolysaccharide (LPS) from Salmonella typhosa increased LPS-induced NO formation in vivo in the liver, intestine, lung, heart, kidney and spleen by 10-20-fold. This process was monitored by the intensity of the EPR signal due to mononitrosyl iron complex (MNIC) formation with exogenous diethyldithiocarbamate (DETC) recorded in the tissues. The NO synthase inhibitor, NG-nitro-L-arginine, prevented this complex formation in the liver of mice treated with both LPS and Fe(2+)-citrate complex. Thus, administration of LPS and Fe(2+)-citrate complex to mice induced NO biosynthesis in this tissue via an L-arginine-dependent pathway, presumably by facilitating the entry of Ca2+ ions into NO-producing cells through Fe(2+)-induced cell membrane lesions. PMID:7682442

  9. Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism.

    PubMed

    Abruzzese, Giselle Adriana; Heber, Maria Florencia; Ferreira, Silvana Rocio; Velez, Leandro Martin; Reynoso, Roxana; Pignataro, Omar Pedro; Motta, Alicia Beatriz

    2016-07-01

    Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats were hyperandrogenized with testosterone. At pubertal age, the prenatally hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid oxidation pathway, oxidant/antioxidant balance and proinflammatory status. We also evaluated the general metabolic status through growth rate curve, basal glucose and insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile. Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty oxidation pathways were altered. The PH groups also showed impaired oxidant/antioxidant balance, a decrease in the proinflammatory pathway (measured by prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance of circulating lipids and increased risk of metabolic syndrome. We conclude that prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of liver alterations, imbalance in lipid metabolism and increased risk of developing metabolic syndrome. The anovulatory phenotype showed more alterations in liver lipogenesis and a more impaired balance of insulin and glucose metabolism, being more susceptible to the development of steatosis.

  10. Hexavalent chromium induced stress and metabolic responses in hybrid willows.

    PubMed

    Yu, Xiao-Zhang; Gu, Ji-Dong; Huang, Shen-Zhuo

    2007-04-01

    Metabolic responses to hexavalent chromium (Cr(6+)) stress and the uptake and translocation of Cr(6+ )were investigated using pre-rooted hybrid willows (Salix matsudana Koidz x Salix alba L.) exposed to hydroponic solution spiked with K(2)CrO(4) at 24.0 +/- 1 degrees C for 192 h. Various physiological parameters of the plants were monitored to determine toxicity from Cr(6+ )exposure. At Cr(6+) treatments of 50% higher than that of the non-treated control plants. As Cr concentrations were increased further, a slight increase in the transpiration rate was also observed compared with the controls. Negligible difference in the chlorophyll contents in leaves between the treated and the non-treated control plants was measured, except for willows exposed to 1.05 mg Cr/l. The response of soluble proteins in leaves of willows to Cr treatments was remarkable. Cr-induced toxicity appeared in all treatments resulting in reduced activities of catalase (CAT) and peroxidase (POD) compared to the controls. Superoxide dismutases (SOD) activity in the leaf cells showed a positive increase after Cr exposure. Of all selected parameters, soluble proteins in leaves were the most sensitive to Cr(6+ )doses, showing a significant linear correlation negatively (R (2) = 0.931). Uptake of Cr(6+) by willows grown in flasks was found to increase linearly with the added Cr(6+ )(a zero order kinetics), as indicated by the high R (2) (0.9322). Recovery of Cr in different parts of plant materials varied significantly with roots being the dominant site of Cr accumulation. Although the translocation to shoots was detected, the amount of Cr translocated to shoots was considerably small. The capacity of willows to assimilate Cr(6+ )was also evaluated using detached leaves and roots in sealed glass vessels in vivo. Uptake of Cr by roots was mediated possibly through an active transport mechanism, whereas the cuticle of leaves was the major obstacle

  11. Integration of Genome-Scale Metabolic Nodels of Iron-Reducing Bacteria With Subsurface Flow and Geochemical Reactive Transport Models

    NASA Astrophysics Data System (ADS)

    Scheibe, T. D.; Mahadevan, R.; Fang, Y.; Garg, S.; Long, P. E.; Lovley, D. M.

    2008-12-01

    Several field and laboratory experiments have demonstrated that the growth and activity of iron-reducing bacteria can be stimulated in many subsurface environments by amendment of groundwater with a soluble electron donor. Under strong iron-reducing conditions, these organisms mediate reactions that can impact a wide range of subsurface contaminants including chlorinated hydrocarbons, metals, and radionuclides. Therefore there is strong interest in in-situ bioremediation as a potential technology for cleanup of contaminated aquifers. To evaluate and design bioremediation systems, as well as to evaluate the viability of monitored natural attenuation as an alternative, quantitative models of biogeochemically reactive transport are needed. To date, most such models represent microbial activity in terms of kinetic rate (e.g., Monod- type) formulations. Such models do not account for fundamental changes in microbial functionality (such as utilization of alternative respiratory pathways) that occur as the result of spatial and temporal variations in the geochemical environment experienced by microorganisms. Constraint-based genome-scale in silico models of microbial metabolism present an alternative to simplified rate formulations that provide flexibility to account for changes in microbial function in response to local geochemical conditions. We have developed and applied a methodology for coupling a constraint-based in silico model of Geobacter sulfurreducens with a conventional model of groundwater flow, transport, and geochemical reaction. Two uses of the in silico model are tested: 1) incorporation of modified microbial growth yield coefficients based on the in silico model, and 2) variation of reaction rates in a reactive transport model based on in silico modeling of a range of local geochemical conditions. Preliminary results from this integrated model will be presented.

  12. Genotypic variability within Tunisian grapevine varieties (Vitis vinifera L.) facing bicarbonate-induced iron deficiency.

    PubMed

    Ksouri, Riadh; Debez, Ahmed; Mahmoudi, Henda; Ouerghi, Zeineb; Gharsalli, Mohamed; Lachaâl, Mokhtar

    2007-05-01

    Morpho-physiological responses to bicarbonate-induced Fe deficiency were investigated in five Vitis vinifera L. Tunisian varieties (Khamri, Blanc3, Arich Dressé, Beldi, and Balta4). One-month-old woody cuttings were cultivated for 85days on a free calcareous soil irrigated with tap water containing increasing bicarbonate levels (0, 4, 8, 12, and 16mM NaHCO(3)). After this screening, a second experiment compared root biochemical responses of two contrasting genotypes (tolerant-sensitive) dealing with bicarbonate-induced iron deprivation (20microM Fe+/-10mM HCO(3)(-)) for 75days. Using morpho-physiological criteria, grapevine tolerance to HCO(3)(-)-induced Fe shortage appeared to be genotype-dependent: Balta4 and Beldi varieties showed the highest leaf-chlorosis score (especially at the extreme HCO(3)(-) levels), in contrast to Khamri variety. Growth parameters (shoot height, total leaf area, leaf number, and biomass production) as well as juvenile leaf chlorophyll content were also differently affected depending on both genotype and bicarbonate dose. At 16mM HCO(3)(-), Khamri was the less sensitive variety, contrasting with Balta4. On the other hand, chlorophyll content correlated positively with HCl-extractible Fe content of the juvenile leaves, suggesting that the grapevine response to iron deficiency may partly depend on to the plant ability to adequately supply young leaves with this element. Root biochemical responses revealed a relatively higher root acidification capacity in Khamri (tolerant) under Fe-deficiency while no significant changes occurred in Balta4 (sensitive). In addition, Fe(III)-reductase and phosphoenolpyruvate carboxylase (PEPC, EC 4.1.1.31) activities were strongly stimulated by Fe-deficiency in Khamri, while remaining constant in Balta4. These findings suggest that biochemical parameters may constitute reliable criteria for the selection of tolerant grapevine genotypes to iron chlorosis. PMID:17468003

  13. Ferrous Iron Induces Nrf2 Expression in Mouse Brain Astrocytes to Prevent Neurotoxicity.

    PubMed

    Cui, Zhenwen; Zhong, Zhihong; Yang, Yong; Wang, Baofeng; Sun, Yuhao; Sun, Qingfang; Yang, Guo-Yuan; Bian, Liuguan

    2016-08-01

    Free radical damage caused by ferrous iron is involved in the pathogenesis of secondary brain injury after intracerebral hemorrhage (ICH). NF-E2-related factor 2 (Nrf2), a major phase II gene regulator that binds to antioxidant response element, represents an important cellular cytoprotective mechanism against oxidative damage. We hypothesized that Nrf2 might protect astrocytes from damage by Fe(2+) . Therefore, we examined cytotoxicity in primary astrocytes induced by iron overload and evaluated the effects of Fe(2+) on Nrf2 expression. The results demonstrated that 24-h Fe(2+) exposure exerted time- and concentration-dependent cytotoxicity in astrocytes. Furthermore, Fe(2+) exposure in astrocytes resulted in time- and concentration-dependent increases in Nrf2 expression, which preceded Fe(2+) toxicity. Nrf2-specific siRNA further knocked down Nrf2 levels, resulting in greater Fe(2+) -induced astrocyte cytotoxicity. These data indicate that induction of Nrf2 expression could serve as an adaptive self-defense mechanism, although it is insufficient to completely protect primary astrocytes from Fe(2+) -induced neurotoxicity. PMID:27037625

  14. Hyperinsulinemia may boost both hematocrit and iron absorption by up-regulating activity of hypoxia-inducible factor-1alpha.

    PubMed

    McCarty, M F

    2003-01-01

    There is growing evidence that increases in both hematocrit and body iron stores are components of the insulin resistance syndrome. The ability of insulin and of IGF-I - whose effective activity is increased in the context of insulin resistance - to boost activity of the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), may be at least partially responsible for this association. HIF-1alpha, which functions physiologically as a detector of both hypoxia and iron-deficiency, promotes synthesis of erythropoietin, and may also mediate the up-regulatory impact of hypoxia on intestinal iron absorption. Insulin/IGF-I may also influence erythropoiesis more directly, as they are growth factors for developing reticulocytes. Conversely, the activation of HIF-1alpha associated with iron deficiency may be responsible for the increased glucose tolerance noted in iron-deficient animals; HIF-1alpha promotes efficient glucose uptake and glycolysis - a sensible adaptation to hypoxia - by inducing increased synthesis of glucose transporters and glycolytic enzymes. Recent reports that phlebotomy can increase the efficiency of muscle glucose uptake in lean healthy omnivores are intriguing and require further confirmation. Whether increased iron stores contribute to the elevated vascular risk associated with insulin resistance is doubtful, inasmuch as most prospective studies fail to correlate serum ferritin or transferrin saturation with subsequent vascular events. However, current data are reasonably consistent with the possibility that moderately elevated iron stores are associated with increased overall risk for cancer - and for colorectal cancer in particular; free iron may play a catalytic role in 'spontaneous' mutagenesis. Thus, iron excess may mediate at least some of the increased cancer risk associated with insulin resistance and heme-rich diets. People who are insulin resistant can minimize any health risk associated with iron overload by avoiding heme

  15. Nitrite Induces the Extravasation of Iron Oxide Nanoparticles in Hypoxic Tumor Tissue

    PubMed Central

    Mistry, Nilesh; Stokes, Ashley M; Van Gambrell, James; Quarles, Christopher Chad

    2014-01-01

    Nitrite undergoes reconversion to nitric oxide (NO) under conditions characteristic of the tumor microenvironment, such as hypoxia and low pH. This selective conversion of nitrite into NO in tumor tissue has led to the possibility of using nitrite to enhance drug delivery and radiation response. In this work we propose to serially characterize the vascular response of brain tumor bearing rats to nitrite using contrast-enhanced R2* mapping. Imaging is performed using a multi-echo gradient echo sequence at baseline, post iron-oxide nanoparticle injection, and post-nitrite injection, while the animal is breathing air. The results indicate that nitrite sufficiently increases vascular permeability in C6 gliomas such that the iron oxide nanoparticles accumulate within the tumor tissue. When animals breathed 100% oxygen, the contrast agent remained within the vasculature indicating that the conversion of nitrite to nitric oxide occurs in the presence of hypoxia within the tumor. The hypoxia-dependent, nitrite-induced extravasation of iron-oxide nanoparticles observed herein has implications for the enhancement of conventional and nanotherapeutic drug delivery. PMID:24470164

  16. Loss of GLUT4 induces metabolic reprogramming and impairs viability of breast cancer cells.

    PubMed

    Garrido, Pablo; Osorio, Fernando G; Morán, Javier; Cabello, Estefanía; Alonso, Ana; Freije, José M P; González, Celestino

    2015-01-01

    Metabolic reprogramming strategies focus on the normalization of metabolism of cancer cells and constitute promising targets for cancer treatment. Here, we demonstrate that the glucose transporter 4 (GLUT4) has a prominent role in basal glucose uptake in MCF7 and MDA-MB-231 breast cancer cells. We show that shRNA-mediated down-regulation of GLUT4 diminishes glucose uptake and induces metabolic reprogramming by reallocating metabolic flux to oxidative phosphorylation. This reallocation is reflected on an increased activity of the mitochondrial oxidation of pyruvate and lower lactate release. Altogether, GLUT4 inhibition compromises cell proliferation and critically affects cell viability under hypoxic conditions, providing proof-of-principle for the feasibility of using pharmacological approaches to inhibit GLUT4 in order to induce metabolic reprogramming in vivo in breast cancer models.

  17. [In Vitro and in Vivo Assessments of Drug-induced Hepatotoxicity and Drug Metabolism in Humans].

    PubMed

    Sanoh, Seigo

    2015-01-01

    Drug-induced hepatotoxicity is of concern in drug discovery and development. Reactive metabolites generated by drug metabolizing enzymes in the liver contribute to the induction of hepatotoxicity. Therefore, drug-induced hepatotoxicity, drug metabolism, and pharmacokinetics were evaluated in vitro and in vivo in this pre-clinical study. First, hepatotoxicity was tested in vitro using three-dimensional hepatocyte cultures. Hepatocyte spheroids formed in the three-dimensional culture systems maintain various liver functions such as the expression of drug metabolizing enzymes. High dose exposure to acetaminophen (APAP) induces hepatotoxicity because of the formation of reactive metabolites by CYP. Using fluorescence imaging, we observed that cell viability and glutathione levels were reduced in hepatocyte spheroids exposed to APAP mediated by the metabolic activation of CYP. On the other hand, there are species differences in the expression of drug metabolizing enzymes and metabolite profiles between animals and humans. Therefore, chimeric mice transfected with human hepatocytes were used for the in vivo assessment of metabolic profiles in humans. We found that drug metabolism and pharmacokinetics mediated by CYP and non-CYP enzymes, such as UDP-glucuronosyltransferase and aldehyde oxidase, in chimeric mice with humanized liver were similar to those in humans. The combination of in vitro and in vivo assessments using spheroids and chimeric mice with humanized liver, respectively, during the screening of drug candidates may help to reveal hepatotoxicity induced by the formation of metabolites. PMID:26521876

  18. Effects of iron-reducing bacteria on carbon steel corrosion induced by thermophilic sulfate-reducing consortia.

    PubMed

    Valencia-Cantero, Eduardo; Peña-Cabriales, Juan José

    2014-02-28

    Four thermophilic bacterial species, including the iron-reducing bacterium Geobacillus sp. G2 and the sulfate-reducing bacterium Desulfotomaculum sp. SRB-M, were employed to integrate a bacterial consortium. A second consortium was integrated with the same bacteria, except for Geobacillus sp. G2. Carbon steel coupons were subjected to batch cultures of both consortia. The corrosion induced by the complete consortium was 10 times higher than that induced by the second consortium, and the ferrous ion concentration was consistently higher in iron-reducing consortia. Scanning electronic microscopy analysis of the carbon steel surface showed mineral films colonized by bacteria. The complete consortium caused profuse fracturing of the mineral film, whereas the non-iron-reducing consortium did not generate fractures. These data show that the iron-reducing activity of Geobacillus sp. G2 promotes fracturing of mineral films, thereby increasing steel corrosion.

  19. Role of Cardiovascular Disease-associated iron overload in Libby amphibole-induced acute pulmonary injury and inflammation

    EPA Science Inventory

    Pulmonary toxicity induced by asbestos is thought to be mediated through redox-cycling of fiber-bound and bioavailable iron (Fe). We hypothesized that Libby amphibole (LA)-induced cute lung injury will be exacerbated in rat models of cardiovascular disease (CVD)-associated Fe-ove...

  20. Secondary mineralization pathways induced by dissimilatory iron reduction of ferrihydrite under advective flow

    NASA Astrophysics Data System (ADS)

    Hansel, Colleen M.; Benner, Shawn G.; Neiss, Jim; Dohnalkova, Alice; Kukkadapu, Ravi K.; Fendorf, Scott

    2003-08-01

    Iron (hydr)oxides not only serve as potent sorbents and repositories for nutrients and contaminants but also provide a terminal electron acceptor for microbial respiration. The microbial reduction of Fe (hydr)oxides and the subsequent secondary solid-phase transformations will, therefore, have a profound influence on the biogeochemical cycling of Fe as well as associated metals. Here we elucidate the pathways and mechanisms of secondary mineralization during dissimilatory iron reduction by a common iron-reducing bacterium, Shewanella putrefaciens (strain CN32), of 2-line ferrihydrite under advective flow conditions. Secondary mineralization of ferrihydrite occurs via a coupled, biotic-abiotic pathway primarily resulting in the production of magnetite and goethite with minor amounts of green rust. Operating mineralization pathways are driven by competing abiotic reactions of bacterially generated ferrous iron with the ferrihydrite surface. Subsequent to the initial sorption of ferrous iron on ferrihydrite, goethite (via dissolution/reprecipitation) and/or magnetite (via solid-state conversion) precipitation ensues resulting in the spatial coupling of both goethite and magnetite with the ferrihydrite surface. The distribution of goethite and magnetite within the column is dictated, in large part, by flow-induced ferrous Fe profiles. While goethite precipitation occurs over a large Fe(II) concentration range, magnetite accumulation is only observed at concentrations exceeding 0.3 mmol/L (equivalent to 0.5 mmol Fe[II]/g ferrihydrite) following 16 d of reaction. Consequently, transport-regulated ferrous Fe profiles result in a progression of magnetite levels downgradient within the column. Declining microbial reduction over time results in lower Fe(II) concentrations and a subsequent shift in magnetite precipitation mechanisms from nucleation to crystal growth. While the initial precipitation rate of goethite exceeds that of magnetite, continued growth is inhibited by

  1. Antagonist of prostaglandin E2 receptor 4 induces metabolic alterations in liver of mice.

    PubMed

    Li, Ning; Zhang, Limin; An, Yanpeng; Zhang, Lulu; Song, Yipeng; Wang, Yulan; Tang, Huiru

    2015-03-01

    Prostaglandin E2 receptor 4 (EP4) is one of the receptors for prostaglandin E2 and plays important roles in various biological functions. EP4 antagonists have been used as anti-inflammatory drugs. To investigate the effects of an EP4 antagonist (L-161982) on the endogenous metabolism in a holistic manner, we employed a mouse model, and obtained metabolic and transcriptomic profiles of multiple biological matrixes, including serum, liver, and urine of mice with and without EP4 antagonist (L-161982) exposure. We found that this EP4 antagonist caused significant changes in fatty acid metabolism, choline metabolism, and nucleotide metabolism. EP4 antagonist exposure also induced oxidative stress to mice. Our research is the first of its kind to report information on the alteration of metabolism associated with an EP4 antagonist. This information could further our understanding of current and new biological functions of EP4.

  2. Changes in brain oxidative metabolism induced by water maze training.

    PubMed

    Conejo, N M; González-Pardo, H; Vallejo, G; Arias, J L

    2007-03-16

    Although the hippocampus has been shown to be essential for spatial memory, the contribution of associated brain regions is not well established. Wistar rats were trained to find a hidden escape platform in the water maze during eight days. Following training, the oxidative metabolism in different brain regions was evaluated using cytochrome oxidase histochemistry. Metabolic activations were found in the prelimbic cortex, cornu ammonis (CA) 1 subfield of the dorsal hippocampus and the anterior thalamic nuclei, relative to yoked swim controls and naïve rats. In addition, many cross-correlations in brain metabolism were observed among the latter regions. These results support the implication of a hippocampal-prefrontal-thalamic system to spatial memory in rats. PMID:17222984

  3. Systemic elevation of PTEN induces a tumor suppressive metabolic state

    PubMed Central

    Garcia-Cao, Isabel; Song, Min Sup; Hobbs, Robin M.; Laurent, Gaelle; Giorgi, Carlotta; de Boer, Vincent C.J.; Anastasiou, Dimitrios; Ito, Keisuke; Sasaki, Atsuo T.; Rameh, Lucia; Carracedo, Arkaitz; Vander Heiden, Matthew G.; Cantley, Lewis C.; Pinton, Paolo; Haigis, Marcia C.; Pandolfi, Pier Paolo

    2012-01-01

    SUMMARY Decremental loss of PTEN results in cancer susceptibility and tumor progression. In turn this raises the possibility that PTEN elevation might be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with variably elevated PTEN expression levels, taking advantage of BAC (Bacterial Artificial Chromosome)-mediated transgenesis. Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake, increased mitochondrial oxidative phosphorylation, and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and independent pathways, and negatively impacts two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect. PMID:22401813

  4. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice

    SciTech Connect

    Guenancia, Charles; Li, Na; Hachet, Olivier; Rigal, Eve; Cottin, Yves; Dutartre, Patrick; Rochette, Luc; Vergely, Catherine

    2015-04-15

    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran–iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran–iron (15 mg/kg) for 3 weeks (D0–D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6 mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran–iron (125–1000 μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+ 22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice. - Highlights: • The effects of iron on cardiomyocytes were opposite to those on cancer cell lines. • In our model, iron overload did not potentiate anthracycline cardiotoxicity. • Chronic oxidative stress induced by iron could mitigate doxorubicin cardiotoxicity. • The role of iron in

  5. Tidal switch on metabolic activity: Salinity induced responses on bacterioplankton metabolic capabilities in a tropical estuary

    NASA Astrophysics Data System (ADS)

    Thottathil, Shoji D.; Balachandran, K. K.; Jayalakshmy, K. V.; Gupta, G. V. M.; Nair, Shanta

    2008-07-01

    "Biolog" plates were used to study the changes in the metabolic capabilities of bacterioplankton over a complete tidal cycle in a tropical ecosystem (Cochin Estuary) along southwest coast of India. The pattern of utilization of carbon sources showed a definite shift in the community metabolism along a salinity gradient. Multivariate statistical analysis revealed two communities, namely allochthonous bacterioplankton sensitive to salinity and autochthonous bacterioplankton, which are tolerant to wide salinity fluctuations. Regression analysis showed salinity as the most important parameter influencing the physiological profile of bacterioplankton, irrespective of tide. Apart from salinity, limno-tolerant retrievable counts and halo-tolerant retrievable counts also accounted for the metabolic variation of bacterioplankton during low and high tides, respectively. The shift in the substrate utilization from carbohydrates to amino acids appears to be due to the physiological adaptation or nitrogen limitation of bacterial community with increasing salinity.

  6. Hepcidin: A Promising Therapeutic Target for Iron Disorders

    PubMed Central

    Liu, Jing; Sun, Bingbing; Yin, Huijun; Liu, Sijin

    2016-01-01

    Abstract Iron is required for most forms of organisms, and it is the most essential element for the functions of many iron-containing proteins involved in oxygen transport, cellular respiration, DNA replication, and so on. Disorders of iron metabolism are associated with diverse diseases, including anemias (e.g., iron-deficiency anemia and anemia of chronic diseases) and iron overload diseases, such as hereditary hemochromatosis and β-thalassemia. Hepcidin (encoded by Hamp gene) is a peptide hormone synthesized by hepatocytes, and it plays an important role in regulating the systematic iron homeostasis. As the systemic iron regulator, hepcidin, not only controls dietary iron absorption and iron egress out of iron storage cells, but also induces iron redistribution in various organs. Deregulated hepcidin is often seen in a variety of iron-related diseases including anemias and iron overload disorders. In the case of iron overload disorders (e.g., hereditary hemochromatosis and β-thalassemia), hepatic hepcidin concentration is significantly reduced. Since hepcidin deregulation is responsible for iron disorder-associated diseases, the purpose of this review is to summarize the recent findings on therapeutics targeting hepcidin. Continuous efforts have been made to search for hepcidin mimics and chemical compounds that could be used to increase hepcidin level. Here, a literature search was conducted in PubMed, and research papers relevant to hepcidin regulation or hepcidin-centered therapeutic work were reviewed. On the basis of literature search, we recapitulated recent findings on therapeutic studies targeting hepcidin, including agonists and antagonists to modulate hepcidin expression or its downstream signaling. We also discussed the molecular mechanisms by which hepcidin level and iron metabolism are modulated. Elevating hepcidin concentration is an optimal strategy to ameliorate iron overload diseases, and also to relieve β-thalassemia phenotypes by improving

  7. Aconitase post-translational modification as a key in linkage between Krebs cycle, iron homeostasis, redox signaling, and metabolism of reactive oxygen species.

    PubMed

    Lushchak, Oleh V; Piroddi, Marta; Galli, Francesco; Lushchak, Volodymyr I

    2014-01-01

    Aconitase, an enzyme possessing an iron-sulfur cluster that is sensitive to oxidation, is involved in the regulation of cellular metabolism. There are two isoenzymes of aconitase (Aco)--mitochondrial (mAco) and cytosolic (cAco) ones. The primary role of mAdco is believed to be to control cellular ATP production via regulation of intermediate flux in the Krebs cycle. The cytosolic Aco in its reduced form operates as an enzyme, whereas in the oxidized form it is involved in the control of iron homeostasis as iron regulatory protein 1 (IRP1). Reactive oxygen species (ROS) play a central role in regulation of Aco functions. Catalytic Aco activity is regulated by reversible oxidation of [4Fe-4S]²⁺ cluster and cysteine residues, so redox-dependent posttranslational modifications (PTMs) have gained increasing consideration as regards possible regulatory effects. These include modifications of cysteine residues by oxidation, nitrosylation and thiolation, as well as Tyr nitration and oxidation of Lys residues to carbonyls. Redox-independent PTMs such as phosphorylation and transamination also have been described. In the presence of a sustained ROS flux, redox-dependent PTMs may lead to enzyme damage and cell stress by impaired energy and iron metabolism. Aconitase has been identified as a protein that undergoes oxidative modification and inactivation in aging and certain oxidative stress-related disorders. Here we describe possible mechanisms of involvement of the two aconitase isoforms, cAco and mAco, in the control of cell metabolism and iron homeostasis, balancing the regulatory, and damaging effects of ROS.

  8. Metabolism and epigenetics in the nervous system: Creating cellular fitness and resistance to neuronal death in neurological conditions via modulation of oxygen-, iron-, and 2-oxoglutarate-dependent dioxygenases.

    PubMed

    Karuppagounder, Saravanan S; Kumar, Amit; Shao, Diana S; Zille, Marietta; Bourassa, Megan W; Caulfield, Joseph T; Alim, Ishraq; Ratan, Rajiv R

    2015-12-01

    Modern definitions of epigenetics incorporate models for transient but biologically important changes in gene expression that are unrelated to DNA code but responsive to environmental changes such as injury-induced stress. In this scheme, changes in oxygen levels (hypoxia) and/or metabolic co-factors (iron deficiency or diminished 2-oxoglutarate levels) are transduced into broad genetic programs that return the cell and the organism to a homeostatic set point. Over the past two decades, exciting studies have identified a superfamily of iron-, oxygen-, and 2-oxoglutarate-dependent dioxygenases that sit in the nucleus as modulators of transcription factor stability, co-activator function, histone demethylases, and DNA demethylases. These studies have provided a concrete molecular scheme for how changes in metabolism observed in a host of neurological conditions, including stroke, traumatic brain injury, and Alzheimer's disease, could be transduced into adaptive gene expression to protect the nervous system. We will discuss these enzymes in this short review, focusing primarily on the ten eleven translocation (TET) DNA demethylases, the jumonji (JmJc) histone demethylases, and the oxygen-sensing prolyl hydroxylase domain enzymes (HIF PHDs). This article is part of a Special Issue entitled SI: Neuroprotection. PMID:26232572

  9. Nuclear Receptor Involvement in PPAA-Induced Metabolic Changes.

    EPA Science Inventory

    It has been proposed that certain xenobiotics commonly identified in biomonitoring studies may play a role in the incidence of obesity and metabolic syndrome in the United States and other countries. The list of potential "environmental obesogens" includes endocrine disrupting co...

  10. Similar Metabolic Changes Induced by HIPVs Exposure as Herbivore in Ammopiptanthus mongolicus

    PubMed Central

    Sun, Jingru; Zhang, Xiao; Cao, Chuanjian; Mei, Xindi; Wang, Ningning; Yan, Suli; Zong, Shixiang; Luo, Youqing; Yang, Haijun; Shen, Yingbai

    2014-01-01

    Herbivore-induced plant volatiles (HIPVs) are important compounds to prim neighboring undamaged plants; however, the mechanism for this priming process remains unclear. To reveal metabolic changes in plants exposed to HIPVs, metabolism of leaves and roots of Ammopiptanthus mongolicus seedlings exposed to HIPVs released from conspecific plants infested with larvae of Orgyia ericae were analyzed together with control and infested seedlings using nuclear magnetic resonance (NMR)-based metabolic technology and multi variate data analysis. Results presented showed that HIPVs exposure led to similar but specific metabolic changes compared with those induced by infestation in both leaves and roots. Furthermore, both HIPVs exposure and herbivore attack resulted in metabolic changes involving a series of primary and secondary metabolites in both leaves and roots. Taken together, these results suggested that priming of yet-damaged plants may be achieved by reconfiguring metabolic pathways in leaves and roots to make similar concentrations for all metabolites as those in seedlings infested. Therefore, we propose that improved readiness of defense induction of primed plants toward subsequent herbivore attack may be based on the similar metabolic profiling induced by HIPVs exposure as those caused by herbivore. PMID:24748156

  11. Herbivore-induced changes in tomato (Solanum lycopersicum) primary metabolism: a whole plant perspective.

    PubMed

    Steinbrenner, Adam D; Gómez, Sara; Osorio, Sonia; Fernie, Alisdair R; Orians, Colin M

    2011-12-01

    Induced changes in primary metabolism are important plant responses to herbivory, providing energy and metabolic precursors for defense compounds. Metabolic shifts also can lead to reallocation of leaf resources to storage tissues, thus increasing a plant's tolerance. We characterized whole-plant metabolic responses of tomato (Solanum lycopersicum) 24 h after leaf herbivory by two caterpillars (the generalist Helicoverpa zea and the specialist Manduca sexta) by using GC-MS. We measured 56 primary metabolites across the leaves, stems, roots, and apex, comparing herbivore-attacked plants to undamaged plants and mechanically damaged plants. Induced metabolic change, in terms of magnitude and number of individual concentration changes, was stronger in the apex and root tissues than in undamaged leaflets of damaged leaves, indicating rapid and significant whole-plant responses to damage. Helicoverpa zea altered many more metabolites than M. sexta across most tissues, suggesting an enhanced plant response to H. zea herbivory. Helicoverpa zea herbivory strongly affected concentrations of defense-related metabolites (simple phenolics and precursor amino acids), while M. sexta altered metabolites associated with carbon and nitrogen transport. We conclude that herbivory induces many systemic primary metabolic changes in tomato, and that changes often are specific to a single tissue or type of herbivore. The potential implications of primary metabolic changes are discussed in relation to resistance and tolerance.

  12. Mitochondrial translocation of Nur77 induced by ROS contributed to cardiomyocyte apoptosis in metabolic syndrome

    SciTech Connect

    Xu, Aibin; Liu, Jingyi; Liu, Peilin; Jia, Min; Wang, Han; Tao, Ling

    2014-04-18

    Highlights: • Metabolic syndrome exacerbated MI/R induced injury accompanied by decreased Nur77. • ROS led to Nur77 translocation in metabolic syndrome. • Inhibiting relocation of Nur77 to mitochondria reduced ROS-induced cardiomyocyte injury in metabolic syndrome. - Abstract: Metabolic syndrome is a major risk factor for cardiovascular diseases, and increased cardiomyocyte apoptosis which contributes to cardiac dysfunction after myocardial ischemia/reperfusion (MI/R) injury. Nur77, a nuclear orphan receptor, is involved in such various cellular events as apoptosis, proliferation, and glucose and lipid metabolism in several cell types. Apoptosis is positively correlated with mitochondrial translocation of Nur77 in the cancer cells. However, the roles of Nur77 on cardiac myocytes in patients with metabolic syndrome remain unclear. The objective of this study was to determine whether Nur77 may contribute to cardiac apoptosis in patients with metabolic syndrome after I/R injury, and, if so, to identify the underlying molecular mechanisms responsible. We used leptin-deficient (ob/ob) mice to make metabolic syndrome models. In this report, we observed that, accompanied by the substantial decline in apoptosis inducer Nur77, MI/R induced cardiac dysfunction was manifested as cardiomyopathy and increased ROS. Using the neonatal rat cardiac myocytes cultured in a high-glucose and high-fat medium, we found that excessive H{sub 2}O{sub 2} led to the significant alteration in mitochondrial membrane potential and translocation of Nur77 from the nucleus to the mitochondria. However, inhibition of the relocation of Nur77 to mitochondria via Cyclosporin A reversed the changes in membrane potential mediated by H{sub 2}O{sub 2} and reduced myocardial cell injury. Therefore, these data provide a potential underlying mechanism for cardiac dysfunction in metabolic syndrome and the suppression of Nur77 translocation may provide an effective approach to reduce cardiac injury in the

  13. Role of Metabolism by Intestinal Bacteria in Arbutin-Induced Suppression of Lymphoproliferative Response in vitro

    PubMed Central

    Kang, Mi Jeong; Ha, Hyun Woo; Kim, Ghee Hwan; Lee, Sang Kyu; Ahn, Young Tae; Kim, Dong Hyun; Jeong, Hye Gwang; Jeong, Tae Cheon

    2012-01-01

    Role of metabolism by intestinal bacteria in arbutin-induced immunotoxicity was investigated in splenocyte cultures. Following an incubation of arbutin with 5 different intestinal bacteria for 24 hr, its aglycone hydroquinone could be produced and detected in the bacterial culture media with different amounts. Toxic effects of activated arbutin by intestinal bacteria on lymphoproliferative response were tested in splenocyte cultures from normal mice. Lipopolysaccharide and concanavalin A were used as mitogens for B- and T-cells, respectively. When bacteria cultured medium with arbutin was treated into the splenocytes for 3 days, the medium cultured with bacteria producing large amounts of hydroquinone induced suppression of lymphoproliferative responses, indicating that metabolic activation by intestinal bacteria might be required in arbutin-induced toxicity. The results indicated that the present testing system might be applied for determining the possible role of metabolism by intestinal bacteria in certain chemical-induced immunotoxicity in animal cell cultures. PMID:24116295

  14. Combined deficiency of iron and (n-3) fatty acids in male rats disrupts brain monoamine metabolism and produces greater memory deficits than iron deficiency or (n-3) fatty acid deficiency alone.

    PubMed

    Baumgartner, Jeannine; Smuts, Cornelius M; Malan, Linda; Arnold, Myrtha; Yee, Benjamin K; Bianco, Laura E; Boekschoten, Mark V; Müller, Michael; Langhans, Wolfgang; Hurrell, Richard F; Zimmermann, Michael B

    2012-08-01

    Deficiencies of iron (Fe) (ID) and (n-3) fatty acids (FA) [(n-3)FAD] may impair brain development and function through shared mechanisms. However, little is known about the potential interactions between these 2 common deficiencies. We studied the effects of ID and (n-3)FAD, alone and in combination, on brain monoamine pathways (by measuring monoamines and related gene expression) and spatial working and reference memory (by Morris water maze testing). Using a 2 × 2 design, male rats were fed an ID, (n-3)FAD, ID+(n-3)FAD, or control diet for 5 wk postweaning (postnatal d 21-56) after (n-3)FAD had been induced over 2 generations. The (n-3)FAD and ID diets decreased brain (n-3) FA by 70-76% and Fe by 20-32%, respectively. ID and (n-3)FAD significantly increased dopamine (DA) concentrations in the olfactory bulb (OB) and striatum, with an additive 1- to 2-fold increase in ID+(n-3)FAD rats compared with controls (P < 0.05). ID decreased serotonin (5-HT) levels in OB, with a significant decrease in ID+(n-3)FAD rats. Furthermore, norepinephrine concentrations were increased 2-fold in the frontal cortex (FC) of (n-3)FAD rats (P < 0.05). Dopa decarboxylase was downregulated in the hippocampus of ID and ID+(n-3)FAD rats (fold-change = -1.33; P < 0.05). ID and (n-3)FAD significantly impaired working memory performance and the impairment positively correlated with DA concentrations in FC (r = 0.39; P = 0.026). Reference memory was impaired in the ID+(n-3)FAD rats (P < 0.05) and was negatively associated with 5-HT in FC (r = -0.42; P = 0.018). These results suggest that the combined deficiencies of Fe and (n-3) FA disrupt brain monoamine metabolism and produce greater deficits in reference memory than ID or (n-3)FAD alone.

  15. Lysosomal iron mobilization and induction of the mitochondrial permeability transition in acetaminophen-induced toxicity to mouse hepatocytes.

    PubMed

    Kon, Kazuyoshi; Kim, Jae-Sung; Uchiyama, Akira; Jaeschke, Hartmut; Lemasters, John J

    2010-09-01

    Acetaminophen induces the mitochondrial permeability transition (MPT) in hepatocytes. Reactive oxygen species (ROS) trigger the MPT and play an important role in AAP-induced hepatocellular injury. Because iron is a catalyst for ROS formation, our aim was to investigate the role of chelatable iron in MPT-dependent acetaminophen toxicity to mouse hepatocytes. Hepatocytes were isolated from fasted male C3Heb/FeJ mice. Necrotic cell killing was determined by propidium iodide fluorometry. Mitochondrial membrane potential was visualized by confocal microscopy of tetramethylrhodamine methylester. Chelatable ferrous ion was monitored by calcein quenching, and 70 kDa rhodamine-dextran was used to visualize lysosomes. Cell killing after acetaminophen (10mM) was delayed and decreased by more than half after 6 h by 1mM desferal or 1mM starch-desferal. In a cell-free system, ferrous but not ferric iron quenched calcein fluorescence, an effect reversed by dipyridyl, a membrane-permeable iron chelator. In hepatocytes loaded with calcein, intracellular calcein fluorescence decreased progressively beginning about 4 h after acetaminophen. Mitochondria then depolarized after about 6 h. Dipyridyl (20mM) dequenched calcein fluorescence. Desferal and starch-desferal conjugate prevented acetaminophen-induced calcein quenching and mitochondrial depolarization. As calcein fluorescence became quenched, lysosomes disappeared, consistent with release of iron from ruptured lysosomes. In conclusion, an increase of cytosolic chelatable ferrous iron occurs during acetaminophen hepatotoxicity, which triggers the MPT and cell killing. Disrupted lysosomes are the likely source of iron, and chelation of this iron decreases acetaminophen toxicity to hepatocytes.

  16. Microbially induced iron precipitation associated with a neutrophilic spring at Borra Caves, Vishakhapatnam, India.

    PubMed

    Baskar, Sushmitha; Baskar, Ramanathan; Thorseth, Ingunn H; Ovreås, Lise; Pedersen, Rolf B

    2012-04-01

    The present investigation uncovers various pieces of evidence for the possible biologically induced mineralization in iron mats associated with a pH-neutral spring in the Borra caves, Vishakhapatnam, India. Electron microscopy [scanning electron microscopy (SEM) and transmission electron microscopy (TEM)] demonstrated large numbers of (i) hollow tubes (diameter ∼1 μm) resembling sheaths of the iron-oxidizing bacteria Leptothrix, (ii) thin (diameter <1 μm) solid fibers of uncertain origin, (iii) nanoscale subspherical to irregularly shaped particles encrusting tubes and fibers, and (iv) aggregates of broken and partially disintegrated sheaths, fibers, and particles embedded in extracellular polymeric substances (EPS) occasionally including microbial cells. X-ray microanalyses by energy dispersive spectroscopy (EDS) revealed that the mat accumulated largely Fe but also smaller amounts of Si and traces of P and Ca. Particles rich in Si and Al (possibly kaolinite) and Ca (carbonate) were also observed. High-resolution TEM/EDS of unstained ultrathin sections suggests that microbial sheaths were highly mineralized by amorphous to cryptocrystalline Fe-rich phases and less frequently by other fine-grained and fibrous authigenic claylike minerals. Total number of microorganisms in the iron mats was 5.8×10(5) cells, g sed(-1) (wet weight). Analysis of the 16S rRNA gene diversity revealed microorganisms assigned to eight different phyla [Proteobacteria (62%), Chloroflexi (8%), Bacteroidetes (7%), Planctomycetes (1%), Actinobacteria (5%), Acidobacteria (6%), Nitrospira (1%), Firmicutes (5%)]. Within the Proteobacteria, Betaproteobacteria was the predominant class, which accounted for 28% of the sequences. Within this class some obvious similarities between the obtained sequences and sequences from other cave systems could be seen, especially sequences affiliated with Leptothrix, Siderooxidans, Crenothrix, Comamonadaceae, Dechloromonas, and many uncultured

  17. Earth's core formation aided by flow channelling instabilities induced by iron diapirs

    NASA Astrophysics Data System (ADS)

    Golabek, G. J.; Tackley, P. J.; Schmeling, H.

    2008-09-01

    The core formation process remains poorly known. Isotopic constraints by Hf/W systematics indicate a fast process which was largely completed within 33 Ma for the Earth. An unstable gravitational configuration of dense molten metallic ponds overlying a chondritic protocore is predicted by most studies for the time a planetary embryo reaches Mars-size. This leads to the formation of Rayleigh-Taylor instabilities. We propose the application of Stevenson's (1989) stress-induced melt channelling mechanism in the regions surrounding incipient iron diapirs. We therefore perform numerical experiments solving the two-phase, two compositions flow equations within a 2D rectangular box or 3D cuboid with symmetrical boundary conditions. We apply the Compaction Boussinesq Approximation (CBA) and include a depth-dependent gravity. For simplicity we use a constant viscosity for the solid phase and melt-fraction dependent rheology for the partially molten region around the diapir. We investigate the development of the channelling instability in cases with and without interaction with surrounding diapirs. In interactive cases we vary the distance between the diapir centres between 1 and 5 diapir radii and apply pseudoplasticity with power law factors between 1 and 6. As a result for single diapirs we observe for sufficiently small retention numbers the development of iron-rich melt channels within a region of approximately twice the diapir's size. This could lead to effective draining of the surrounding region and might initiate cascading daughter diapirs or iron dykes. For small distances between interactive diapirs the channelling mechanism is delayed for several Million years and preferentially develops in directions pointing away from the diapirs or in the area between them, whereas plastic effects seem to have negligible influence on the channel formation. The iron channels propose an effective mechanism to extract iron melt also from deeper parts of the initially chondritic

  18. Earth's core formation aided by flow channelling instabilities induced by iron diapirs

    NASA Astrophysics Data System (ADS)

    Golabek, G. J.; Tackley, P. J.; Schmeling, H.

    2008-09-01

    Abstract The core formation process remains poorly known. Isotopic constraints by Hf/W systematics indicate a fast process which was largely completed within 33 Ma for the Earth. An unstable gravitational configuration of dense molten metallic ponds overlying a chondritic protocore is predicted by most studies for the time a planetary embryo reaches Marssize. This leads to the formation of Rayleigh-Taylor instabilities. We propose the application of Stevenson's (1989) [1] stress-induced melt channelling mechanism in the regions surrounding incipient iron diapirs. We therefore perform numerical experiments solving the two-phase, two compositions flow equations within a 2D rectangular box or 3D cuboid with symmetrical boundary conditions. We apply the Compaction Boussinesq Approximation (CBA) and include a depth-dependent gravity. For simplicity we use a constant viscosity for the solid phase and meltfraction dependent rheology for the partially molten region around the diapir. We investigate the development of the channelling instability in cases with and without interaction with surrounding diapirs. In interactive cases we vary the distance between the diapir centres between 1 and 5 diapir radii and apply pseudoplasticity with power law factors between 1 and 6. As a result for single diapirs we observe for sufficiently small retention numbers the development of iron-rich melt channels within a region of approximately twice the diapir's size. This could lead to effective draining of the surrounding region and might initiate cascading daughter diapirs or iron dykes. For small distances between interactive diapirs the channelling mechanism is delayed for several Million years and preferentially develops in directions pointing away from the diapirs or in the area between them, whereas plastic effects seem to have negligible influence on the channel formation. The iron channels propose an effective mechanism to extract iron melt also from deeper parts of the initially

  19. Metabolic basis of ethanol-induced cytotoxicity in recombinant HepG2 cells: Role of nonoxidative metabolism

    SciTech Connect

    Wu Hai; Cai Ping; Clemens, Dahn L.; Jerrells, Thomas R.; Ansari, G.A. Shakeel; Kaphalia, Bhupendra S. . E-mail: bkaphali@utmb.edu

    2006-10-15

    Chronic alcohol abuse, a major health problem, causes liver and pancreatic diseases and is known to impair hepatic alcohol dehydrogenase (ADH). Hepatic ADH-catalyzed oxidation of ethanol is a major pathway for the ethanol disposition in the body. Hepatic microsomal cytochrome P450 (CYP2E1), induced in chronic alcohol abuse, is also reported to oxidize ethanol. However, impaired hepatic ADH activity in a rat model is known to facilitate a nonoxidative metabolism resulting in formation of nonoxidative metabolites of ethanol such as fatty acid ethyl esters (FAEEs) via a nonoxidative pathway catalyzed by FAEE synthase. Therefore, the metabolic basis of ethanol-induced cytotoxicity was determined in HepG2 cells and recombinant HepG2 cells transfected with ADH (VA-13), CYP2E1 (E47) or ADH + CYP2E1 (VL-17A). Western blot analysis shows ADH deficiency in HepG2 and E47 cells, compared to ADH-overexpressed VA-13 and VL-17A cells. Attached HepG2 cells and the recombinant cells were incubated with ethanol, and nonoxidative metabolism of ethanol was determined by measuring the formation of FAEEs. Significantly higher levels of FAEEs were synthesized in HepG2 and E47 cells than in VA-13 and VL-17A cells at all concentrations of ethanol (100-800 mg%) incubated for 6 h (optimal time for the synthesis of FAEEs) in cell culture. These results suggest that ADH-catalyzed oxidative metabolism of ethanol is the major mechanism of its disposition, regardless of CYP2E1 overexpression. On the other hand, diminished ADH activity facilitates nonoxidative metabolism of ethanol to FAEEs as found in E47 cells, regardless of CYP2E1 overexpression. Therefore, CYP2E1-mediated oxidation of ethanol could be a minor mechanism of ethanol disposition. Further studies conducted only in HepG2 and VA-13 cells showed lower ethanol disposition and ATP concentration and higher accumulation of neutral lipids and cytotoxicity (apoptosis) in HepG2 cells than in VA-13 cells. The apoptosis observed in HepG2 vs

  20. Modulation of cellular iron metabolism by hydrogen peroxide. Effects of H2O2 on the expression and function of iron-responsive element-containing mRNAs in B6 fibroblasts.

    PubMed

    Caltagirone, A; Weiss, G; Pantopoulos, K

    2001-06-01

    Cellular iron uptake and storage are coordinately controlled by binding of iron-regulatory proteins (IRP), IRP1 and IRP2, to iron-responsive elements (IREs) within the mRNAs encoding transferrin receptor (TfR) and ferritin. Under conditions of iron starvation, both IRP1 and IRP2 bind with high affinity to cognate IREs, thus stabilizing TfR and inhibiting translation of ferritin mRNAs. The IRE/IRP regulatory system receives additional input by oxidative stress in the form of H(2)O(2) that leads to rapid activation of IRP1. Here we show that treating murine B6 fibroblasts with a pulse of 100 microm H(2)O(2) for 1 h is sufficient to alter critical parameters of iron homeostasis in a time-dependent manner. First, this stimulus inhibits ferritin synthesis for at least 8 h, leading to a significant (50%) reduction of cellular ferritin content. Second, treatment with H(2)O(2) induces a approximately 4-fold increase in TfR mRNA levels within 2-6 h, and subsequent accumulation of newly synthesized protein after 4 h. This is associated with a profound increase in the cell surface expression of TfR, enhanced binding to fluorescein-tagged transferrin, and stimulation of transferrin-mediated iron uptake into cells. Under these conditions, no significant alterations are observed in the levels of mitochondrial aconitase and the Divalent Metal Transporter DMT1, although both are encoded by two as yet lesser characterized IRE-containing mRNAs. Finally, H(2)O(2)-treated cells display an increased capacity to sequester (59)Fe in ferritin, despite a reduction in the ferritin pool, which results in a rearrangement of (59)Fe intracellular distribution. Our data suggest that H(2)O(2) regulates cellular iron acquisition and intracellular iron distribution by both IRP1-dependent and -independent mechanisms.

  1. Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone.

    PubMed

    Zhao, Liangliang; Hadziahmetovic, Majda; Wang, Chenguang; Xu, Xueying; Song, Ying; Jinnah, H A; Wodzinska, Jolanta; Iacovelli, Jared; Wolkow, Natalie; Krajacic, Predrag; Weissberger, Alyssa Cwanger; Connelly, John; Spino, Michael; Lee, Michael K; Connor, James; Giasson, Benoit; Harris, Z Leah; Dunaief, Joshua L

    2015-12-01

    Brain iron accumulates in several neurodegenerative diseases and can cause oxidative damage, but mechanisms of brain iron homeostasis are incompletely understood. Patients with mutations in the cellular iron-exporting ferroxidase ceruloplasmin (Cp) have brain iron accumulation causing neurodegeneration. Here, we assessed the brains of mice with combined mutation of Cp and its homolog hephaestin. Compared to single mutants, brain iron accumulation was accelerated in double mutants in the cerebellum, substantia nigra, and hippocampus. Iron accumulated within glia, while neurons were iron deficient. There was loss of both neurons and glia. Mice developed ataxia and tremor, and most died by 9 months. Treatment with the oral iron chelator deferiprone diminished brain iron levels, protected against neuron loss, and extended lifespan. Ferroxidases play important, partially overlapping roles in brain iron homeostasis by facilitating iron export from glia, making iron available to neurons. Above: Iron (Fe) normally moves from capillaries to glia to neurons. It is exported from the glia by ferroportin (Fpn) with ferroxidases ceruloplasmin (Cp) and/or Hephaestin (Heph). Below: In mice with mutation of Cp and Heph, iron accumulates in glia, while neurons have low iron levels. Both neurons and glia degenerate and mice become ataxic unless given an iron chelator. PMID:26303407

  2. Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone.

    PubMed

    Zhao, Liangliang; Hadziahmetovic, Majda; Wang, Chenguang; Xu, Xueying; Song, Ying; Jinnah, H A; Wodzinska, Jolanta; Iacovelli, Jared; Wolkow, Natalie; Krajacic, Predrag; Weissberger, Alyssa Cwanger; Connelly, John; Spino, Michael; Lee, Michael K; Connor, James; Giasson, Benoit; Harris, Z Leah; Dunaief, Joshua L

    2015-12-01

    Brain iron accumulates in several neurodegenerative diseases and can cause oxidative damage, but mechanisms of brain iron homeostasis are incompletely understood. Patients with mutations in the cellular iron-exporting ferroxidase ceruloplasmin (Cp) have brain iron accumulation causing neurodegeneration. Here, we assessed the brains of mice with combined mutation of Cp and its homolog hephaestin. Compared to single mutants, brain iron accumulation was accelerated in double mutants in the cerebellum, substantia nigra, and hippocampus. Iron accumulated within glia, while neurons were iron deficient. There was loss of both neurons and glia. Mice developed ataxia and tremor, and most died by 9 months. Treatment with the oral iron chelator deferiprone diminished brain iron levels, protected against neuron loss, and extended lifespan. Ferroxidases play important, partially overlapping roles in brain iron homeostasis by facilitating iron export from glia, making iron available to neurons. Above: Iron (Fe) normally moves from capillaries to glia to neurons. It is exported from the glia by ferroportin (Fpn) with ferroxidases ceruloplasmin (Cp) and/or Hephaestin (Heph). Below: In mice with mutation of Cp and Heph, iron accumulates in glia, while neurons have low iron levels. Both neurons and glia degenerate and mice become ataxic unless given an iron chelator.

  3. Initial Characterization of Carbon Metabolism in Iron Oxidizing Microbial Communities of Acidic Hot Springs in Norris Geyser Basin, Yellowstone National Park

    NASA Astrophysics Data System (ADS)

    Kreuzer, H. W.; Jennings, R. D.; Whitmore, L.; Inskeep, W. P.; Moran, J.

    2012-12-01

    the organism produces during autotrophic growth, and are conducting isotopic labeling experiments to determine if these compounds serve as substrates for the iron oxide mat communities. However, isotopic analysis of DIC in the springs as well as bulk iron oxide mat definitively show that fixation of DIC by M. yellowstonensis is not the only source of C within the mats. Metagenome analysis of the microbial communities and genome analysis of isolates suggest the presence of heterotrophic metabolic pathways. Indeed, initial labeling experiments demonstrate strong heterotrophic metabolism in the iron oxide mats as well as in M. yellowstonensis. Several potential sources of reduced C are available in the springs, but whether any of these potential substrates actually feed the iron mat communities is yet to be determined. Carbon isotope ratios of the bulk iron mat communities and potential heterotrophic C sources suggest that heterotrophic uptake of these sources, like autotrophy of DIC, is not the only source of C in the system. Identifying the major active carbon pools and potential geochemical and microbial carbon links will illuminate carbon cycling in this system and should provide insights into how energy is transferred from key chemolithotrophic reactions to other components of the microbial system.

  4. Monolayer expansion induces an oxidative metabolism and ROS in chondrocytes

    SciTech Connect

    Heywood, H.K. Lee, D.A.

    2008-08-22

    This study tests the hypothesis that articular chondrocytes shift from a characteristically glycolytic to an oxidative energy metabolism during population expansion in monolayer. Bovine articular chondrocytes were cultured in monolayer under standard incubator conditions for up to 14 days. Cellular proliferation, oxygen consumption, lactate production, protein content, ROS generation and mitochondrial morphology were examined. Lactate release increased {approx}5-fold within 1 week, but this was limited to {approx}2-fold increase when normalized to cellular protein content. By contrast, per cell oxidative phosphorylation increased 98-fold in 1 week. The increase in oxidative phosphorylation was evident within 24 h, preceding cell proliferation and was associated with augmented reactive oxygen species generation. The autologous chondrocyte implantation procedure requires 14-21 days for population expansion. The alterations in metabolic phenotype we report within 7 days in vitro are thus pertinent to autologous chondrocyte implantation with significant implications for the chondrocyte functionality.

  5. Shear stress induced stimulation of mammalian cell metabolism

    NASA Technical Reports Server (NTRS)

    Mcintire, L. V.; Frangos, J. A.; Eskin, S. G.

    1988-01-01

    A flow apparatus was developed for the study of the metabolic response of anchorage dependent cells to a wide range of steady and pulsatile shear stresses under well controlled conditions. Human umbilical vein endothelial cell monolayers were subjected to steady shear stresses of up to 24 dynes/sq cm, and the production of prostacyclin was determined. The onset of flow led to a burst in prostacyclin production which decayed to a long term steady state rate (SSR). The SSR of cells exposed to flow was greater than the basal release level, and increased linearly with increasing shear stress. It is demonstrated that shear stresses in certain ranges may not be detrimental to mammalian cell metabolism. In fact, throughout the range of shear stresses studied, metabolite production is maximized by maximizing shear stress.

  6. Metabolism

    MedlinePlus

    Metabolism refers to all the physical and chemical processes in the body that convert or use energy, ... Tortora GJ, Derrickson BH. Metabolism. In: Tortora GJ, Derrickson BH. Principles of Anatomy and Physiology . 14th ed. Hoboken, NJ: John H Wiley and Sons; 2013: ...

  7. Anti-oxidative protection against iron overload-induced liver damage in mice by Cajanus cajan (L.) Millsp. leaf extract.

    PubMed

    Sarkar, Rhitajit; Hazra, Bibhabasu; Mandal, Nripendranath

    2013-02-01

    In view of the contribution of iron deposition in the oxidative pathologic process of liver disease, the potential of 70% methanolic extract of C. cajan leaf (CLME) towards antioxidative protection against iron-overload-induced liver damage in mice has been investigated. DPPH radical scavenging and protection of Fenton reaction induced DNA damage was conducted in vitro. Post oral administration of CLME to iron overloaded mice, the levels of antioxidant and serum enzymes, hepatic iron, serum ferritin, lipid peroxidation, and protein carbonyl and hydroxyproline contents were measured, in comparison to deferasirox treated mice. Oral treatment of the plant extract effectively lowered the elevated levels of liver iron, lipid peroxidation, protein carbonyl and hydroxyproline. There was notable increment in the dropped levels of hepatic antioxidants. The dosage of the plant extract not only made the levels of serum enzymes approach normal value, but also counteracted the overwhelmed serum ferritin level. The in vitro studies indicated potential antioxidant activity of CLME. The histopathological observations also substantiated the ameliorative function of the plant extract. Accordingly, it is suggested that Cajanus cajan leaf can be a useful herbal remedy to suppress oxidative damage caused by iron overload. PMID:23923610

  8. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop.

    PubMed

    Settembre, Carmine; De Cegli, Rossella; Mansueto, Gelsomina; Saha, Pradip K; Vetrini, Francesco; Visvikis, Orane; Huynh, Tuong; Carissimo, Annamaria; Palmer, Donna; Klisch, Tiemo Jürgen; Wollenberg, Amanda C; Di Bernardo, Diego; Chan, Lawrence; Irazoqui, Javier E; Ballabio, Andrea

    2013-06-01

    The lysosomal-autophagic pathway is activated by starvation and plays an important role in both cellular clearance and lipid catabolism. However, the transcriptional regulation of this pathway in response to metabolic cues is uncharacterized. Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via Ppargc1α and Ppar1α. Thus, during starvation a transcriptional mechanism links the autophagic pathway to cellular energy metabolism. The conservation of this mechanism in Caenorhabditis elegans suggests a fundamental role for TFEB in the evolution of the adaptive response to food deprivation. Viral delivery of TFEB to the liver prevented weight gain and metabolic syndrome in both diet-induced and genetic mouse models of obesity, suggesting a new therapeutic strategy for disorders of lipid metabolism.

  9. Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in acute lymphoblastic leukemia

    PubMed Central

    Herranz, Daniel; Ambesi-Impiombato, Alberto; Sudderth, Jessica; Sánchez-Martín, Marta; Belver, Laura; Tosello, Valeria; Xu, Luyao; Wendorff, Agnieszka A.; Castillo, Mireia; Haydu, J. Erika; Márquez, Javier; Matés, José M.; Kung, Andrew L.; Rayport, Stephen; Cordon-Cardo, Carlos; DeBerardinis, Ralph J.; Ferrando, Adolfo A.

    2015-01-01

    Activating mutations in NOTCH1 are common in T-cell acute lymphoblastic leukemia (TALL). Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of clinical response to anti-NOTCH1 therapies. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, both inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapies. Moreover, we demonstrate that Pten loss induces increased glycolysis and consequently rescues leukemic cell metabolism abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL. PMID:26390244

  10. Impaired cellular energy metabolism contributes to bluetongue-virus-induced autophagy.

    PubMed

    Lv, Shuang; Xu, Qingyuan; Sun, Encheng; Zhang, Jikai; Wu, Donglai

    2016-10-01

    Bluetongue virus (BTV) has been found to trigger autophagy to favor its replication, but the underlying mechanisms have not been clarified. Here, we show that cellular energy metabolism is involved in BTV-induced autophagy. Cellular ATP synthesis was impaired by BTV1 infection, causing metabolic stress, which was responsible for activation of autophagy, since the conversion of LC3 and aggregation of GFP-LC3 (autophagy markers) were suppressed when infection-caused energy depletion was reversed via MP (metabolic substrate) treatment. The reduced virus yields with MP further supported this view. Overall, our findings suggest that BTV1-induced disruption of cellular energy metabolism contributes to autophagy, and this provides new insights into BTV-host interactions.

  11. Soluble Iron in Alveolar Macrophages Modulates Iron Oxide Particle-Induced Inflammatory Response via Prostaglandin E2 Synthesis

    EPA Science Inventory

    Ambient particulate matter (PM)-associated metals have been shown to play an important role in cardiopulmonary health outcomes. To study the modulation of inflammation by PM-associated soluble metal, we investigated intracellular solubility of radiolabelled iron oxide (59

  12. An integrated metabonomics and transcriptomics approach to understanding metabolic pathway disturbance induced by perfluorooctanoic acid.

    PubMed

    Peng, Siyuan; Yan, Lijuan; Zhang, Jie; Wang, Zhanlin; Tian, Meiping; Shen, Heqing

    2013-12-01

    Perfluorooctanoic acid (PFOA) is one of the most representative perfluorinated compounds and liver is the major organ where PFOA is accumulated. Although the multiple toxicities had been reported, its toxicological profile remained unclear. In this study, a systems toxicology strategy integrating liquid chromatography/mass spectrometry-based metabonomics and transcriptomics analyses was applied for the first time to investigate the effects of PFOA on a representative Chinese normal human liver cell line L-02, with focusing on the metabolic disturbance. Fifteen potential biomarkers were identified on metabolic level and most observations were consistent with the altered levels of gene expression. Our results showed that PFOA induced the perturbations in various metabolic processes in L-02 cells, especially lipid metabolism-related pathways. The up-stream mitochondrial carnitine metabolism was proved to be influenced by PFOA treatment. The specific transformation from carnitine to acylcarnitines, which showed a dose-dependent effect, and the expression level of key genes involved in this pathway were observed to be altered correspondingly. Furthermore, the down-stream cholesterol biosynthesis was directly confirmed to be up-regulated by both increased cholesterol content and elevated expression level of key genes. The PFOA-induced lipid metabolism-related effects in L-02 cells started from the fatty acid catabolism in cytosol, fluctuated to the processes in mitochondria, extended to the cholesterol biosynthesis. Many other metabolic pathways like amino acid metabolism and tricarboxylic acid cycle might also be disturbed. The findings obtained from the systems biological research provide more details about metabolic disorders induced by PFOA in human liver.

  13. RAYLEIGH-TAYLOR STRENGTH EXPERIMENTS OF THE PRESSURE-INDUCED alpha->epsilon->alpha' PHASE TRANSITION IN IRON

    SciTech Connect

    Belof, J L; Cavallo, R M; Olson, R T; King, R S; Gray, G T; Holtkamp, D B; Chen, S R; Rudd, R E; Barton, N R; Arsenlis, A; Remington, B A; Park, H; Prisbrey, S T; Vitello, P A; Bazan, G; Mikaelian, K O; Comley, A J; Maddox, B R; May, M J

    2011-08-10

    We present here the first dynamic Rayleigh-Taylor (RT) strength measurement of a material undergoing solid-solid phase transition. Iron is quasi-isentropically driven across the pressure-induced bcc ({alpha}-Fe) {yields} hcp ({var_epsilon}-Fe) phase transition and the dynamic strength of the {alpha}, {var_epsilon} and reverted {alpha}{prime} phases have been determined via proton radiography of the resulting Rayleigh-Taylor unstable interface between the iron target and high-explosive products. Simultaneous velocimetry measurements of the iron free surface yield the phase transition dynamics and, in conjunction with detailed hydrodynamic simulations, allow for determination of the strength of the distinct phases of iron. Forward analysis of the experiment via hydrodynamic simulations reveals significant strength enhancement of the dynamically-generated {var_epsilon}-Fe and reverted {alpha}{prime}-Fe, comparable in magnitude to the strength of austenitic stainless steels.

  14. MPK3/MPK6 are involved in iron deficiency-induced ethylene production in Arabidopsis

    PubMed Central

    Ye, Lingxiao; Li, Lin; Wang, Lu; Wang, Shoudong; Li, Sen; Du, Juan; Zhang, Shuqun; Shou, Huixia

    2015-01-01

    Iron (Fe) is an essential micronutrient that participates in various biological processes important for plant growth. Ethylene production induced by Fe deficiency plays important roles in plant tolerance to stress induced by Fe deficiency. However, the activation and regulatory mechanisms of 1-Aminocyclopropane-1-carboxylic acid synthase (ACS) genes in this response are not clear. In this study, we demonstrated that Fe deficiency increased the abundance of ACS2, ACS6, ACS7, and ACS11 transcripts in both leaves and roots as well as the abundance of ACS8 transcripts in leaves and ACS9 transcripts in roots. Furthermore, we investigated the role of mitogen-activated protein kinase 3 and 6 (MPK3/MPK6)-regulated ACS2/6 activation in Fe deficiency-induced ethylene production. Our results showed that MPK3/MPK6 transcript abundance and MPK3/MPK6 phosphorylation are elevated under conditions of Fe deficiency. Furthermore, mpk3 and mpk6 mutants show a lesser induction of ethylene production under Fe deficiency and a greater sensitivity to Fe deficiency. Finally, in mpk3, mpk6, and acs2 mutants under conditions of Fe deficiency, induction of transcript expression of the Fe-deficiency response genes FRO2, IRT1, and FIT is partially compromised. Taken together, our results suggest that the MPK3/MPK6 and ACS2 are part of the Fe starvation-induced ethylene production signaling pathway. PMID:26579185

  15. Effects of acute dietary iron overload in pigs (Sus scrofa) with induced type 2 diabetes mellitus.

    PubMed

    Espinoza, A; Morales, S; Arredondo, M

    2014-06-01

    Epidemiological studies have reported an association between high iron (Fe) levels and elevated risk of developing type 2 diabetes mellitus (T2D). It is believed that the formation of Fe-catalyzed hydroxyl radicals may contribute to the development of diabetes. Our goal was to determine the effect of a diet with a high Fe content on type 2 diabetic pigs. Four groups of piglets were studied: (1) control group, basal diet; (2) Fe group, basal diet with 3,000 ppm ferrous sulfate; (3) diabetic group (streptozotocin-induced type 2 diabetes) with basal diet; (4) diabetic/Fe group, diabetic animals/3,000 ppm ferrous sulfate. For 2 months, biochemical and hematological parameters were evaluated. Tissue samples of liver and duodenum were obtained to determine mRNA relative abundance of DMT1, ferroportin (Fpn), ferritin (Fn), hepcidin (Hpc), and transferrin receptor by qRT-PCR. Fe group presented increased levels of hematological (erythrocytes, hematocrit, and hemoglobin) and iron parameters. Diabetic/Fe group showed similar behavior as Fe group but in lesser extent. The relative abundance of different genes in the four study groups yielded a different expression pattern. DMT1 showed a lower expression in the two iron groups compared with control and diabetic animals, and Hpc showed an increased on its expression in Fe and diabetic/Fe groups. Diabetic/Fe group presents greater expression of Fn and Fpn. These results suggest that there is an interaction between Fe nutrition, inflammation, and oxidative stress in the diabetes development.

  16. Iron inhibits activation-induced cytidine deaminase enzymatic activity and modulates immunoglobulin class switch DNA recombination.

    PubMed

    Li, Guideng; Pone, Egest J; Tran, Daniel C; Patel, Pina J; Dao, Lisa; Xu, Zhenming; Casali, Paolo

    2012-06-15

    Immunoglobulin (Ig) class switch DNA recombination (CSR) and somatic hypermutation (SHM) are critical for the maturation of the antibody response. Activation-induced cytidine deaminase (AID) initiates CSR and SHM by deaminating deoxycytidines (dCs) in switch (S) and V(D)J region DNA, respectively, to generate deoxyuracils (dUs). Processing of dUs by uracil DNA glycosylase (UNG) yields abasic sites, which are excised by apurinic/apyrimidinic endonucleases, eventually generating double strand DNA breaks, the obligatory intermediates of CSR. Here, we found that the bivalent iron ion (Fe(2+), ferrous) suppressed CSR, leading to decreased number of switched B cells, decreased postrecombination Iμ-C(H) transcripts, and reduced titers of secreted class-switched IgG1, IgG3, and IgA antibodies, without alterations in critical CSR factors, such as AID, 14-3-3γ, or PTIP, or in general germline I(H)-S-C(H) transcription. Fe(2+) did not affect B cell proliferation or plasmacytoid differentiation. Rather, it inhibited AID-mediated dC deamination in a dose-dependent fashion. The inhibition of intrinsic AID enzymatic activity by Fe(2+) was specific, as shown by lack of inhibition of AID-mediated dC deamination by other bivalent metal ions, such as Zn(2+), Mn(2+), Mg(2+), or Ni(2+), and the inability of Fe(2+) to inhibit UNG-mediated dU excision. Overall, our findings have outlined a novel role of iron in modulating a B cell differentiation process that is critical to the generation of effective antibody responses to microbial pathogens and tumoral cells. They also suggest a possible role of iron in dampening AID-dependent autoimmunity and neoplastic transformation.

  17. Prenatal caffeine ingestion induces transgenerational neuroendocrine metabolic programming alteration in second generation rats

    SciTech Connect

    Luo, Hanwen; Deng, Zixin; Liu, Lian; Shen, Lang; Kou, Hao; He, Zheng; Ping, Jie; Xu, Dan; Ma, Lu; Chen, Liaobin; Wang, Hui

    2014-02-01

    Our previous studies have demonstrated that prenatal caffeine ingestion induces an increased susceptibility to metabolic syndrome with alterations of glucose and lipid metabolic phenotypes in adult first generation (F1) of intrauterine growth retardation (IUGR) rats, and the underlying mechanism is originated from a hypothalamic–pituitary–adrenal (HPA) axis-associated neuroendocrine metabolic programming alteration in utero. This study aims to investigate the transgenerational effects of this programming alteration in adult second generation (F2). Pregnant Wistar rats were administered with caffeine (120 mg/kg·d) from gestational day 11 until delivery. Four groups in F2 were set according to the cross-mating between control and caffeine-induced IUGR rats. F2 were subjected to a fortnight ice water swimming stimulus on postnatal month 4, and blood samples were collected before and after stress. Results showed that the majority of the activities of HPA axis and phenotypes of glucose and lipid metabolism were altered in F2. Particularly, comparing with the control group, caffeine groups had an enhanced corticosterone levels after chronic stress. Compared with before stress, the serum glucose levels were increased in some groups whereas the triglyceride levels were decreased. Furthermore, total cholesterol gain rates were enhanced but the high-density lipoprotein-cholesterol gain rates were decreased in most caffeine groups after stress. These transgenerational effects were characterized partially with gender and parental differences. Taken together, these results indicate that the reproductive and developmental toxicities and the neuroendocrine metabolic programming mechanism by prenatal caffeine ingestion have transgenerational effects in rats, which may help to explain the susceptibility to metabolic syndrome and associated diseases in F2. - Highlights: • Caffeine-induced neuroendocrine metabolic programming of HPA has hereditary effect. • Caffeine-induced

  18. Microbial metabolic networks in a complex electrogenic biofilm recovered from a stimulus-induced metatranscriptomics approach.

    PubMed

    Ishii, Shun'ichi; Suzuki, Shino; Tenney, Aaron; Norden-Krichmar, Trina M; Nealson, Kenneth H; Bretschger, Orianna

    2015-10-07

    Microorganisms almost always exist as mixed communities in nature. While the significance of microbial community activities is well appreciated, a thorough understanding about how microbial communities respond to environmental perturbations has not yet been achieved. Here we have used a combination of metagenomic, genome binning, and stimulus-induced metatranscriptomic approaches to estimate the metabolic network and stimuli-induced metabolic switches existing in a complex microbial biofilm that was producing electrical current via extracellular electron transfer (EET) to a solid electrode surface. Two stimuli were employed: to increase EET and to stop EET. An analysis of cell activity marker genes after stimuli exposure revealed that only two strains within eleven binned genomes had strong transcriptional responses to increased EET rates, with one responding positively and the other responding negatively. Potential metabolic switches between eleven dominant members were mainly observed for acetate, hydrogen, and ethanol metabolisms. These results have enabled the estimation of a multi-species metabolic network and the associated short-term responses to EET stimuli that induce changes to metabolic flow and cooperative or competitive microbial interactions. This systematic meta-omics approach represents a next step towards understanding complex microbial roles within a community and how community members respond to specific environmental stimuli.

  19. Microbial metabolic networks in a complex electrogenic biofilm recovered from a stimulus-induced metatranscriptomics approach

    PubMed Central

    Ishii, Shun’ichi; Suzuki, Shino; Tenney, Aaron; Norden-Krichmar, Trina M.; Nealson, Kenneth H.; Bretschger, Orianna

    2015-01-01

    Microorganisms almost always exist as mixed communities in nature. While the significance of microbial community activities is well appreciated, a thorough understanding about how microbial communities respond to environmental perturbations has not yet been achieved. Here we have used a combination of metagenomic, genome binning, and stimulus-induced metatranscriptomic approaches to estimate the metabolic network and stimuli-induced metabolic switches existing in a complex microbial biofilm that was producing electrical current via extracellular electron transfer (EET) to a solid electrode surface. Two stimuli were employed: to increase EET and to stop EET. An analysis of cell activity marker genes after stimuli exposure revealed that only two strains within eleven binned genomes had strong transcriptional responses to increased EET rates, with one responding positively and the other responding negatively. Potential metabolic switches between eleven dominant members were mainly observed for acetate, hydrogen, and ethanol metabolisms. These results have enabled the estimation of a multi-species metabolic network and the associated short-term responses to EET stimuli that induce changes to metabolic flow and cooperative or competitive microbial interactions. This systematic meta-omics approach represents a next step towards understanding complex microbial roles within a community and how community members respond to specific environmental stimuli. PMID:26443302

  20. The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress

    PubMed Central

    van der Harg, J M; Nölle, A; Zwart, R; Boerema, A S; van Haastert, E S; Strijkstra, A M; Hoozemans, J JM; Scheper, W

    2014-01-01

    The unfolded protein response (UPR) is activated in neurodegenerative tauopathies such as Alzheimer's disease (AD) in close connection with early stages of tau pathology. Metabolic disturbances are strongly associated with increased risk for AD and are a potent inducer of the UPR. Here, we demonstrate that metabolic stress induces the phosphorylation of endogenous tau via activation of the UPR. Strikingly, upon restoration of the metabolic homeostasis, not only the levels of the UPR markers pPERK, pIRE1α and BiP, but also tau phosphorylation are reversed both in cell models as well as in torpor, a physiological hypometabolic model in vivo. Intervention in the UPR using the global UPR inhibitor TUDCA or a specific small-molecule inhibitor of the PERK signaling pathway, inhibits the metabolic stress-induced phosphorylation of tau. These data support a role for UPR-mediated tau phosphorylation as part of an adaptive response to metabolic stress. Failure to restore the metabolic homeostasis will lead to prolonged UPR activation and tau phosphorylation, and may thus contribute to AD pathogenesis. We demonstrate that the UPR is functionally involved in the early stages of tau pathology. Our data indicate that targeting of the UPR may be employed for early intervention in tau-related neurodegenerative diseases. PMID:25165879

  1. Protective effect of curcumin in fructose-induced metabolic syndrome and in streptozotocin-induced diabetes in rats

    PubMed Central

    Bulboacă, Adriana; D Bolboacă, Sorana; Suci, Soimiţa

    2016-01-01

    Objective: The aim of this study was to investigate the effect of pre-treatment with curcumin on metabolic changes induced by two different pathophysiological mechanisms in rats (fructose diet and streptozotocin (STZ)-induced diabetes mellitus). Materials and Methods: Five groups with 10 rats per group were investigated: control group (healthy rats), fructose diet groups without any pre-treatment (FD), fructose diet groups with curcumin pre-treatment (FDC), STZ-induced diabetes mellitus without any pre-treatment (SID) and STZ-induced diabetes mellitus with curcumin pre-treatment (SIDC). Systolic blood pressure, and several metabolic and oxidative stress parameters were assessed. Results: Systolic blood pressure significantly increased in all groups compared with control group (P<0.001), with significantly lower values on groups with curcumin pre-treatment compared with the group without any pre-treatment and same inducement (FDS vs. FD P<0.0001, SIDC vs. SID P<0.0001). High-density lipoprotein (HDL)-cholesterol was significantly lower in all groups compared with control group (P<0.05) while triglycerides (P<0.05), aspartate aminotransferase (AST, P<0.0001) and alanine aminotransferase (ALT, P<0.0001) were significantly higher. Within the group with same induction, curcumin pre-treatment significantly improved metabolic (total cholesterol, glycaemia, triglycerides, AST, ALT; P<0.05) and oxidative stress parameters (total oxidative status (NOx), Thiol, and malondialdehyde (MDA), P<0.02) compared to untreated groups. Conclusion: The pre-treatment with curcumin in our experimental models significantly improved metabolic (total cholesterol, triglycerides, AST and ALT) as well as oxidative stress parameters (MDA, NOx, and Thiol) in both fructose diet and in STZ-induced diabetes in rats. These properties of curcumin may serve to improve the metabolic and oxidative stress conditions in patients with these pathological features. PMID:27482338

  2. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice.

    PubMed

    Guenancia, Charles; Li, Na; Hachet, Olivier; Rigal, Eve; Cottin, Yves; Dutartre, Patrick; Rochette, Luc; Vergely, Catherine

    2015-04-15

    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1000μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice.

  3. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice.

    PubMed

    Guenancia, Charles; Li, Na; Hachet, Olivier; Rigal, Eve; Cottin, Yves; Dutartre, Patrick; Rochette, Luc; Vergely, Catherine

    2015-04-15

    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1000μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice. PMID:25711856

  4. Pyroglutamic acid-induced metabolic acidosis: a case report.

    PubMed

    Luyasu, S; Wamelink, M M C; Galanti, L; Dive, A

    2014-06-01

    High anion gap metabolic acidosis due to pyroglutamic acid (5-oxoproline) is a rare complication of acetaminophen treatment (which depletes glutathione stores) and is often associated with clinically moderate to severe encephalopathy. Acquired 5-oxoprolinase deficiency (penicillins) or the presence of other risk factors of glutathione depletion such as malnutrition or sepsis seems to be necessary for symptoms development. We report the case of a 55-year-old women who developed a symptomatic overproduction of 5-oxoproline during flucloxacillin treatment for severe sepsis while receiving acetaminophen for fever control. Hemodialysis accelerated the clearance of the accumulated organic acid, and was followed by a sustained clinical improvement.

  5. Effect of cytochrome P450 inducers on the metabolism and toxicity of thiram in rats.

    PubMed

    Dalvi, Prasad S; Wilder-Ofie, Temeri; Mares, Bernadette; Lane, Candace; Dalvi, Ramesh R; Billups, Leonard H

    2002-12-01

    Thiram is a dithiocarbamate compound widely used as an agricultural fungicide. This study examined the effect of cytochrome P450 (CYP) inducers on the metabolism and toxicity of thiram in rats. Rats were pretreated with 3-methyl cholathrene (3-MC), phenobarbital (PB), isoniazid (INH), or pregnenolone-16a-carbonitrile (PCN) as selective inducers of CYP 1A1, 2B1, 2E1 and 3A2, respectively. Thiram was administered ip to induced rats at 0.1 or 0.5 mmol/kg, and the animals were sacrificed 3 or 24 h later to assess P450 interaction and liver damage, respectively. No significant inhibition of 3-me-induced CYP1A1 was observed with either thiram dose at 3 or 24 h after treatment; similar results were noted for rats induced with PB or PCN. By contrast, when INH was the selective inducer of CYP2E1, there was significant inhibition by thiram 3 h and 24 h after treatment, suggesting that thiram was metabolized by the induced CYP2E1; there was a significant increase in ALT activity reflective of liver damage in the rats treated with thiram. The results suggest that CYP2EI induced by INH may be significantly involved in the metabolism of thiram, and the associated liver damage.

  6. Blackcurrant Suppresses Metabolic Syndrome Induced by High-Fructose Diet in Rats

    PubMed Central

    Park, Ji Hun; Kho, Min Chul; Kim, Hye Yoom; Ahn, You Mee; Lee, Yun Jung; Kang, Dae Gill; Lee, Ho Sub

    2015-01-01

    Increased fructose ingestion has been linked to obesity, hyperglycemia, dyslipidemia, and hypertension associated with metabolic syndrome. Blackcurrant (Ribes nigrum; BC) is a horticultural crop in Europe. To induce metabolic syndrome, Sprague-Dawley rats were fed 60% high-fructose diet. Treatment with BC (100 or 300 mg/kg/day for 8 weeks) significantly suppressed increased liver weight, epididymal fat weight, C-reactive protein (CRP), total bilirubin, leptin, and insulin in rats with induced metabolic syndrome. BC markedly prevented increased adipocyte size and hepatic triglyceride accumulation in rats with induced metabolic syndrome. BC suppressed oral glucose tolerance and protein expression of insulin receptor substrate-1 (IRS-1) and phosphorylated AMP-activated protein kinase (p-AMPK) in muscle. BC significantly suppressed plasma total cholesterol, triglyceride, and LDL content. BC suppressed endothelial dysfunction by inducing downregulation of endothelin-1 and adhesion molecules in the aorta. Vascular relaxation of thoracic aortic rings by sodium nitroprusside and acetylcholine was improved by BC. The present study provides evidence of the potential protective effect of BC against metabolic syndrome by demonstrating improvements in dyslipidemia, hypertension, insulin resistance, and obesity in vivo. PMID:26504474

  7. The effect of the competitive season in professional basketball on inflammation and iron metabolism

    PubMed Central

    Dzedzej, A; Ignatiuk, W; Jaworska, J; Grzywacz, T; Lipińska, P; Antosiewicz, J; Korek, A

    2016-01-01

    Following acute physical activity, blood hepcidin concentration appears to increase in response to exercise-induced inflammation, but the long-term impact of exercise on hepcidin remains unclear. Here we investigated changes in hepcidin and the inflammation marker interleukin-6 to evaluate professional basketball players’ response to a season of training and games. The analysis also included vitamin D (25(OH)D3) assessment, owing to its anti-inflammatory effects. Blood samples were collected for 14 players and 10 control non-athletes prior to and after the 8-month competitive season. Athletes’ performance was assessed with the NBA efficiency score. At the baseline hepcidin correlated with blood ferritin (r = 0.61; 90% CL ±0.31), but at the end of the season this correlation was absent. Compared with the control subjects, athletes experienced clear large increases in hepcidin (50%; 90% CI 15-96%) and interleukin-6 (77%; 90% CI 35-131%) and a clear small decrease in vitamin D (-12%; 90% CI -20 to -3%) at the season completion. Correlations between change scores of these variables were unclear (r = -0.21 to 0.24, 90% CL ±0.5), but their uncertainty generally excluded strong relationships. Athletes were hence concluded to have experienced acute inflammation at the beginning but chronic inflammation at the end of the competitive season. At the same time, the moderate correlation between changes in vitamin D and players’ performance (r = 0.43) was suggestive of its beneficial influence. Maintaining the appropriative concentration of vitamin D is thus necessary for basketball players’ performance and efficiency. The assessment of hepcidin has proven to be useful in diagnosing inflammation in response to chronic exercise.

  8. The effect of the competitive season in professional basketball on inflammation and iron metabolism

    PubMed Central

    Dzedzej, A; Ignatiuk, W; Jaworska, J; Grzywacz, T; Lipińska, P; Antosiewicz, J; Korek, A

    2016-01-01

    Following acute physical activity, blood hepcidin concentration appears to increase in response to exercise-induced inflammation, but the long-term impact of exercise on hepcidin remains unclear. Here we investigated changes in hepcidin and the inflammation marker interleukin-6 to evaluate professional basketball players’ response to a season of training and games. The analysis also included vitamin D (25(OH)D3) assessment, owing to its anti-inflammatory effects. Blood samples were collected for 14 players and 10 control non-athletes prior to and after the 8-month competitive season. Athletes’ performance was assessed with the NBA efficiency score. At the baseline hepcidin correlated with blood ferritin (r = 0.61; 90% CL ±0.31), but at the end of the season this correlation was absent. Compared with the control subjects, athletes experienced clear large increases in hepcidin (50%; 90% CI 15-96%) and interleukin-6 (77%; 90% CI 35-131%) and a clear small decrease in vitamin D (-12%; 90% CI -20 to -3%) at the season completion. Correlations between change scores of these variables were unclear (r = -0.21 to 0.24, 90% CL ±0.5), but their uncertainty generally excluded strong relationships. Athletes were hence concluded to have experienced acute inflammation at the beginning but chronic inflammation at the end of the competitive season. At the same time, the moderate correlation between changes in vitamin D and players’ performance (r = 0.43) was suggestive of its beneficial influence. Maintaining the appropriative concentration of vitamin D is thus necessary for basketball players’ performance and efficiency. The assessment of hepcidin has proven to be useful in diagnosing inflammation in response to chronic exercise. PMID:27601776

  9. The effect of the competitive season in professional basketball on inflammation and iron metabolism.

    PubMed

    Dzedzej, A; Ignatiuk, W; Jaworska, J; Grzywacz, T; Lipińska, P; Antosiewicz, J; Korek, A; Ziemann, E

    2016-09-01

    Following acute physical activity, blood hepcidin concentration appears to increase in response to exercise-induced inflammation, but the long-term impact of exercise on hepcidin remains unclear. Here we investigated changes in hepcidin and the inflammation marker interleukin-6 to evaluate professional basketball players' response to a season of training and games. The analysis also included vitamin D (25(OH)D3) assessment, owing to its anti-inflammatory effects. Blood samples were collected for 14 players and 10 control non-athletes prior to and after the 8-month competitive season. Athletes' performance was assessed with the NBA efficiency score. At the baseline hepcidin correlated with blood ferritin (r = 0.61; 90% CL ±0.31), but at the end of the season this correlation was absent. Compared with the control subjects, athletes experienced clear large increases in hepcidin (50%; 90% CI 15-96%) and interleukin-6 (77%; 90% CI 35-131%) and a clear small decrease in vitamin D (-12%; 90% CI -20 to -3%) at the season completion. Correlations between change scores of these variables were unclear (r = -0.21 to 0.24, 90% CL ±0.5), but their uncertainty generally excluded strong relationships. Athletes were hence concluded to have experienced acute inflammation at the beginning but chronic inflammation at the end of the competitive season. At the same time, the moderate correlation between changes in vitamin D and players' performance (r = 0.43) was suggestive of its beneficial influence. Maintaining the appropriative concentration of vitamin D is thus necessary for basketball players' performance and efficiency. The assessment of hepcidin has proven to be useful in diagnosing inflammation in response to chronic exercise. PMID:27601776

  10. The effect of the competitive season in professional basketball on inflammation and iron metabolism.

    PubMed

    Dzedzej, A; Ignatiuk, W; Jaworska, J; Grzywacz, T; Lipińska, P; Antosiewicz, J; Korek, A; Ziemann, E

    2016-09-01

    Following acute physical activity, blood hepcidin concentration appears to increase in response to exercise-induced inflammation, but the long-term impact of exercise on hepcidin remains unclear. Here we investigated changes in hepcidin and the inflammation marker interleukin-6 to evaluate professional basketball players' response to a season of training and games. The analysis also included vitamin D (25(OH)D3) assessment, owing to its anti-inflammatory effects. Blood samples were collected for 14 players and 10 control non-athletes prior to and after the 8-month competitive season. Athletes' performance was assessed with the NBA efficiency score. At the baseline hepcidin correlated with blood ferritin (r = 0.61; 90% CL ±0.31), but at the end of the season this correlation was absent. Compared with the control subjects, athletes experienced clear large increases in hepcidin (50%; 90% CI 15-96%) and interleukin-6 (77%; 90% CI 35-131%) and a clear small decrease in vitamin D (-12%; 90% CI -20 to -3%) at the season completion. Correlations between change scores of these variables were unclear (r = -0.21 to 0.24, 90% CL ±0.5), but their uncertainty generally excluded strong relationships. Athletes were hence concluded to have experienced acute inflammation at the beginning but chronic inflammation at the end of the competitive season. At the same time, the moderate correlation between changes in vitamin D and players' performance (r = 0.43) was suggestive of its beneficial influence. Maintaining the appropriative concentration of vitamin D is thus necessary for basketball players' performance and efficiency. The assessment of hepcidin has proven to be useful in diagnosing inflammation in response to chronic exercise.

  11. A role for tetrahydrofolates in the metabolism of iron-sulfur clusters in all domains of life.

    PubMed

    Waller, Jeffrey C; Alvarez, Sophie; Naponelli, Valeria; Lara-Nuñez, Aurora; Blaby, Ian K; Da Silva, Vanessa; Ziemak, Michael J; Vickers, Tim J; Beverley, Stephen M; Edison, Arthur S; Rocca, James R; Gregory, Jesse F; de Crécy-Lagard, Valérie; Hanson, Andrew D

    2010-06-01

    Iron-sulfur (Fe/S) cluster enzymes are crucial to life. Their assembly requires a suite of proteins, some of which are specific for particular subsets of Fe/S enzymes. One such protein is yeast Iba57p, which aconitase and certain radical S-adenosylmethionine enzymes require for activity. Iba57p homologs occur in all domains of life; they belong to the COG0354 protein family and are structurally similar to various folate-dependent enzymes. We therefore investigated the possible relationship between folates and Fe/S cluster enzymes using the Escherichia coli Iba57p homolog, YgfZ. NMR analysis confirmed that purified YgfZ showed stereoselective folate binding. Inactivating ygfZ reduced the activities of the Fe/S tRNA modification enzyme MiaB and certain other Fe/S enzymes, although not aconitase. When successive steps in folate biosynthesis were ablated, folE (lacking pterins and folates) and folP (lacking folates) mutants mimicked the ygfZ mutant in having low MiaB activities, whereas folE thyA mutants supplemented with 5-formyltetrahydrofolate (lacking pterins and depleted in dihydrofolate) and gcvP glyA mutants (lacking one-carbon tetrahydrofolates) had intermediate MiaB activities. These data indicate that YgfZ requires a folate, most probably tetrahydrofolate. Importantly, the ygfZ mutant was hypersensitive to oxidative stress and grew poorly on minimal media. COG0354 genes of bacterial, archaeal, fungal, protistan, animal, or plant origin complemented one or both of these growth phenotypes as well as the MiaB activity phenotype. Comparative genomic analysis indicated widespread functional associations between COG0354 proteins and Fe/S cluster metabolism. Thus COG0354 proteins have an ancient, conserved, folate-dependent function in the activity of certain Fe/S cluster enzymes. PMID:20489182

  12. p73 regulates basal and starvation-induced liver metabolism in vivo.

    PubMed

    He, Zhaoyue; Agostini, Massimiliano; Liu, He; Melino, Gerry; Simon, Hans-Uwe

    2015-10-20

    As a member of the p53 gene family, p73 regulates cell cycle arrest, apoptosis, neurogenesis, immunity and inflammation. Recently, p73 has been shown to transcriptionally regulate selective metabolic enzymes, such as cytochrome c oxidase subunit IV isoform 1, glucose 6-phosphate dehydrogenase and glutaminase-2, resulting in significant effects on metabolism, including hepatocellular lipid metabolism, glutathione homeostasis and the pentose phosphate pathway. In order to further investigate the metabolic effect of p73, here, we compared the global metabolic profile of livers from p73 knockout and wild-type mice under both control and starvation conditions. Our results show that the depletion of all p73 isoforms cause altered lysine metabolism and glycolysis, distinct patterns for glutathione synthesis and Krebs cycle, as well as an elevated pentose phosphate pathway and abnormal lipid accumulation. These results indicate that p73 regulates basal and starvation-induced fuel metabolism in the liver, a finding that is likely to be highly relevant for metabolism-associated disorders, such as diabetes and cancer.

  13. Irisin, an exercise-induced myokine as a metabolic regulator: an updated narrative review.

    PubMed

    Chen, Ning; Li, Qingxue; Liu, Jun; Jia, Shaohui

    2016-01-01

    Irisin, as a new hormone-like myokine, is discovered in the presence of exercise-induced peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α). Which substance plays an important role in energy metabolism in each organ in the body and the regulation of metabolic diseases such as obesity and diabetes. The finding of irisin can contribute to the exploration of the novel and effective therapeutic targets or therapeutic strategies of these metabolic diseases or metabolism-associated health issues. To date, little is known regarding the functions and regulatory mechanisms of irisin with respect to metabolic diseases or metabolism-associated health issues. In this narrative review article, we systematically introduce its structural characteristics, production and distribution in tissues and organs, and the regulation and corresponding mechanisms for metabolic diseases or metabolism-associated health issues of irisin. Meanwhile, its future prospects and the development of irisin-related products for the promotion of human health have also been proposed, which will benefit future research and application of irisin. Copyright © 2015 John Wiley & Sons, Ltd.

  14. Ceramides mediate cigarette smoke-induced metabolic disruption in mice.

    PubMed

    Thatcher, Mikayla O; Tippetts, Trevor S; Nelson, Michael B; Swensen, Adam C; Winden, Duane R; Hansen, Melissa E; Anderson, Madeline C; Johnson, Ian E; Porter, James P; Reynolds, Paul R; Bikman, Benjamin T

    2014-11-15

    Cigarette smoke exposure increases lung ceramide biosynthesis and alters metabolic function. We hypothesized that ceramides are released from the lung during cigarette smoke exposure and result in elevated skeletal muscle ceramide levels, resulting in insulin resistance and altered mitochondrial respiration. Employing cell and animal models, we explored the effect of cigarette smoke on muscle cell insulin signaling and mitochondrial respiration. Muscle cells were treated with conditioned medium from cigarette smoke extract (CSE)-exposed lung cells, followed by analysis of ceramides and assessment of insulin signaling and mitochondrial function. Mice were exposed to daily cigarette smoke and a high-fat, high-sugar (HFHS) diet with myriocin injections to inhibit ceramide synthesis. Comparisons were conducted between these mice and control animals on standard diets in the absence of smoke exposure and myriocin injections. Muscle cells treated with CSE-exposed conditioned medium were completely unresponsive to insulin stimulation, and mitochondrial respiration was severely blunted. These effects were mitigated when lung cells were treated with the ceramide inhibitor myriocin prior to and during CSE exposure. In mice, daily cigarette smoke exposure and HFHS diet resulted in insulin resistance, which correlated with elevated ceramides. Although myriocin injection was protective against insulin resistance with either smoke or HFHS, it was insufficient to prevent insulin resistance with combined CS and HFHS. However, myriocin injection restored muscle mitochondrial respiration in all treatments. Ceramide inhibition prevents metabolic disruption in muscle cells with smoke exposure and may explain whole body insulin resistance and mitochondrial dysfunction in vivo.

  15. Genetic and biochemical effects induced by iron ore, Fe and Mn exposure in tadpoles of the bullfrog Lithobates catesbeianus.

    PubMed

    Veronez, Alexandra Caroline da Silva; Salla, Rômulo Victor; Baroni, Vinícius Dadalto; Barcarolli, Indianara Fernanda; Bianchini, Adalto; Dos Reis Martinez, Claudia Bueno; Chippari-Gomes, Adriana Regina

    2016-05-01

    For decades, the extraction of minerals has intensified in order to meet the demand of industry. Iron ore deposits are important sources of metals, such as iron (Fe) and manganese (Mn). The particulate ores can be dispersed during extraction, transport and storage, with potential to induce biological impacts. Amphibians are very sensitive to environmental stressors. Therefore, the present study aimed to assess the effects of iron ore, Fe and Mn exposure during the metamorphosis of Lithobates catesbeianus. Endpoints analyzed included morphological (biometrical and developmental analyses), whole body Fe and Mn concentration in, plasma ferritin concentration, erythrocyte DNA damage (measured through comet assay and micronucleus test) and liver activity of enzymes involved in oxidative status [glutathione S-transferase (GST) and catalase (CAT)]. Tadpoles were kept under control condition (no contaminant addition) or exposed to iron ore (3.79mg/L as fine particulate matter); Fe (nominal concentration: 0.51mg/L Fe as C10H12FeN2NaO8; Fe-EDTA); and Mn (nominal concentration: 5.23mg/L Mn as 4H2O.MnCl2) for 30 days. Virtually, no mortality was observed, except for one tadpole found dead in the iron ore treatment. However, tadpoles exposed to iron ore had longer tail than those kept under control conditions while tadpoles exposed to manganese chloride showed higher body length than control ones. Exposure to Fe and Mn induced a delay in tadpole metamorphosis, especially when these metals are presented not as a mixture (iron ore). Tadpoles exposed to iron ore had increased whole body Fe and Mn while those exposed to Fe and Mn accumulated each metal individually. Tadpoles exposed to any of the contaminants tested showed a significant increase in erythrocyte DNA damage and frequency of micronuclei. In addition, they showed higher liver GST activity respect with those kept under control conditions. Plasma ferritin concentration and liver CAT activity were higher only in tadpoles

  16. Genetic and biochemical effects induced by iron ore, Fe and Mn exposure in tadpoles of the bullfrog Lithobates catesbeianus.

    PubMed

    Veronez, Alexandra Caroline da Silva; Salla, Rômulo Victor; Baroni, Vinícius Dadalto; Barcarolli, Indianara Fernanda; Bianchini, Adalto; Dos Reis Martinez, Claudia Bueno; Chippari-Gomes, Adriana Regina

    2016-05-01

    For decades, the extraction of minerals has intensified in order to meet the demand of industry. Iron ore deposits are important sources of metals, such as iron (Fe) and manganese (Mn). The particulate ores can be dispersed during extraction, transport and storage, with potential to induce biological impacts. Amphibians are very sensitive to environmental stressors. Therefore, the present study aimed to assess the effects of iron ore, Fe and Mn exposure during the metamorphosis of Lithobates catesbeianus. Endpoints analyzed included morphological (biometrical and developmental analyses), whole body Fe and Mn concentration in, plasma ferritin concentration, erythrocyte DNA damage (measured through comet assay and micronucleus test) and liver activity of enzymes involved in oxidative status [glutathione S-transferase (GST) and catalase (CAT)]. Tadpoles were kept under control condition (no contaminant addition) or exposed to iron ore (3.79mg/L as fine particulate matter); Fe (nominal concentration: 0.51mg/L Fe as C10H12FeN2NaO8; Fe-EDTA); and Mn (nominal concentration: 5.23mg/L Mn as 4H2O.MnCl2) for 30 days. Virtually, no mortality was observed, except for one tadpole found dead in the iron ore treatment. However, tadpoles exposed to iron ore had longer tail than those kept under control conditions while tadpoles exposed to manganese chloride showed higher body length than control ones. Exposure to Fe and Mn induced a delay in tadpole metamorphosis, especially when these metals are presented not as a mixture (iron ore). Tadpoles exposed to iron ore had increased whole body Fe and Mn while those exposed to Fe and Mn accumulated each metal individually. Tadpoles exposed to any of the contaminants tested showed a significant increase in erythrocyte DNA damage and frequency of micronuclei. In addition, they showed higher liver GST activity respect with those kept under control conditions. Plasma ferritin concentration and liver CAT activity were higher only in tadpoles

  17. Iron-induced Local Complement Component 3 (C3) Up-regulation via Non-canonical Transforming Growth Factor (TGF)-β Signaling in the Retinal Pigment Epithelium*

    PubMed Central

    Li, Yafeng; Song, Delu; Song, Ying; Zhao, Liangliang; Wolkow, Natalie; Tobias, John W.; Song, Wenchao; Dunaief, Joshua L.

    2015-01-01

    Dysregulation of iron homeostasis may be a pathogenic factor in age-related macular degeneration (AMD). Meanwhile, the formation of complement-containing deposits under the retinal pigment epithelial (RPE) cell layer is a pathognomonic feature of AMD. In this study, we investigated the molecular mechanisms by which complement component 3 (C3), a central protein in the complement cascade, is up-regulated by iron in RPE cells. Modulation of TGF-β signaling, involving ERK1/2, SMAD3, and CCAAT/enhancer-binding protein-δ, is responsible for iron-induced C3 expression. The differential effects of spatially distinct SMAD3 phosphorylation sites at the linker region and at the C terminus determined the up-regulation of C3. Pharmacologic inhibition of either ERK1/2 or SMAD3 phosphorylation decreased iron-induced C3 expression levels. Knockdown of SMAD3 blocked the iron-induced up-regulation and nuclear accumulation of CCAAT/enhancer-binding protein-δ, a transcription factor that has been shown previously to bind the basic leucine zipper 1 domain in the C3 promoter. We show herein that mutation of this domain reduced iron-induced C3 promoter activity. In vivo studies support our in vitro finding of iron-induced C3 up-regulation. Mice with a mosaic pattern of RPE-specific iron overload demonstrated co-localization of iron-induced ferritin and C3d deposits. Humans with aceruloplasminemia causing RPE iron overload had increased RPE C3d deposition. The molecular events in the iron-C3 pathway represent therapeutic targets for AMD or other diseases exacerbated by iron-induced local complement dysregulation. PMID:25802332

  18. The role of iron in sulfide induced corrosion of sewer concrete.

    PubMed

    Jiang, Guangming; Wightman, Elaine; Donose, Bogdan C; Yuan, Zhiguo; Bond, Philip L; Keller, Jurg

    2014-02-01

    The sulfide-induced corrosion of concrete sewer is a widespread and expensive problem for water utilities worldwide. Fundamental knowledge of the initiation and propagation of sewer corrosion, especially the interactions between chemical reactions and physical structure changes, is still largely unknown. Advanced mineral analytical techniques were applied to identify the distribution of corrosion products and the micro-cracking that developed along the corrosion boundary. It was found that sewer concrete corrosion caused by reactions with sulfuric acid progressed uniformly in the cement of concrete. In contrast to conventional knowledge, iron rust rather than gypsum and ettringite was likely the factor responsible for cracking ahead of the corrosion front. The analysis also allowed quantitative determination of the major corrosion products, i.e., gypsum and ettringite, with the latter found closer to the corrosion front. The conceptual model based on these findings clearly demonstrated the complex interactions among different chemical reactions, diffusion, and micro-structure changes. PMID:24326021

  19. A shock-induced phase change in iron-silicate garnet.

    NASA Technical Reports Server (NTRS)

    Ahrens, T. J.; Graham, E. K.

    1972-01-01

    Hugoniot measurements on iron-silicate garnet demonstrate that above a shock pressure of about 205 kbar transition to a high-pressure phase(s), having an apparent zero-pressure density and bulk modulus of 4.44 g/cu cm and 3.3 Mbar, occurs. Crystal chemical systematics and Debye-Scherrer X-ray patterns of a recovered phase(s), which may be the shock-induced high-pressure form, suggest possible formation of a phase with a density of 4.48/cu cm. Occurrence of such a polymorph of garnet in the mantle would give rise to an increase in density and seismic velocity below 600 km in the earth.

  20. The role of iron in sulfide induced corrosion of sewer concrete.

    PubMed

    Jiang, Guangming; Wightman, Elaine; Donose, Bogdan C; Yuan, Zhiguo; Bond, Philip L; Keller, Jurg

    2014-02-01

    The sulfide-induced corrosion of concrete sewer is a widespread and expensive problem for water utilities worldwide. Fundamental knowledge of the initiation and propagation of sewer corrosion, especially the interactions between chemical reactions and physical structure changes, is still largely unknown. Advanced mineral analytical techniques were applied to identify the distribution of corrosion products and the micro-cracking that developed along the corrosion boundary. It was found that sewer concrete corrosion caused by reactions with sulfuric acid progressed uniformly in the cement of concrete. In contrast to conventional knowledge, iron rust rather than gypsum and ettringite was likely the factor responsible for cracking ahead of the corrosion front. The analysis also allowed quantitative determination of the major corrosion products, i.e., gypsum and ettringite, with the latter found closer to the corrosion front. The conceptual model based on these findings clearly demonstrated the complex interactions among different chemical reactions, diffusion, and micro-structure changes.

  1. Metabolism of benzene and phenol by a reconstituted purified phenobarbital induced rat liver mixed function oxidase system

    SciTech Connect

    Griffiths, J.C.

    1986-01-01

    Cytochrome P-450 and the electron-donor, NADPH-cytochrome c reductase were isolated from phenobarbital induced rat liver microsomes. Both benzene and its primary metabolite phenol, were substrates for the reconstituted purified phenobarbital induced rat liver mixed function oxidase system. Benzene was metabolized to phenol and the polyhydroxylated metabolites; catechol, hydroquinone and 1,2,4 benzenetriol. Benzene elicited a Type I spectral change upon its interaction with the cytochrome P-450 while phenol's interaction with the cytochrome P-450 produced a reverse Type I spectra. The formation of phenol showed a pH optimum of 7.0 compared with 6.6-6.8 for the production of the polyhyrdoxylated metabolites. Cytochrome P-450 inhibitors, such as metyrapone and SKF 525A, diminished the production of phenol from benzene but not the production of the polyhydroxylated metabolites from phenol. The radical trapping agents, DMSO, KTBA and mannitol, decreased the recovery of polyhydroxylated metabolites, from /sup 14/C-labeled benzene and/or phenol. As KTBA and DMSO interacted with OH. There was a concomitant release of ethylene and methane, which was measured. Desferrioxamine, an iron-chelator and catalase also depressed the recovery of polyhydroxylated metabolites. In summary, benzene and phenol were both substrates for this reconstituted purified enzyme system, but they differed in binding to cytochrome P-450, pH optima and mode of hydroxylation.

  2. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer

    PubMed Central

    Matassa, D S; Amoroso, M R; Lu, H; Avolio, R; Arzeni, D; Procaccini, C; Faicchia, D; Maddalena, F; Simeon, V; Agliarulo, I; Zanini, E; Mazzoccoli, C; Recchi, C; Stronach, E; Marone, G; Gabra, H; Matarese, G; Landriscina, M; Esposito, F

    2016-01-01

    Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC. PMID:27206315

  3. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer.

    PubMed

    Matassa, D S; Amoroso, M R; Lu, H; Avolio, R; Arzeni, D; Procaccini, C; Faicchia, D; Maddalena, F; Simeon, V; Agliarulo, I; Zanini, E; Mazzoccoli, C; Recchi, C; Stronach, E; Marone, G; Gabra, H; Matarese, G; Landriscina, M; Esposito, F

    2016-09-01

    Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC. PMID:27206315

  4. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer.

    PubMed

    Matassa, D S; Amoroso, M R; Lu, H; Avolio, R; Arzeni, D; Procaccini, C; Faicchia, D; Maddalena, F; Simeon, V; Agliarulo, I; Zanini, E; Mazzoccoli, C; Recchi, C; Stronach, E; Marone, G; Gabra, H; Matarese, G; Landriscina, M; Esposito, F

    2016-09-01

    Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC.

  5. Metabolic profiling reveals potential metabolic markers associated with Hypoxia Inducible Factor-mediated signalling in hypoxic cancer cells

    PubMed Central

    Armitage, Emily G.; Kotze, Helen L.; Allwood, J. William; Dunn, Warwick B.; Goodacre, Royston; Williams, Kaye J.

    2015-01-01

    Hypoxia inducible factors (HIFs) plays an important role in oxygen compromised environments and therefore in tumour survival. In this research, metabolomics has been applied to study HIFs metabolic function in two cell models: mouse hepatocellular carcinoma and human colon carcinoma, whereby the metabolism has been profiled for a range of oxygen potentials. Wild type cells have been compared to cells deficient in HIF signalling to reveal its effect on cellular metabolism under normal oxygen conditions as well as low oxygen, hypoxic and anoxic environments. Characteristic responses to hypoxia that were conserved across both cell models involved the anti-correlation between 2-hydroxyglutarate, 2-oxoglutarate, fructose, hexadecanoic acid, hypotaurine, pyruvate and octadecenoic acid with 4-hydroxyproline, aspartate, cysteine, glutamine, lysine, malate and pyroglutamate. Further to this, network-based correlation analysis revealed HIF specific pathway responses to each oxygen condition that were also conserved between cell models. From this, 4-hydroxyproline was revealed as a regulating hub in low oxygen survival of WT cells while fructose appeared to be in HIF deficient cells. Pathways surrounding these hubs were built from the direct connections of correlated metabolites that look beyond traditional pathways in order to understand the mechanism of HIF response to low oxygen environments. PMID:26508589

  6. Iron accelerates while magnesium inhibits nickel-induced carcinogenesis in the rat kidney.

    PubMed

    Kasprzak, K S; Diwan, B A; Rice, J M

    1994-05-31

    Effects of magnesium basic carbonate (MgCarb) and metallic iron powder (Fe0) on nickel subsulfide (Ni3S2)-induced carcinogenesis were studied in kidneys of male F344/NCr rats. The rats, 20-40/group, received injections of Ni3S2 alone (62 mumol Ni) or with equimolar doses of MgCarb or Fe0 into the renal cortex of each pole of the right kidney. Control rats were given MgCarb, Fe0, or 0.1 ml of 50% aqueous glycerol, the injection vehicle. Final incidence of renal tumors 2 years after the injection of Ni3S2 alone or mixed with Fe0 was 60%. However, rats given Ni3S2 + Fe0 developed renal tumors much more rapidly. In contrast, the incidence of renal tumors in rats given Ni3S2 + MgCarb was only 20% (P < 0.01 vs. Ni3S2 alone). No kidney tumors were observed in the control rats. Between weeks 4 and 32 post injection, Ni3S2 alone caused erythrocytosis. This effect was attenuated by Fe0, but not by MgCarb. Hence, there is no firm correlation between carcinogenic activity of nickel and its ability to induce erythropoiesis. All kidney tumors were of mesenchymal cell origin and resembled the sarcomatous variant of the classic rat renal mesenchymal tumor. Some of them metastasized to the lungs and other organs. In 3-35 days post-injection, kidneys of rats treated with Ni3S2 alone showed moderate to extensive necrosis, inflammation, fibrosis, and degenerative and regenerative proliferative changes in the proximal tubular epithelium at the injection site. Similar, but more severe and multifocal changes were observed in the kidneys of Ni3S2 + Fe0-treated rats. The necrosis was less severe in kidneys injected with Ni3S2 + MgCarb, but fibrosis and degenerative and regenerative changes in proximal tubular epithelium were similar to those observed in other treatment groups. Ni3S2 deposits were seen inside macrophages and proximal tubular epithelial cells of Ni3S2 and Ni3S2+ Fe0-treated kidneys more frequently than in Ni3S2 + MgCarb-treated kidneys. Thus, magnesium antagonizes nickel

  7. Coordinated induction of Nrf2 target genes protects against iron nitrilotriacetate (FeNTA)-induced nephrotoxicity

    SciTech Connect

    Tanaka, Yuji; Aleksunes, Lauren M. |; Goedken, Michael J.; Chen, Chuan; Reisman, Scott A.; Manautou, Jose E.; Klaassen, Curtis D.

    2008-09-15

    The iron chelate, ferric nitrilotriacetate (FeNTA), induces acute proximal tubular necrosis as a consequence of lipid peroxidation and oxidative tissue damage. Chronic exposure of FeNTA leads to a high incidence of renal adenocarcinomas in rodents. NF-E2-related factor 2 (Nrf2) is a transcription factor that is activated by oxidative stress and electrophiles, and regulates the basal and inducible expression of numerous detoxifying and antioxidant genes. To determine the roles of Nrf2 in regulating renal gene expression and protecting against oxidative stress-induced kidney damage, wild-type and Nrf2-null mice were administered FeNTA. Renal Nrf2 protein translocated to the nucleus at 6h after FeNTA treatment. FeNTA increased mRNA levels of Nrf2 target genes, including NQO1, GCLC, GSTpi1/2, Mrp1, 2, and 4 in kidneys from wild-type mice, but not Nrf2-null mice. Protein expression of NQO1, a prototypical Nrf2 target gene, was increased in wild-type mice, with no change in Nrf2-null mice. FeNTA produced more nephrotoxicity in Nrf2-null mice than wild-type mice as indicated by higher serum urea nitrogen and creatinine levels, as more urinary NAG, stronger 4-hydroxynonenal protein adduct staining, and more extensive proximal tubule damage. Furthermore, pretreatment with CDDO-Im, a potent small molecule Nrf2 activator, protected mice against FeNTA-induced renal toxicity. Collectively, these results suggest that activation of Nrf2 protects mouse kidneys from FeNTA-induced oxidative stress damage by coordinately up-regulating the expression of cytoprotective genes.

  8. The Loss of Myocardial Benefit following Ischemic Preconditioning Is Associated with Dysregulation of Iron Homeostasis in Diet-Induced Diabetes

    PubMed Central

    Berenshtein, Eduard; Eliashar, Ron; Chevion, Mordechai

    2016-01-01

    Whether the diabetic heart benefits from ischemic preconditioning (IPC), similar to the non-diabetic heart, is a subject of controversy. We recently proposed new roles for iron and ferritin in IPC-protection in Type 1-like streptozotocin-induced diabetic rat heart. Here, we investigated iron homeostasis in Cohen diabetic sensitive rat (CDs) that develop hyperglycemia when fed on a high-sucrose/low-copper diet (HSD), but maintain normoglycemia on regular-diet (RD). Control Cohen-resistant rats (CDr) maintain normoglycemia on either diet. The IPC procedure improved the post-ischemic recovery of normoglycemic hearts (CDr-RD, CDr-HSD and CDs-RD). CDs-HSD hearts failed to show IPC-associated protection. The recovery of these CDs-HSD hearts following I/R (without prior IPC) was better than their RD controls. During IPC ferritin levels increased in normoglycemic hearts, and its level was maintained nearly constant during the subsequent prolonged ischemia, but decayed to its baseline level during the reperfusion phase. In CDs-HSD hearts the baseline levels of ferritin and ferritin-saturation with iron were notably higher than in the controls, and remained unchanged during the entire experiment. This unique and abnormal pattern of post-ischemic recovery of CDs-HSD hearts is associated with marked changes in myocardial iron homeostasis, and suggests that iron and iron-proteins play a causative role/s in the etiology of diabetes-associated cardiovascular disorders. PMID:27458721

  9. Adherent-Invasive Escherichia coli Production of Cellulose Influences Iron-Induced Bacterial Aggregation, Phagocytosis, and Induction of Colitis.

    PubMed

    Ellermann, Melissa; Huh, Eun Young; Liu, Bo; Carroll, Ian M; Tamayo, Rita; Sartor, R Balfour

    2015-10-01

    Adherent-invasive Escherichia coli (AIEC), a functionally distinct subset of resident intestinal E. coli associated with Crohn's disease, is characterized by enhanced epithelial adhesion and invasion, survival within macrophages, and biofilm formation. Environmental factors, such as iron, modulate E. coli production of extracellular structures, which in turn influence the formation of multicellular communities, such as biofilms, and bacterial interactions with host cells. However, the physiological and functional responses of AIEC to variable iron availability have not been thoroughly investigated. We therefore characterized the impact of iron on the physiology of AIEC strain NC101 and subsequent interactions with macrophages. Iron promoted the cellulose-dependent aggregation of NC101. Bacterial cells recovered from the aggregates were more susceptible to phagocytosis than planktonic cells, which corresponded with the decreased macrophage production of the proinflammatory cytokine interleukin-12 (IL-12) p40. Prevention of aggregate formation through the disruption of cellulose production reduced the phagocytosis of iron-exposed NC101. In contrast, under iron-limiting conditions, where NC101 aggregation is not induced, the disruption of cellulose production enhanced NC101 phagocytosis and decreased macrophage secretion of IL-12 p40. Finally, abrogation of cellulose production reduced NC101 induction of colitis when NC101 was monoassociated in inflammation-prone Il10(-/-) mice. Taken together, our results introduce cellulose as a novel physiological factor that impacts host-microbe-environment interactions and alters the proinflammatory potential of AIEC.

  10. The Loss of Myocardial Benefit following Ischemic Preconditioning Is Associated with Dysregulation of Iron Homeostasis in Diet-Induced Diabetes.

    PubMed

    Vinokur, Vladimir; Weksler-Zangen, Sarah; Berenshtein, Eduard; Eliashar, Ron; Chevion, Mordechai

    2016-01-01

    Whether the diabetic heart benefits from ischemic preconditioning (IPC), similar to the non-diabetic heart, is a subject of controversy. We recently proposed new roles for iron and ferritin in IPC-protection in Type 1-like streptozotocin-induced diabetic rat heart. Here, we investigated iron homeostasis in Cohen diabetic sensitive rat (CDs) that develop hyperglycemia when fed on a high-sucrose/low-copper diet (HSD), but maintain normoglycemia on regular-diet (RD). Control Cohen-resistant rats (CDr) maintain normoglycemia on either diet. The IPC procedure improved the post-ischemic recovery of normoglycemic hearts (CDr-RD, CDr-HSD and CDs-RD). CDs-HSD hearts failed to show IPC-associated protection. The recovery of these CDs-HSD hearts following I/R (without prior IPC) was better than their RD controls. During IPC ferritin levels increased in normoglycemic hearts, and its level was maintained nearly constant during the subsequent prolonged ischemia, but decayed to its baseline level during the reperfusion phase. In CDs-HSD hearts the baseline levels of ferritin and ferritin-saturation with iron were notably higher than in the controls, and remained unchanged during the entire experiment. This unique and abnormal pattern of post-ischemic recovery of CDs-HSD hearts is associated with marked changes in myocardial iron homeostasis, and suggests that iron and iron-proteins play a causative role/s in the etiology of diabetes-associated cardiovascular disorders. PMID:27458721

  11. Lactose-Inducible System for Metabolic Engineering of Clostridium ljungdahlii

    SciTech Connect

    Banerjee, A; Leang, C; Ueki, T; Nevin, KP; Lovley, DR

    2014-03-25

    The development of tools for genetic manipulation of Clostridium ljungdahlii has increased its attractiveness as a chassis for autotrophic production of organic commodities and biofuels from syngas and microbial electrosynthesis and established it as a model organism for the study of the basic physiology of acetogenesis. In an attempt to expand the genetic toolbox for C. ljungdahlii, the possibility of adapting a lactose-inducible system for gene expression, previously reported for Clostridium perfringens, was investigated. The plasmid pAH2, originally developed for C. perfringens with a gusA reporter gene, functioned as an effective lactose-inducible system in C. ljungdahlii. Lactose induction of C. ljungdahlii containing pB1, in which the gene for the aldehyde/alcohol dehydrogenase AdhE1 was downstream of the lactose-inducible promoter, increased expression of adhE1 30-fold over the wild-type level, increasing ethanol production 1.5-fold, with a corresponding decrease in acetate production. Lactose-inducible expression of adhE1 in a strain in which adhE1 and the adhE1 homolog adhE2 had been deleted from the chromosome restored ethanol production to levels comparable to those in the wild-type strain. Inducing expression of adhE2 similarly failed to restore ethanol production, suggesting that adhE1 is the homolog responsible for ethanol production. Lactose-inducible expression of the four heterologous genes necessary to convert acetyl coenzyme A (acetyl-CoA) to acetone diverted ca. 60% of carbon flow to acetone production during growth on fructose, and 25% of carbon flow went to acetone when carbon monoxide was the electron donor. These studies demonstrate that the lactose-inducible system described here will be useful for redirecting carbon and electron flow for the biosynthesis of products more valuable than acetate. Furthermore, this tool should aid in optimizing microbial electrosynthesis and for basic studies on the physiology of acetogenesis.

  12. Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats.

    PubMed

    Panchal, Sunil K; Poudyal, Hemant; Brown, Lindsay

    2012-06-01

    Metabolic syndrome is a risk factor for cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). We investigated the responses to the flavonol, quercetin, in male Wistar rats (8-9 wk old) divided into 4 groups. Two groups were given either a corn starch-rich (C) or high-carbohydrate, high-fat (H) diet for 16 wk; the remaining 2 groups were given either a C or H diet for 8 wk followed by supplementation with 0.8 g/kg quercetin in the food for the following 8 wk (CQ and HQ, respectively). The H diet contained ~68% carbohydrates, mainly as fructose and sucrose, and ~24% fat from beef tallow; the C diet contained ~68% carbohydrates as polysaccharides and ~0.7% fat. Compared with the C rats, the H rats had greater body weight and abdominal obesity, dyslipidemia, higher systolic blood pressure, impaired glucose tolerance, cardiovascular remodeling, and NAFLD. The H rats had lower protein expressions of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and carnitine palmitoyltransferase 1 (CPT1) with greater expression of NF-κB in both the heart and the liver and less expression of caspase-3 in the liver than in C rats. HQ rats had higher expression of Nrf2, HO-1, and CPT1 and lower expression of NF-κB than H rats in both the heart and the liver. HQ rats had less abdominal fat and lower systolic blood pressure along with attenuation of changes in structure and function of the heart and the liver compared with H rats, although body weight and dyslipidemia did not differ between the H and HQ rats. Thus, quercetin treatment attenuated most of the symptoms of metabolic syndrome, including abdominal obesity, cardiovascular remodeling, and NAFLD, with the most likely mechanisms being decreases in oxidative stress and inflammation.

  13. High-Throughput and Combinatorial Gene Expression on a Chip for Metabolism-Induced Toxicology Screening

    PubMed Central

    Kwon, Seok Joon; Lee, Dong Woo; Shah, Dhiral A.; Ku, Bosung; Jeon, Sang Youl; Solanki, Kusum; Ryan, Jessica D.; Clark, Douglas S.; Dordick, Jonathan S.; Lee, Moo-Yeal

    2014-01-01

    Differential expression of various drug-metabolizing enzymes in the human liver may cause deviations of pharmacokinetic profiles, resulting in inter-individual variability of drug toxicity and/or efficacy. Here we present the “Transfected Enzyme and Metabolism Chip” (TeamChip), which predicts potential metabolism-induced drug or drug-candidate toxicity. The TeamChip is prepared by delivering genes into miniaturized three-dimensional cellular microarrays on a micropillar chip using recombinant adenoviruses in a complementary microwell chip. The device enables users to manipulate the expression of individual and multiple human metabolizing-enzyme genes (such as CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2E1, and UGT1A4) in THLE-2 cell microarrays. To identify specific enzymes involved in drug detoxification, we created 84 combinations of metabolic-gene expressions in a combinatorial fashion on a single microarray. Thus, the TeamChip platform can provide critical information necessary for evaluating metabolism-induced toxicity in a high-throughput manner. PMID:24799042

  14. Maternal taurine supplementation attenuates maternal fructose-induced metabolic and inflammatory dysregulation and partially reverses adverse metabolic programming in offspring.

    PubMed

    Li, M; Reynolds, C M; Sloboda, D M; Gray, C; Vickers, M H

    2015-03-01

    Excessive fructose consumption is associated with insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD), and high fructose intake during pregnancy can lead to compromised fetal development in the rat. Evidence suggests that the amino acid taurine can ameliorate fructose-induced IR and NAFLD in nonpregnant animals. This study investigated the efficacy of taurine supplementation on maternal fructose-induced metabolic dysfunction and neonatal health. Time-mated Wistar rats were randomized to four groups during pregnancy and lactation: (a) control diet (CON), (b) CON supplemented with 1.5% taurine in drinking water (CT), (c) CON supplemented with fructose solution (F) and (d) F supplemented with taurine (FT). Maternal and neonatal weights, plasma cytokines and hepatic gene expression were analyzed. Maternal hyperinsulinemia, increased homeostasis model assessment of IR indices and elevated proinflammatory cytokines were observed in F group and normalized in FT group. Maternal fructose-induced hepatic steatosis accompanied with increased liver weight was ameliorated with taurine supplementation. Maternal hepatic sterol regulatory element-binding protein-1c and fatty acid synthase expression was significantly increased in the F group compared to the CON, CT and FT groups. Neonatal hepatic phosphoenolpyruvate carboxykinase expression was increased in male F neonates compared to the CON, CT and FT groups and was increased in female F and FT neonates compared to CON and CT. Interleukin-1β expression was decreased in male CT and FT neonates compared to other male groups. Hepatic tumour necrosis factor receptor-1 was lower in the male FT group than the F group. These results demonstrate that maternal taurine supplementation can partially reverse fructose-induced maternal metabolic dysfunction and may ameliorate adverse developmental programming effects in offspring in a sex-specific manner.

  15. Regional brain glucose metabolism and blood flow in streptozocin-induced diabetic rats

    SciTech Connect

    Jakobsen, J.; Nedergaard, M.; Aarslew-Jensen, M.; Diemer, N.H. )

    1990-04-01

    Brain regional glucose metabolism and regional blood flow were measured from autoradiographs by the uptake of ({sup 3}H)-2-deoxy-D-glucose and ({sup 14}C)iodoantipyrine in streptozocin-induced diabetic (STZ-D) rats. After 2 days of diabetes, glucose metabolism in the neocortex, basal ganglia, and white matter increased by 34, 37, and 8%, respectively, whereas blood flow was unchanged. After 4 mo, glucose metabolism in the same three regions was decreased by 32, 43, and 60%. This reduction was paralleled by a statistically nonsignificant reduction in blood flow in neocortex and basal ganglia. It is suggested that the decrease of brain glucose metabolism in STZ-D reflects increased ketone body oxidation and reduction of electrochemical work.

  16. Microbially Induced Reductive Dissolution of Trace Element-Rich Lacustrine Iron-Oxides

    NASA Astrophysics Data System (ADS)

    Crowe, S. A.; Kulczykci, E.; O'Neill, A. H.; Roberts, J. A.; Fowle, D. A.

    2004-12-01

    Iron (oxy)hydroxides are ubiquitous components of surfacial materials and are often the dominant redox buffering solid phases in soils and sediments. As a result, the geochemical behavior of these minerals has a profound influence on the global biogeochemical cycling of trace elements, including heavy metals and arsenic (As), in addition to nutrients such as, sulfur (S), carbon (C), nitrogen (N), and phosphorus (P). Understanding the behavior of trace elements and nutrients during biological and abiotic processes that effect iron (Fe) mineral phase transformations is paramount for predicting their distribution, mobility, and bioavailability in the environment. To evaluate the impact of dissimilatory Fe-reduction (DIR) on trace element mobility we have conducted batch incubations of Fe-rich lateritic lacustrine sediments. In contrast to mid-latitude lakes where Fe (oxy)hydroxides constitute only a small fraction of the total sediment, tropical lake sediments have been known to comprise up to 40-60 wt. % Fe-oxides. Under suboxic and nonsulphidogenic conditions it is likely that DIR plays a prominent role in early diagenesis and therefore may exert control on the fate and distribution of many trace elements in this environment (e.g. Crowe et al. 2004). In batch incubations conducted in a minimal media of similar composition to typical freshwater the lacustrine Fe-oxides were reductively dissolved at a rate very similar to pure synthetic goethite of similar surface area (measured by N2-BET). This is in contrast to the slower rates previously observed for trace element substituted Fe-oxides. These slower rates have been attributed to surface passivation by secondary Al and Cr mineral precipitation. We propose that these passivation effects may be offset in minimal media incubations by enhanced microbial metabolism due the presence of nutrients (P, Co and other metals) in the lacustrine Fe-oxides. These nutrients became available with progressive reduction as the

  17. Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death.

    PubMed

    Parra, Valentina; Moraga, Francisco; Kuzmicic, Jovan; López-Crisosto, Camila; Troncoso, Rodrigo; Torrealba, Natalia; Criollo, Alfredo; Díaz-Elizondo, Jessica; Rothermel, Beverly A; Quest, Andrew F G; Lavandero, Sergio

    2013-08-01

    Ceramides are important intermediates in the biosynthesis and degradation of sphingolipids that regulate numerous cellular processes, including cell cycle progression, cell growth, differentiation and death. In cardiomyocytes, ceramides induce apoptosis by decreasing mitochondrial membrane potential and promoting cytochrome-c release. Ca(2+) overload is a common feature of all types of cell death. The aim of this study was to determine the effect of ceramides on cytoplasmic Ca(2+) levels, mitochondrial function and cardiomyocyte death. Our data show that C2-ceramide induces apoptosis and necrosis in cultured cardiomyocytes by a mechanism involving increased Ca(2+) influx, mitochondrial network fragmentation and loss of the mitochondrial Ca(2+) buffer capacity. These biochemical events increase cytosolic Ca(2+) levels and trigger cardiomyocyte death via the activation of calpains.

  18. Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death

    PubMed Central

    Parra, Valentina; Moraga, Francisco; Kuzmicic, Jovan; López-Crisosto, Camila; Troncoso, Rodrigo; Torrealba, Natalia; Criollo, Alfredo; Díaz-Elizondo, Jessica; Rothermel, Beverly A.; Quest, Andrew F.G.; Lavandero, Sergio

    2014-01-01

    Ceramides are important intermediates in the biosynthesis and degradation of sphingolipids that regulatenumerous cellular processes, including cell cycle progression, cell growth, differentiation and death. In cardiomyocytes, ceramides induce apoptosis by decreasing mitochondrial membrane potential and promoting cytochrome-c release. Ca2+ overload is a common feature of all types of cell death. The aim of this study was to determine the effect of ceramides on cytoplasmic Ca2+ levels, mitochondrial function and cardiomyocyte death. Our data show that C2-ceramide induces apoptosis and necrosis in cultured cardiomyocytes by a mechanism involving increased Ca2+ influx, mitochondrial network fragmentation and loss of the mitochondrial Ca2+ buffer capacity. These biochemical events increase cytosolic Ca2+ levels and trigger cardiomyocyte death via the activation of calpains. PMID:23602992

  19. Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death.

    PubMed

    Parra, Valentina; Moraga, Francisco; Kuzmicic, Jovan; López-Crisosto, Camila; Troncoso, Rodrigo; Torrealba, Natalia; Criollo, Alfredo; Díaz-Elizondo, Jessica; Rothermel, Beverly A; Quest, Andrew F G; Lavandero, Sergio

    2013-08-01

    Ceramides are important intermediates in the biosynthesis and degradation of sphingolipids that regulate numerous cellular processes, including cell cycle progression, cell growth, differentiation and death. In cardiomyocytes, ceramides induce apoptosis by decreasing mitochondrial membrane potential and promoting cytochrome-c release. Ca(2+) overload is a common feature of all types of cell death. The aim of this study was to determine the effect of ceramides on cytoplasmic Ca(2+) levels, mitochondrial function and cardiomyocyte death. Our data show that C2-ceramide induces apoptosis and necrosis in cultured cardiomyocytes by a mechanism involving increased Ca(2+) influx, mitochondrial network fragmentation and loss of the mitochondrial Ca(2+) buffer capacity. These biochemical events increase cytosolic Ca(2+) levels and trigger cardiomyocyte death via the activation of calpains. PMID:23602992

  20. Assessment of salinity-induced photorespiratory glycolate metabolism in Anabaena sp. PCC 7120.

    PubMed

    Srivastava, Ashish Kumar; Alexova, Ralitza; Jeon, Young Jae; Kohli, Gurjeet S; Neilan, Brett A

    2011-03-01

    This paper reports an investigation of salinity-induced glycolate metabolism in the cyanobacterium Anabaena sp. PCC 7120 (hereafter Anabaena PCC 7120). Quantitative analysis of transcripts for the photosynthesis-associated genes encoding ribulose-1,5-bisphosphate carboxylase oxygenase (Rubisco), phosphoribulokinase and transketolase, as well as those involved in glycolate metabolism (phosphoglycolate phosphatase, glycolate oxidase, alanine-glyoxylate aminotransferase and serine hydroxymethyltransferase) was performed. The expression of all investigated photosynthesis-associated genes except Rubisco was downregulated after 24 h NaCl treatment. However, under the same conditions, the transcripts encoding enzymes involved in glycolate metabolism were overexpressed. This was further confirmed by the quantitative analysis of the intermediates involved in glycolate metabolism. The intracellular levels of organic acids (glyceric, glycolic and glyoxylic acids) and amino acids (glycine and serine) were elevated in salt-treated cells as compared to those in the control cells. Transcriptional inhibition of photosynthesis-associated genes, and upregulation of genes and enhanced synthesis of intermediates associated with glycolate metabolism, indicate the occurrence of this photorespiratory metabolic pathway metabolism in Anabaena PCC 7120 under salt stress. PMID:21163840

  1. Assessment of salinity-induced photorespiratory glycolate metabolism in Anabaena sp. PCC 7120.

    PubMed

    Srivastava, Ashish Kumar; Alexova, Ralitza; Jeon, Young Jae; Kohli, Gurjeet S; Neilan, Brett A

    2011-03-01

    This paper reports an investigation of salinity-induced glycolate metabolism in the cyanobacterium Anabaena sp. PCC 7120 (hereafter Anabaena PCC 7120). Quantitative analysis of transcripts for the photosynthesis-associated genes encoding ribulose-1,5-bisphosphate carboxylase oxygenase (Rubisco), phosphoribulokinase and transketolase, as well as those involved in glycolate metabolism (phosphoglycolate phosphatase, glycolate oxidase, alanine-glyoxylate aminotransferase and serine hydroxymethyltransferase) was performed. The expression of all investigated photosynthesis-associated genes except Rubisco was downregulated after 24 h NaCl treatment. However, under the same conditions, the transcripts encoding enzymes involved in glycolate metabolism were overexpressed. This was further confirmed by the quantitative analysis of the intermediates involved in glycolate metabolism. The intracellular levels of organic acids (glyceric, glycolic and glyoxylic acids) and amino acids (glycine and serine) were elevated in salt-treated cells as compared to those in the control cells. Transcriptional inhibition of photosynthesis-associated genes, and upregulation of genes and enhanced synthesis of intermediates associated with glycolate metabolism, indicate the occurrence of this photorespiratory metabolic pathway metabolism in Anabaena PCC 7120 under salt stress.

  2. Rhizobacterial volatiles and photosynthesis-related signals coordinate MYB72 expression in Arabidopsis roots during onset of induced systemic resistance and iron-deficiency responses.

    PubMed

    Zamioudis, Christos; Korteland, Jolanda; Van Pelt, Johan A; van Hamersveld, Muriël; Dombrowski, Nina; Bai, Yang; Hanson, Johannes; Van Verk, Marcel C; Ling, Hong-Qing; Schulze-Lefert, Paul; Pieterse, Corné M J

    2015-10-01

    In Arabidopsis roots, the transcription factor MYB72 plays a dual role in the onset of rhizobacteria-induced systemic resistance (ISR) and plant survival under conditions of limited iron availability. Previously, it was shown that MYB72 coordinates the expression of a gene module that promotes synthesis and excretion of iron-mobilizing phenolic compounds in the rhizosphere, a process that is involved in both iron acquisition and ISR signaling. Here, we show that volatile organic compounds (VOCs) from ISR-inducing Pseudomonas bacteria are important elicitors of MYB72. In response to VOC treatment, MYB72 is co-expressed with the iron uptake-related genes FERRIC REDUCTION OXIDASE 2 (FRO2) and IRON-REGULATED TRANSPORTER 1 (IRT1) in a manner that is dependent on FER-LIKE IRON DEFICIENCY TRANSCRIPTION FACTOR (FIT), indicating that MYB72 is an intrinsic part of the plant's iron-acquisition response that is typically activated upon iron starvation. However, VOC-induced MYB72 expression is activated independently of iron availability in the root vicinity. Moreover, rhizobacterial VOC-mediated induction of MYB72 requires photosynthesis-related signals, while iron deficiency in the rhizosphere activates MYB72 in the absence of shoot-derived signals. Together, these results show that the ISR- and iron acquisition-related transcription factor MYB72 in Arabidopsis roots is activated by rhizobacterial volatiles and photosynthesis-related signals, and enhances the iron-acquisition capacity of roots independently of the iron availability in the rhizosphere. This work highlights the role of MYB72 in plant processes by which root microbiota simultaneously stimulate systemic immunity and activate the iron-uptake machinery in their host plants.

  3. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.

    PubMed

    Stout, Stephen M; Cimino, Nina M

    2014-02-01

    Exogenous cannabinoids are structurally and pharmacologically diverse compounds that are widely used. The purpose of this systematic review is to summarize the data characterizing the potential for these compounds to act as substrates, inhibitors, or inducers of human drug metabolizing enzymes, with the aim of clarifying the significance of these properties in clinical care and drug interactions. In vitro data were identified that characterize cytochrome P-450 (CYP-450) enzymes as potential significant contributors to the primary metabolism of several exogenous cannabinoids: tetrahydrocannabinol (THC; CYPs 2C9, 3A4); cannabidiol (CBD; CYPs 2C19, 3A4); cannabinol (CBN; CYPs 2C9, 3A4); JWH-018 (CYPs 1A2, 2C9); and AM2201 (CYPs 1A2, 2C9). CYP-450 enzymes may also contribute to the secondary metabolism of THC, and UDP-glucuronosyltransferases have been identified as capable of catalyzing both primary (CBD, CBN) and secondary (THC, JWH-018, JWH-073) cannabinoid metabolism. Clinical pharmacogenetic data further support CYP2C9 as a significant contributor to THC metabolism, and a pharmacokinetic interaction study using ketoconazole with oromucosal cannabis extract further supports CYP3A4 as a significant metabolic pathway for THC and CBD. However, the absence of interaction between CBD from oromucosal cannabis extract with omeprazole suggests a less significant role of CYP2C19 in CBD metabolism. Studies of THC, CBD, and CBN inhibition and induction of major human CYP-450 isoforms generally reflect a low risk of clinically significant drug interactions with most use, but specific human data are lacking. Smoked cannabis herb (marijuana) likely induces CYP1A2 mediated theophylline metabolism, although the role of cannabinoids specifically in eliciting this effect is questionable.

  4. Loxapine for Reversal of Antipsychotic-Induced Metabolic Disturbances: A Chart Review

    ERIC Educational Resources Information Center

    Jain, Seema; Andridge, Rebecca; Hellings, Jessica A.

    2016-01-01

    Loxapine substitution is a promising option for patients with autism spectrum disorder (ASD) who develop antipsychotic-induced metabolic illness. We performed a chart review of 15 adolescents and adults meeting DSM-IV-TR criteria for ASD, all with antipsychotic-associated weight gain, who received low dose loxapine in an attempt to taper or…

  5. A comparison of mutations induced by accelerated iron particles versus those induced by low earth orbit space radiation in the FEM-3 gene of Caenorhabditis elegans.

    PubMed

    Hartman, P S; Hlavacek, A; Wilde, H; Lewicki, D; Schubert, W; Kern, R G; Kazarians, G A; Benton, E V; Benton, E R; Nelson, G A

    2001-03-01

    The fem-3 gene of Caenorhabditis elegans was employed to determine the mutation frequency as well as the nature of mutations induced by low earth orbit space radiation ambient to Space Shuttle flight STS-76. Recovered mutations were compared to those induced by accelerated iron ions generated by the AGS synchrotron accelerator at Brookhaven National Laboratory. For logistical reasons, dauer larvae were prepared at TCU, transported to either Kennedy Space Center or Brookhaven National Laboratory, flown in space or irradiated, returned to TCU and screened for mutants. A total of 25 fem-3 mutants were recovered after the shuttle flight and yielded a mutation frequency of 2.1x10(-5), roughly 3.3-fold higher than the spontaneous rate of 6.3x10(-6). Four of the mutations were homozygous inviable, suggesting that they were large deletions encompassing fem-3 as well as neighboring, essential genes. Southern blot analyses revealed that one of the 25 contained a polymorphism in fem-3, further evidence that space radiation can induce deletions. While no polymorphisms were detected among the iron ion-induced mutations, three of the 15 mutants were homozygous inviable, which is in keeping with previous observations that high LET iron particles generate deficiencies. These data provide evidence, albeit indirect, that an important mutagenic component of ambient space radiation is high LET charged particles such as iron ions.

  6. A comparison of mutations induced by accelerated iron particles versus those induced by low earth orbit space radiation in the FEM-3 gene of Caenorhabditis elegans

    NASA Technical Reports Server (NTRS)

    Hartman, P. S.; Hlavacek, A.; Wilde, H.; Lewicki, D.; Schubert, W.; Kern, R. G.; Kazarians, G. A.; Benton, E. V.; Benton, E. R.; Nelson, G. A.

    2001-01-01

    The fem-3 gene of Caenorhabditis elegans was employed to determine the mutation frequency as well as the nature of mutations induced by low earth orbit space radiation ambient to Space Shuttle flight STS-76. Recovered mutations were compared to those induced by accelerated iron ions generated by the AGS synchrotron accelerator at Brookhaven National Laboratory. For logistical reasons, dauer larvae were prepared at TCU, transported to either Kennedy Space Center or Brookhaven National Laboratory, flown in space or irradiated, returned to TCU and screened for mutants. A total of 25 fem-3 mutants were recovered after the shuttle flight and yielded a mutation frequency of 2.1x10(-5), roughly 3.3-fold higher than the spontaneous rate of 6.3x10(-6). Four of the mutations were homozygous inviable, suggesting that they were large deletions encompassing fem-3 as well as neighboring, essential genes. Southern blot analyses revealed that one of the 25 contained a polymorphism in fem-3, further evidence that space radiation can induce deletions. While no polymorphisms were detected among the iron ion-induced mutations, three of the 15 mutants were homozygous inviable, which is in keeping with previous observations that high LET iron particles generate deficiencies. These data provide evidence, albeit indirect, that an important mutagenic component of ambient space radiation is high LET charged particles such as iron ions.

  7. Nitrate Acts as a Signal to Induce Organic Acid Metabolism and Repress Starch Metabolism in Tobacco.

    PubMed Central

    Scheible, W. R.; Gonzalez-Fontes, A.; Lauerer, M.; Muller-Rober, B.; Caboche, M.; Stitt, M.

    1997-01-01

    Nia30(145) transformants with very low nitrate reductase activity provide an in vivo screen to identify processes that are regulated by nitrate. Nia30(145) resembles nitrate-limited wild-type plants with respect to growth rate and protein and amino acid content but accumulates large amounts of nitrate when it is grown on high nitrate. The transcripts for nitrate reductase (NR), nitrite reductase, cytosolic glutamine synthetase, and glutamate synthase increased; NR and nitrite reductase activity increased in leaves and roots; and glutamine synthetase activity increased in roots. The transcripts for phosphoenolpyruvate carboxylase, cytosolic pyruvate kinase, citrate synthase, and NADP-isocitrate dehydrogenase increased; phosphoenolpyruvate carboxylase activity increased; and malate, citrate, isocitrate, and [alpha]-oxoglutarate accumulated in leaves and roots. There was a decrease of the ADP-glucose pyrophosphorylase transcript and activity, and starch decreased in the leaves and roots. After adding 12 mM nitrate to nitrate-limited Nia30(145), the transcripts for NR and phosphoenolpyruvate carboxylase increased, and the transcripts for ADP-glucose pyrophosphorylase decreased within 2 and 4 hr, respectively. Starch was remobilized at almost the same rate as in wild-type plants, even though growth was not stimulated in Nia30(145). It is proposed that nitrate acts as a signal to initiate coordinated changes in carbon and nitrogen metabolism. PMID:12237366

  8. Influence of the availability of iron during hypoxia on the genes associated with apoptotic activity and local iron metabolism in rat H9C2 cardiomyocytes and L6G8C5 skeletal myocytes.

    PubMed

    Dziegala, Magdalena; Kasztura, Monika; Kobak, Kamil; Bania, Jacek; Banasiak, Waldemar; Ponikowski, Piotr; Jankowska, Ewa A

    2016-10-01

    The differential availability of iron during hypoxia is presumed to affect the functioning of cardiac and skeletal myocytes. Rat H9C2 cardiomyocytes and L6G8C5 myocytes were cultured for 48 h in normoxic or hypoxic conditions at the optimal, reduced or increased iron concentration. The mRNA expression levels of markers of apoptosis [B‑cell lymphoma‑2 (Bcl2; inhibition) and Bcl‑2‑activated X protein (Bax; induction)], atrophy (Atrogin), glycolysis (pyruvate kinase 2; PKM2) and iron metabolism [transferrin receptor 1 (TfR1; iron importer), ferroportin 1 (FPN1; iron exporter), ferritin heavy chain (FTH; iron storage protein) and hepcidin (HAMP; iron regulator)] were determined using reverse transcription‑quantitative polymerase chain reaction, and cell viability was measured using an tetrazolium reduction assay. Cardiomyocytes and myocytes, when exposed to hypoxia, demonstrated an increased Bax/Bcl‑2 gene expression ratio (P<0.05). Additional deferoxamine (DFO) treatment resulted in further increases in Bax/Bcl‑2 in each cell type (P<0.001 each) and this was associated with the 15% loss in viability. The analogous alterations were observed in both cell types upon ammonium ferric citrate (AFC) treatment during hypoxia; however, the increased Bax/Bcl‑2 ratio and associated viability loss was lower compared with that in case of DFO treatment (P<0.05 each). Under hypoxic conditions, myocytes demonstrated an increased expression of PKM2 (P<0.01). Additional DFO treatment caused an increase in the mRNA expression levels of PKM2 and Atrogin‑1 (P<0.001 and P<0.05, respectively), whereas AFC treatment caused an increased mRNA expression of PKM2 (P<0.01) and accompanied decreased mRNA expression of Atrogin‑1 (P<0.05). The expression augmentation of PKM2 during hypoxia was greater upon low iron compared with that of ferric salt treatment (P<0.01). Both cell types upon DFO during hypoxia demonstrated the increased expression of TfR1

  9. Influence of the availability of iron during hypoxia on the genes associated with apoptotic activity and local iron metabolism in rat H9C2 cardiomyocytes and L6G8C5 skeletal myocytes.

    PubMed

    Dziegala, Magdalena; Kasztura, Monika; Kobak, Kamil; Bania, Jacek; Banasiak, Waldemar; Ponikowski, Piotr; Jankowska, Ewa A

    2016-10-01

    The differential availability of iron during hypoxia is presumed to affect the functioning of cardiac and skeletal myocytes. Rat H9C2 cardiomyocytes and L6G8C5 myocytes were cultured for 48 h in normoxic or hypoxic conditions at the optimal, reduced or increased iron concentration. The mRNA expression levels of markers of apoptosis [B‑cell lymphoma‑2 (Bcl2; inhibition) and Bcl‑2‑activated X protein (Bax; induction)], atrophy (Atrogin), glycolysis (pyruvate kinase 2; PKM2) and iron metabolism [transferrin receptor 1 (TfR1; iron importer), ferroportin 1 (FPN1; iron exporter), ferritin heavy chain (FTH; iron storage protein) and hepcidin (HAMP; iron regulator)] were determined using reverse transcription‑quantitative polymerase chain reaction, and cell viability was measured using an tetrazolium reduction assay. Cardiomyocytes and myocytes, when exposed to hypoxia, demonstrated an increased Bax/Bcl‑2 gene expression ratio (P<0.05). Additional deferoxamine (DFO) treatment resulted in further increases in Bax/Bcl‑2 in each cell type (P<0.001 each) and this was associated with the 15% loss in viability. The analogous alterations were observed in both cell types upon ammonium ferric citrate (AFC) treatment during hypoxia; however, the increased Bax/Bcl‑2 ratio and associated viability loss was lower compared with that in case of DFO treatment (P<0.05 each). Under hypoxic conditions, myocytes demonstrated an increased expression of PKM2 (P<0.01). Additional DFO treatment caused an increase in the mRNA expression levels of PKM2 and Atrogin‑1 (P<0.001 and P<0.05, respectively), whereas AFC treatment caused an increased mRNA expression of PKM2 (P<0.01) and accompanied decreased mRNA expression of Atrogin‑1 (P<0.05). The expression augmentation of PKM2 during hypoxia was greater upon low iron compared with that of ferric salt treatment (P<0.01). Both cell types upon DFO during hypoxia demonstrated the increased expression of TfR1

  10. Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism

    PubMed Central

    Kelly, A.; Lunt, P.; Rodrigues, F.; Berry, P; Flynn, D.; McKiernan, P.; Kelly, D.; Mieli-Vergani, G.; Cox, T.

    2001-01-01

    Neonatal haemochromatosis (NH) is a severe and newly recognised syndrome of uncertain aetiology, characterised by congenital cirrhosis or fulminant hepatitis and widespread tissue iron deposition. NH occurs in the context of maternal disease including viral infection, as a complication of metabolic disease in the fetus, and sporadically or recurrently, without overt cause, in sibs. Although an underlying genetic basis for NH has been suspected, no test is available for predictive analysis in at risk pregnancies.
  As a first step towards an understanding of the putative genetic basis for neonatal haemochromatosis, we have conducted a systematic study of the mode of transmission of this disorder in a total of 40 infants born to 27 families. We have moreover carried out a molecular analysis of candidate genes (β2-microglobulin, HFE, and haem oxygenases 1 and 2) implicated in iron metabolism. No pathogenic mutations in these genes were identified that segregate consistently with the disease phenotype in multiplex pedigrees. However, excluding four pedigrees with clear evidence of maternal infection associated with NH, a pedigree showing transmission of maternal antinuclear factor and ribonucleoprotein antibodies to the affected infants, and two families with possible matrilineal inheritance of disease in maternal half sibs, a large subgroup of the affected pedigrees point to the inheritance of an autosomal recessive trait. This included 14 pedigrees with affected and unaffected infants and a single pedigree where all four affected infants were the sole offspring of consanguineous but otherwise healthy parents.
  We thus report three distinct patterns of disease transmission in neonatal haemochromatosis. In the differentiation of a large subgroup showing transmission of disease in a manner suggesting autosomal recessive inheritance, we also provide the basis for further genome wide studies to define chromosomal determinants of iron storage disease in the

  11. Senescence-induced iron mobilization in source leaves of barley (Hordeum vulgare) plants.

    PubMed

    Shi, Rongli; Weber, Günther; Köster, Jessica; Reza-Hajirezaei, Mohammad; Zou, Chunqin; Zhang, Fusuo; von Wirén, Nicolaus

    2012-07-01

    • Retranslocation of iron (Fe) from source leaves to sinks requires soluble Fe binding forms. As much of the Fe is protein-bound and associated with the leaf nitrogen (N) status, we investigated the role of N in Fe mobilization and retranslocation under N deficiency- vs dark-induced leaf senescence. • By excluding Fe retranslocation from the apoplastic root pool, Fe concentrations in source and sink leaves from hydroponically grown barley (Hordeum vulgare) plants were determined in parallel with the concentrations of potential Fe chelators and the expression of genes involved in phytosiderophore biosynthesis. • N supply showed opposing effects on Fe pools in source leaves, inhibiting Fe export out of source leaves under N sufficiency but stimulating Fe export from source leaves under N deficiency, which partially alleviated Fe deficiency-induced chlorosis. Both triggers of leaf senescence, shading and N deficiency, enhanced NICOTIANAMINE SYNTHASE2 gene expression, soluble Fe pools in source leaves, and phytosiderophore and citrate rather than nicotianamine concentrations. • These results indicate that Fe mobilization within senescing leaves is independent of a concomitant N sink in young leaves and that phytosiderophores enhance Fe solubility in senescing source leaves, favoring subsequent Fe retranslocation.

  12. Characterization of MxFIT, an iron deficiency induced transcriptional factor in Malus xiaojinensis.

    PubMed

    Yin, Lili; Wang, Yi; Yuan, Mudan; Zhang, Xinzhong; Xu, Xuefeng; Han, Zhenhai

    2014-02-01

    Iron deficiency often results in nutritional disorder in fruit trees. Transcription factors play an important role in the regulation of iron uptake. In this study, we isolated an iron deficiency response transcription factor gene, MxFIT, from an iron-efficient apple genotype of Malus xiaojinensis. MxFIT encoded a basic helix-loop-helix protein and contained a 966 bp open reading frame. MxFIT protein was targeted to the nucleus in onion epidermal cells and showed strong transcriptional activation in yeast cells. Spatiotemporal expression analysis revealed that MxFIT was up-regulated in roots under iron deficiency at both mRNA and protein levels, while almost no expression was detected in leaves irrespective of iron supply. Ectopic expression of MxFIT resulted in enhanced iron deficiency responses in Arabidopsis under iron deficiency and stronger resistance to iron deficiency. Thus, MxFIT might be involved in iron uptake and plays an important role in iron deficiency response.

  13. Investigation of moisture-induced embrittlement of iron aluminides. Final report

    SciTech Connect

    Alven, D.A.; Stoloff, N.S.

    1997-06-05

    Iron-aluminum alloys with 28 at.% Al and 5 at.% Cr were shown to be susceptible to hydrogen embrittlement by exposure to both gaseous hydrogen and water vapor. This study examined the effect of the addition of zirconium and carbon on the moisture-induced hydrogen embrittlement of an Fe{sub 3}Al,Cr alloy through the evaluation of tensile properties and fatigue crack growth resistance in hydrogen gas and moisture-bearing air. Susceptibility to embrittlement was found to vary with the zirconium content while the carbon addition was found to only affect the fracture toughness. Inherent fatigue crack growth resistance and fracture toughness, as measured in an inert environment, was found to increase with the addition of 0.5 at.% Zr. The combined addition of 0.5 at.% Zr and carbon only increased the fracture toughness. The addition of 1 at.% Zr and carbon was found to have no effect on the crack growth rate when compared to the base alloy. Susceptibility to embrittlement in moisture-bearing environments was found to decrease with the addition of 0.5 at.% Zr. In gaseous hydrogen, the threshold value of the Zr-containing alloys was found to increase above that found in the inert environment while the crack growth resistance was much lower. By varying the frequency of fatigue loading, it was shown that the corrosion fatigue component of the fatigue crack growth rate in an embrittling environment displays a frequency dependence. Hydrogen transport in iron aluminides was shown to occur primarily by a dislocation-assisted transport mechanism. This mechanism, in conjunction with fractography, indicates that the zirconium-containing precipitates act as traps for the hydrogen that is carried along by the dislocations through the lattice.

  14. Iron Corrosion Induced by Nonhydrogenotrophic Nitrate-Reducing Prolixibacter sp. Strain MIC1-1

    PubMed Central

    Ito, Kimio; Wakai, Satoshi; Tsurumaru, Hirohito; Ohkuma, Moriya; Harayama, Shigeaki

    2014-01-01

    Microbiologically influenced corrosion (MIC) of metallic materials imposes a heavy economic burden. The mechanism of MIC of metallic iron (Fe0) under anaerobic conditions is usually explained as the consumption of cathodic hydrogen by hydrogenotrophic microorganisms that accelerates anodic Fe0 oxidation. In this study, we describe Fe0 corrosion induced by a nonhydrogenotrophic nitrate-reducing bacterium called MIC1-1, which was isolated from a crude-oil sample collected at an oil well in Akita, Japan. This strain requires specific electron donor-acceptor combinations and an organic carbon source to grow. For example, the strain grew anaerobically on nitrate as a sole electron acceptor with pyruvate as a carbon source and Fe0 as the sole electron donor. In addition, ferrous ion and l-cysteine served as electron donors, whereas molecular hydrogen did not. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain MIC1-1 was a member of the genus Prolixibacter in the order Bacteroidales. Thus, Prolixibacter sp. strain MIC1-1 is the first Fe0-corroding representative belonging to the phylum Bacteroidetes. Under anaerobic conditions, Prolixibacter sp. MIC1-1 corroded Fe0 concomitantly with nitrate reduction, and the amount of iron dissolved by the strain was six times higher than that in an aseptic control. Scanning electron microscopy analyses revealed that microscopic crystals of FePO4 developed on the surface of the Fe0 foils, and a layer of FeCO3 covered the FePO4 crystals. We propose that cells of Prolixibacter sp. MIC1-1 accept electrons directly from Fe0 to reduce nitrate. PMID:25548048

  15. Iron corrosion induced by nonhydrogenotrophic nitrate-reducing Prolixibacter sp. strain MIC1-1.

    PubMed

    Iino, Takao; Ito, Kimio; Wakai, Satoshi; Tsurumaru, Hirohito; Ohkuma, Moriya; Harayama, Shigeaki

    2015-03-01

    Microbiologically influenced corrosion (MIC) of metallic materials imposes a heavy economic burden. The mechanism of MIC of metallic iron (Fe(0)) under anaerobic conditions is usually explained as the consumption of cathodic hydrogen by hydrogenotrophic microorganisms that accelerates anodic Fe(0) oxidation. In this study, we describe Fe(0) corrosion induced by a nonhydrogenotrophic nitrate-reducing bacterium called MIC1-1, which was isolated from a crude-oil sample collected at an oil well in Akita, Japan. This strain requires specific electron donor-acceptor combinations and an organic carbon source to grow. For example, the strain grew anaerobically on nitrate as a sole electron acceptor with pyruvate as a carbon source and Fe(0) as the sole electron donor. In addition, ferrous ion and l-cysteine served as electron donors, whereas molecular hydrogen did not. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain MIC1-1 was a member of the genus Prolixibacter in the order Bacteroidales. Thus, Prolixibacter sp. strain MIC1-1 is the first Fe(0)-corroding representative belonging to the phylum Bacteroidetes. Under anaerobic conditions, Prolixibacter sp. MIC1-1 corroded Fe(0) concomitantly with nitrate reduction, and the amount of iron dissolved by the strain was six times higher than that in an aseptic control. Scanning electron microscopy analyses revealed that microscopic crystals of FePO4 developed on the surface of the Fe(0) foils, and a layer of FeCO3 covered the FePO4 crystals. We propose that cells of Prolixibacter sp. MIC1-1 accept electrons directly from Fe(0) to reduce nitrate.

  16. Signal transduction triggered by iron to induce the nuclear importation of a Myb3 transcription factor in the parasitic protozoan Trichomonas vaginalis.

    PubMed

    Hsu, Hong-Ming; Lee, Yu; Hsu, Pang-Hung; Liu, Hsing-Wei; Chu, Chien-Hsin; Chou, Ya-Wen; Chen, Yet-Ran; Chen, Shu-Hui; Tai, Jung-Hsiang

    2014-10-17

    Iron was previously shown to induce rapid nuclear translocation of a Myb3 transcription factor in the protozoan parasite, Trichomonas vaginalis. In the present study, iron was found to induce a transient increase in cellular cAMP, followed by the nuclear influx of Myb3, whereas the latter was also induced by 8-bromo-cyclic AMP. Iron-inducible cAMP production and nuclear influx of Myb3 were inhibited by suramin and SQ22536, respective inhibitors of the Gα subunit of heterotrimeric G proteins and adenylyl cyclases. In contrast, the nuclear influx of Myb3 induced by iron or 8-bromo-cAMP was delayed or inhibited, respectively, by H89, the inhibitor of protein kinase A. Using liquid chromatography-coupled tandem mass spectrometry, Thr(156) and Lys(143) in Myb3 were found to be phosphorylated and ubiquitinated, respectively. These modifications were induced by iron and inhibited by H89, as shown by immunoprecipitation-coupled Western blotting. Iron-inducible ubiquitination and nuclear influx were aborted in T156A and K143R, but T156D was constitutively ubiquitinated and persistently localized to the nucleus. Myb3 was phosphorylated in vitro by the catalytic subunit of a T. vaginalis protein kinase A, TvPKAc. A transient interaction between TvPKAc and Myb3 and the phosphorylation of both proteins were induced in the parasite shortly after iron or 8-bromo-cAMP treatment. Together, these observations suggest that iron may induce production of cAMP and activation of TvPKAc, which then induces the phosphorylation of Myb3 and subsequent ubiquitination for accelerated nuclear influx. It is conceivable that iron probably exerts a much broader impact on the physiology of the parasite than previously thought to encounter environmental changes.

  17. Obesity promotes alterations in iron recycling.

    PubMed

    Citelli, Marta; Fonte-Faria, Thaís; Nascimento-Silva, Vany; Renovato-Martins, Mariana; Silva, Raphael; Luna, Aderval Severino; Silva, Simone Vargas da; Barja-Fidalgo, Christina

    2015-01-01

    Hepcidin is a key hormone that induces the degradation of ferroportin (FPN), a protein that exports iron from reticuloendothelial macrophages and enterocytes. The aim of the present study was to experimentally evaluate if the