WorldWideScience

Sample records for altered iron homeostasis

  1. Brain iron homeostasis.

    Science.gov (United States)

    Moos, Torben

    2002-11-01

    Iron is essential for virtually all types of cells and organisms. The significance of the iron for brain function is reflected by the presence of receptors for transferrin on brain capillary endothelial cells. The transport of iron into the brain from the circulation is regulated so that the extraction of iron by brain capillary endothelial cells is low in iron-replete conditions and the reverse when the iron need of the brain is high as in conditions with iron deficiency and during development of the brain. Whereas there is good agreement that iron is taken up by means of receptor-mediated uptake of iron-transferrin at the brain barriers, there are contradictory views on how iron is transported further on from the brain barriers and into the brain extracellular space. The prevailing hypothesis for transport of iron across the BBB suggests a mechanism that involves detachment of iron from transferrin within barrier cells followed by recycling of apo-transferrin to blood plasma and release of iron as non-transferrin-bound iron into the brain interstitium from where the iron is taken up by neurons and glial cells. Another hypothesis claims that iron-transferrin is transported into the brain by means of transcytosis through the BBB. This thesis deals with the topic "brain iron homeostasis" defined as the attempts to maintain constant concentrations of iron in the brain internal environment via regulation of iron transport through brain barriers, cellular iron uptake by neurons and glia, and export of iron from brain to blood. The first part deals with transport of iron-transferrin complexes from blood to brain either by transport across the brain barriers or by uptake and retrograde axonal transport in motor neurons projecting beyond the blood-brain barrier. The transport of iron and transport into the brain was examined using radiolabeled iron-transferrin. Intravenous injection of [59Fe-125]transferrin led to an almost two-fold higher accumulation of 59Fe than of

  2. Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency.

    Science.gov (United States)

    Foka, Pelagia; Dimitriadis, Alexios; Karamichali, Eirini; Kyratzopoulou, Eleni; Giannimaras, Dionyssios; Koskinas, John; Varaklioti, Agoritsa; Mamalaki, Avgi; Georgopoulou, Urania

    2016-08-17

    Mechanisms that favor Hepatitis C virus (HCV) persistence over clearance are unclear, but involve defective innate immunity. Chronic infection is characterized by hepatic iron overload, hyperferraemia and hyperferittinaemia. Hepcidin modulates iron egress via ferroportin and its storage in ferritin. Chronic HCV patients have decreased hepcidin, while HCV replication is modified by HAMP silencing. We aimed to investigate interactions between HCV and hepcidin, during acute and chronic disease, and putative alterations in cellular iron homeostasis that enhance HCV propagation and promote viral persistence. Thus, we used HCV JFH-1-infected co-cultures of Huh7.5 hepatoma and THP-1 macrophage cells, HCV patients' sera and Huh7 hepcidin-expressing cells transfected with HCV replicons. Hepcidin levels were elevated in acutely infected patients, but correlated with viral load in chronic patients. HAMP expression was up-regulated early in HCV infection in vitro, with corresponding changes in ferritin and FPN. Hepcidin overexpression enhanced both viral translation and replication. In HCV-infected co-cultures, we observed increased hepcidin, reduced hepatoma ferritin and a concurrent rise in macrophaghic ferritin over time. Altered iron levels complemented amplified replication in hepatoma cells and one replication round in macrophages. Iron-loading of macrophages led to enhancement of hepatic HCV replication through reversed ferritin "flow." Viral transmissibility from infected macrophages to naïve hepatoma cells was induced by iron. We propose that HCV control over iron occurs both by intracellular iron sequestration, through hepcidin, and intercellular iron mobilisation via ferritin, as means toward enhanced replication. Persistence could be achieved through HCV-induced changes in macrophagic iron that enhances viral replication in these cells. PMID:27058404

  3. Epigenetic regulation of iron homeostasis in Arabidopsis.

    Science.gov (United States)

    Xing, Jiewen; Wang, Tianya; Ni, Zhongfu

    2015-01-01

    Iron (Fe) is one of the most important microelement required for plant growth and development because of its unique property of catalyzing oxidation/reduction reactions. Iron deficiency impairs fundamental processes which could lead to a decrease in chlorophyll production and pollen fertility, thus influencing crop productivity and quality. However, iron in excess is toxic to the cell and is harmful to the plant. To exactly control the iron content in all tissues, plants have evolved many strategies to regulate iron homeostasis, which refers to 2 successive steps: iron uptake at the root surface, and iron distribution in vivo. In the last decades, a number of transporters and regulatory factors involved in this process have been isolated and identified. To cope with the complicated flexible environmental conditions, plants apply diverse mechanisms to regulate the expression and activity of these components. One of the most important mechanisms is epigenetic regulation of iron homeostasis. This review has been presented to provide an update on the information supporting the involvement of histone modifications in iron homeostasis and possible future course of the field. PMID:26313698

  4. Caenorhabditis elegans ATAD-3 modulates mitochondrial iron and heme homeostasis.

    Science.gov (United States)

    van den Ecker, Daniela; Hoffmann, Michael; Müting, Gesine; Maglioni, Silvia; Herebian, Diran; Mayatepek, Ertan; Ventura, Natascia; Distelmaier, Felix

    2015-11-13

    ATAD3 (ATPase family AAA domain-containing protein 3) is a mitochondrial protein, which is essential for cell viability and organismal development. ATAD3 has been implicated in several important cellular processes such as apoptosis regulation, respiratory chain function and steroid hormone biosynthesis. Moreover, altered expression of ATAD3 has been associated with several types of cancer. However, the exact mechanisms underlying ATAD3 effects on cellular metabolism remain largely unclear. Here, we demonstrate that Caenorhabditis elegans ATAD-3 is involved in mitochondrial iron and heme homeostasis. Knockdown of atad-3 caused mitochondrial iron- and heme accumulation. This was paralleled by changes in the expression levels of several iron- and heme-regulatory genes as well as an increased heme uptake. In conclusion, our data indicate a regulatory role of C. elegans ATAD-3 in mitochondrial iron and heme metabolism.

  5. Effects of Environmental Pollutants on Cellular Iron Homeostasis and Ultimate Links to Human Disease.

    Science.gov (United States)

    Schreinemachers, Dina M; Ghio, Andrew J

    2016-01-01

    Chronic disease has increased in the past several decades, and environmental pollutants have been implicated. The magnitude and variety of diseases may indicate the malfunctioning of some basic mechanisms underlying human health. Environmental pollutants demonstrate a capability to complex iron through electronegative functional groups containing oxygen, nitrogen, or sulfur. Cellular exposure to the chemical or its metabolite may cause a loss of requisite functional iron from intracellular sites. The cell is compelled to acquire further iron critical to its survival by activation of iron-responsive proteins and increasing iron import. Iron homeostasis in the exposed cells is altered due to a new equilibrium being established between iron-requiring cells and the inappropriate chelator (the pollutant or its catabolite). Following exposure to environmental pollutants, the perturbation of functional iron homeostasis may be the mechanism leading to adverse biological effects. Understanding the mechanism may lead to intervention methods for this major public health concern.

  6. Intestinal Iron Homeostasis and Colon Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Yatrik M. Shah

    2013-06-01

    Full Text Available Colorectal cancer (CRC is the third most common cause of cancer-related deaths in industrialized countries. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Iron is an essential nutrient for cell growth. Iron overload caused by hereditary mutations or excess dietary iron uptake has been identified as a risk factor for CRC. Intestinal iron is tightly controlled by iron transporters that are responsible for iron uptake, distribution, and export. Dysregulation of intestinal iron transporters are observed in CRC and lead to iron accumulation in tumors. Intratumoral iron results in oxidative stress, lipid peroxidation, protein modification and DNA damage with consequent promotion of oncogene activation. In addition, excess iron in intestinal tumors may lead to increase in tumor-elicited inflammation and tumor growth. Limiting intratumoral iron through specifically chelating excess intestinal iron or modulating activities of iron transporter may be an attractive therapeutic target for CRC.

  7. Immunity to plant pathogens and iron homeostasis.

    Science.gov (United States)

    Aznar, Aude; Chen, Nicolas W G; Thomine, Sebastien; Dellagi, Alia

    2015-11-01

    Iron is essential for metabolic processes in most living organisms. Pathogens and their hosts often compete for the acquisition of this nutrient. However, iron can catalyze the formation of deleterious reactive oxygen species. Hosts may use iron to increase local oxidative stress in defense responses against pathogens. Due to this duality, iron plays a complex role in plant-pathogen interactions. Plant defenses against pathogens and plant response to iron deficiency share several features, such as secretion of phenolic compounds, and use common hormone signaling pathways. Moreover, fine tuning of iron localization during infection involves genes coding iron transport and iron storage proteins, which have been shown to contribute to immunity. The influence of the plant iron status on the outcome of a given pathogen attack is strongly dependent on the nature of the pathogen infection strategy and on the host species. Microbial siderophores emerged as important factors as they have the ability to trigger plant defense responses. Depending on the plant species, siderophore perception can be mediated by their strong iron scavenging capacity or possibly via specific recognition as pathogen associated molecular patterns. This review highlights that iron has a key role in several plant-pathogen interactions by modulating immunity. PMID:26475190

  8. Hepcidin and Iron Homeostasis during Pregnancy

    Directory of Open Access Journals (Sweden)

    Mary Dawn Koenig

    2014-08-01

    Full Text Available Hepcidin is the master regulator of systemic iron bioavailability in humans. This review examines primary research articles that assessed hepcidin during pregnancy and postpartum and report its relationship to maternal and infant iron status and birth outcomes; areas for future research are also discussed. A systematic search of the databases Medline and Cumulative Index to Nursing and Allied Health returned 16 primary research articles including 10 human and six animal studies. Collectively, the results indicate that hepcidin is lower during pregnancy than in a non-pregnant state, presumably to ensure greater iron bioavailability to the mother and fetus. Pregnant women with undetectable serum hepcidin transferred a greater quantity of maternally ingested iron to their fetus compared to women with detectable hepcidin, indicating that maternal hepcidin in part determines the iron bioavailability to the fetus. However, inflammatory states, including preeclampsia, malaria infection, and obesity were associated with higher hepcidin during pregnancy compared to healthy controls, suggesting that maternal and fetal iron bioavailability could be compromised in such conditions. Future studies should examine the relative contribution of maternal versus fetal hepcidin to the control of placental iron transfer as well as optimizing maternal and fetal iron bioavailability in pregnancies complicated by inflammation.

  9. NCOA4 Deficiency Impairs Systemic Iron Homeostasis

    Directory of Open Access Journals (Sweden)

    Roberto Bellelli

    2016-01-01

    Full Text Available The cargo receptor NCOA4 mediates autophagic ferritin degradation. Here we show that NCOA4 deficiency in a knockout mouse model causes iron accumulation in the liver and spleen, increased levels of transferrin saturation, serum ferritin, and liver hepcidin, and decreased levels of duodenal ferroportin. Despite signs of iron overload, NCOA4-null mice had mild microcytic hypochromic anemia. Under an iron-deprived diet (2–3 mg/kg, mice failed to release iron from ferritin storage and developed severe microcytic hypochromic anemia and ineffective erythropoiesis associated with increased erythropoietin levels. When fed an iron-enriched diet (2 g/kg, mice died prematurely and showed signs of liver damage. Ferritin accumulated in primary embryonic fibroblasts from NCOA4-null mice consequent to impaired autophagic targeting. Adoptive expression of the NCOA4 COOH terminus (aa 239–614 restored this function. In conclusion, NCOA4 prevents iron accumulation and ensures efficient erythropoiesis, playing a central role in balancing iron levels in vivo.

  10. Hepcidin and Iron Homeostasis during Pregnancy

    OpenAIRE

    Mary Dawn Koenig; Lisa Tussing-Humphreys; Jessica Day; Brooke Cadwell; Elizabeta Nemeth

    2014-01-01

    Hepcidin is the master regulator of systemic iron bioavailability in humans. This review examines primary research articles that assessed hepcidin during pregnancy and postpartum and report its relationship to maternal and infant iron status and birth outcomes; areas for future research are also discussed. A systematic search of the databases Medline and Cumulative Index to Nursing and Allied Health returned 16 primary research articles including 10 human and six animal studies. Collectively...

  11. Maternal dietary restriction alters offspring's sleep homeostasis.

    Directory of Open Access Journals (Sweden)

    Noriyuki Shimizu

    Full Text Available Nutritional state in the gestation period influences fetal growth and development. We hypothesized that undernutrition during gestation would affect offspring sleep architecture and/or homeostasis. Pregnant female mice were assigned to either control (fed ad libitum; AD or 50% dietary restriction (DR groups from gestation day 12 to parturition. After parturition, dams were fed AD chow. After weaning, the pups were also fed AD into adulthood. At adulthood (aged 8-9 weeks, we carried out sleep recordings. Although offspring mice displayed a significantly reduced body weight at birth, their weights recovered three days after birth. Enhancement of electroencephalogram (EEG slow wave activity (SWA during non-rapid eye movement (NREM sleep was observed in the DR mice over a 24-hour period without changing the diurnal pattern or amounts of wake, NREM, or rapid eye movement (REM sleep. In addition, DR mice also displayed an enhancement of EEG-SWA rebound after a 6-hour sleep deprivation and a higher threshold for waking in the face of external stimuli. DR adult offspring mice exhibited small but significant increases in the expression of hypothalamic peroxisome proliferator-activated receptor α (Pparα and brain-specific carnitine palmitoyltransferase 1 (Cpt1c mRNA, two genes involved in lipid metabolism. Undernutrition during pregnancy may influence sleep homeostasis, with offspring exhibiting greater sleep pressure.

  12. Deficiency of a alpha-1-antitrypsin influences systemic iron homeostasis

    Science.gov (United States)

    Abstract Background: There is evidence that proteases and anti-proteases participate in the iron homeostasis of cells and living systems. We tested the postulate that alpha-1 antitrypsin (A1AT) polymorphism and the consequent deficiency of this anti-protease in humans are asso...

  13. Iron Homeostasis in Yellowstone National Park Hot Spring Microbial Communities

    Science.gov (United States)

    Brown, I.; Tringe, S. G.; Franklin, H.; Bryant, D. A.; Klatt, C. G.; Sarkisova, S. A.; Guevara, M.

    2010-01-01

    It has been postulated that life may have originated on Earth, and possibly on Mars, in association with hydrothermal activity and high concentrations of ferrous iron. However, it is not clear how an iron-rich thermal hydrosphere could be hospitable to microbes, since reduced iron appears to stimulate oxidative stress in all domains of life and particularly in oxygenic phototrophs. Therefore, the study of microbial diversity in iron-depositing hot springs (IDHS) and the mechanisms of iron homeostasis and suppression of oxidative stress may help elucidate how Precambrian organisms could withstand the extremely high concentrations of reactive oxygen species (ROS) produced by interaction between environmental Fe(2+) and O2. Proteins and clusters of orthologous groups (COGs) involved in the maintenance of Fe homeostasis found in cyanobacteria (CB) inhabiting environments with high and low [Fe] were main target of this analysis. Preliminary results of the analysis suggest that the Chocolate Pots (CP) microbial community is heavily dominated by phototrophs from the cyanobacteria (CB), Chloroflexi and Chlorobi phyla, while the Mushroom Spring (MS) effluent channel harbors a more diverse community in which Chloroflexi are the dominant phototrophs. It is speculated that CB inhabiting IDHS have an increased tolerance to both high concentrations of Fe(2+) and ROS produced in the Fenton reaction. This hypothesis was explored via a comparative analysis of the diversity of proteins and COGs involved in Fe and redox homeostasis in the CP and MS microbiomes.

  14. Dissecting plant iron homeostasis under short and long-term iron fluctuations

    DEFF Research Database (Denmark)

    Shirvanehdeh, Behrooz Darbani; Briat, Jean-Francois; Holm, Preben Bach;

    2013-01-01

    A wealth of information on the different aspects of iron homeostasis in plants has been obtained during the last decade. However, there is no clear road-map integrating the relationships between the various components. The principal aim of the current review is to fill this gap. In this context we...... discuss the lack of low affinity iron uptake mechanisms in plants, the utilization of a different uptake mechanism by graminaceous plants compared to the others, as well as the roles of riboflavin, ferritin isoforms, nitric oxide, nitrosylation, heme, aconitase, and vacuolar pH. Cross-homeostasis between...... elements is also considered, with a specific emphasis on the relationship between iron homeostasis and phosphorus and copper deficiencies. As the environment is a crucial parameter for modulating plant responses, we also highlight how diurnal fluctuations govern iron metabolism. Evolutionary aspects...

  15. Dysregulation of iron and copper homeostasis innonalcoholic fatty liver

    Institute of Scientific and Technical Information of China (English)

    Elmar Aigner; Günter Weiss; Christian Datz

    2015-01-01

    Elevated iron stores as indicated by hyperferritinemiawith normal or mildly elevated transferrin saturationand mostly mild hepatic iron deposition are acharacteristic finding in subjects with non-alcoholicfatty liver disease (NAFLD). Excess iron is observedin approximately one third of NAFLD patients andis commonly referred to as the "dysmetabolic ironoverload syndrome". Clinical evidence suggests thatelevated body iron stores aggravate the clinical courseof NAFLD with regard to liver-related and extrahepaticdisease complications which relates to the fact thatexcess iron catalyses the formation of toxic hydroxylradicalssubsequently resulting in cellular damage. Ironremoval improves insulin sensitivity, delays the onsetof type 2 diabetes mellitus, improves pathologic liverfunction tests and likewise ameliorates NAFLD histology.Several mechanisms contribute to pathologic ironaccumulation in NAFLD. These include impaired ironexport from hepatocytes and mesenchymal Kupffer cellsas a consequence of imbalances in the concentrationsof iron regulatory factors, such as hepcidin, cytokines,copper or other dietary factors. This review summarizesthe knowledge about iron homeostasis in NAFLD andthe rationale for its therapeutic implications.

  16. Misregulation of iron homeostasis in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Gajowiak, Anna; Styś, Agnieszka; Starzyński, Rafał R; Staroń, Robert; Lipiński, Paweł

    2016-01-01

    Iron is essential for all mammalian cells, but it is toxic in excess. Our understanding of molecular mechanisms ensuring iron homeostasis at both cellular and systemic levels has dramatically increased over the past 15 years. However, despite major advances in this field, homeostatic regulation of iron in the central nervous system (CNS) requires elucidation. It is unclear how iron moves in the CNS and how its transfer to the CNS across the blood-brain and the blood-cerebrospinal fluid barriers, which separate the CNS from the systemic circulation, is regulated. Increasing evidence indicates the role of iron dysregulation in neuronal cell death observed in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disorder characterized by selective cortical czynand spinal motor neuron dysfunction that results from a complex interplay among various pathogenic factors including oxidative stress. The latter is known to strongly affect cellular iron balance, creating a vicious circle to exacerbate oxidative injury. The role of iron in the pathogenesis of ALS is confirmed by therapeutic effects of iron chelation in ALS mouse models. These models are of great importance for deciphering molecular mechanisms of iron accumulation in neurons. Most of them consist of transgenic rodents overexpressing the mutated human superoxide dismutase 1 (SOD1) gene. Mutations in the SOD1 gene constitute one of the most common genetic causes of the inherited form of ALS. However, it should be considered that overexpression of the SOD1 gene usually leads to increased SOD1 enzymatic activity, a condition which does not occur in human pathology and which may itself change the expression of iron metabolism genes. PMID:27356602

  17. Nicotianamine synthase overexpression positively modulates iron homeostasis-related genes in high iron rice.

    Science.gov (United States)

    Wang, Meng; Gruissem, Wilhelm; Bhullar, Navreet K

    2013-01-01

    Nearly one-third of the world population, mostly women and children, suffer from iron malnutrition and its consequences, such as anemia or impaired mental development. Biofortification of rice, which is a staple crop for nearly half of the world's population, can significantly contribute in alleviating iron deficiency. NFP rice (transgenic rice expressing nicotianamine synthase, ferritin and phytase genes) has a more than six-fold increase in iron content in polished rice grains, resulting from the synergistic action of nicotianamine synthase (NAS) and ferritin transgenes. We investigated iron homeostasis in NFP plants by analyzing the expression of 28 endogenous rice genes known to be involved in the homeostasis of iron and other metals, in iron-deficient and iron-sufficient conditions. RNA was collected from different tissues (roots, flag leaves, grains) and at three developmental stages during grain filling. NFP plants showed increased sensitivity to iron-deficiency conditions and changes in the expression of endogenous genes involved in nicotianamine (NA) metabolism, in comparison to their non-transgenic siblings (NTS). Elevated transcript levels were detected in NFP plants for several iron transporters. In contrast, expression of OsYSL2, which encodes a member of yellow stripe like protein family, and a transporter of the NA-Fe(II) complex was reduced in NFP plants under low iron conditions, indicating that expression of OsYSL2 is regulated by the endogenous iron status. Expression of the transgenes did not significantly affect overall iron homeostasis in NFP plants, which establishes the engineered push-pull mechanism as a suitable strategy to increase rice endosperm iron content.

  18. Nicotianamine synthase overexpression positively modulates iron homeostasis-related genes in high iron rice

    Directory of Open Access Journals (Sweden)

    Meng eWang

    2013-05-01

    Full Text Available Nearly one-third of the world population, mostly women and children, suffer from iron malnutrition and its consequences, such as anemia or impaired mental development. Biofortification of rice, which is a staple crop for nearly half of the world’s population, can significantly contribute in alleviating iron deficiency. NFP rice (transgenic rice expressing nicotianamine synthase, ferritin and phytase genes has a more than six-fold increase in iron content in polished rice grains, resulting from the synergistic action of nicotianamine synthase (NAS and ferritin transgenes. We investigated iron homeostasis in NFP plants by analyzing the expression of 28 endogenous rice genes known to be involved in the homeostasis of iron and other metals, in iron-deficient and iron-sufficient conditions. RNA was collected from different tissues (roots, flag leaves, grains and at three developmental stages during grain filling. NFP plants showed increased sensitivity to iron-deficiency conditions and changes in the expression of endogenous genes involved in nicotianamine (NA metabolism, in comparison to their non-transgenic siblings. Elevated transcript levels were detected in NFP plants for several iron transporters. In contrast, expression of OsYSL2, which encodes a member of Yellow Stripe-like protein family, and a transporter of the NA-Fe(II complex was reduced in NFP plants under low iron conditions, indicating that expression of OsYSL2 is regulated by the endogenous iron status. Expression of the transgenes did not significantly affect overall iron homeostasis in NFP plants, which establishes the engineered push-pull mechanism as a suitable strategy to increase rice endosperm iron content.

  19. Iron homeostasis and oxidative stress in idiopathic pulmonary alveolar proteinosis: a case-control study

    Directory of Open Access Journals (Sweden)

    Roggli Victor L

    2008-01-01

    Full Text Available Abstract Background Lung injury caused by both inhaled dusts and infectious agents depends on increased availability of iron and metal-catalyzed oxidative stress. Because inhaled particles, such as silica, and certain infections can cause secondary pulmonary alveolar proteinosis (PAP, we tested the hypothesis that idiopathic PAP is associated with an altered iron homeostasis in the human lung. Methods Healthy volunteers (n = 20 and patients with idiopathic PAP (n = 20 underwent bronchoalveolar lavage and measurements were made of total protein, iron, tranferrin, transferrin receptor, lactoferrin, and ferritin. Histochemical staining for iron and ferritin was done in the cell pellets from control subjects and PAP patients, and in lung specimens of patients without cardiopulmonary disease and with PAP. Lavage concentrations of urate, glutathione, and ascorbate were also measured as indices of oxidative stress. Results Lavage concentrations of iron, transferrin, transferrin receptor, lactoferrin, and ferritin were significantly elevated in PAP patients relative to healthy volunteers. The cells of PAP patients had accumulated significant iron and ferritin, as well as considerable amounts of extracellular ferritin. Immunohistochemistry for ferritin in lung tissue revealed comparable amounts of this metal-storage protein in the lower respiratory tract of PAP patients both intracellularly and extracellularly. Lavage concentrations of ascorbate, glutathione, and urate were significantly lower in the lavage fluid of the PAP patients. Conclusion Iron homeostasis is altered in the lungs of patients with idiopathic PAP, as large amounts of catalytically-active iron and low molecular weight anti-oxidant depletion are present. These findings suggest a metal-catalyzed oxidative stress in the maintenance of this disease.

  20. The PICALM protein plays a key role in iron homeostasis and cell proliferation.

    Directory of Open Access Journals (Sweden)

    Paula B Scotland

    Full Text Available The ubiquitously expressed phosphatidylinositol binding clathrin assembly (PICALM protein associates with the plasma membrane, binds clathrin, and plays a role in clathrin-mediated endocytosis. Alterations of the human PICALM gene are present in aggressive hematopoietic malignancies, and genome-wide association studies have recently linked the PICALM locus to late-onset Alzheimer's disease. Inactivating and hypomorphic Picalm mutations in mice cause different degrees of severity of anemia, abnormal iron metabolism, growth retardation and shortened lifespan. To understand PICALM's function, we studied the consequences of PICALM overexpression and characterized PICALM-deficient cells derived from mutant fit1 mice. Our results identify a role for PICALM in transferrin receptor (TfR internalization and demonstrate that the C-terminal PICALM residues are critical for its association with clathrin and for the inhibitory effect of PICALM overexpression on TfR internalization. Murine embryonic fibroblasts (MEFs that are deficient in PICALM display several characteristics of iron deficiency (increased surface TfR expression, decreased intracellular iron levels, and reduced cellular proliferation, all of which are rescued by retroviral PICALM expression. The proliferation defect of cells that lack PICALM results, at least in part, from insufficient iron uptake, since it can be corrected by iron supplementation. Moreover, PICALM-deficient cells are particularly sensitive to iron chelation. Taken together, these data reveal that PICALM plays a critical role in iron homeostasis, and offer new perspectives into the pathogenesis of PICALM-associated diseases.

  1. Obesity alters adipose tissue macrophage iron content and tissue iron distribution.

    Science.gov (United States)

    Orr, Jeb S; Kennedy, Arion; Anderson-Baucum, Emily K; Webb, Corey D; Fordahl, Steve C; Erikson, Keith M; Zhang, Yaofang; Etzerodt, Anders; Moestrup, Søren K; Hasty, Alyssa H

    2014-02-01

    Adipose tissue (AT) expansion is accompanied by the infiltration and accumulation of AT macrophages (ATMs), as well as a shift in ATM polarization. Several studies have implicated recruited M1 ATMs in the metabolic consequences of obesity; however, little is known regarding the role of alternatively activated resident M2 ATMs in AT homeostasis or how their function is altered in obesity. Herein, we report the discovery of a population of alternatively activated ATMs with elevated cellular iron content and an iron-recycling gene expression profile. These iron-rich ATMs are referred to as MFe(hi), and the remaining ATMs are referred to as MFe(lo). In lean mice, ~25% of the ATMs are MFe(hi); this percentage decreases in obesity owing to the recruitment of MFe(lo) macrophages. Similar to MFe(lo) cells, MFe(hi) ATMs undergo an inflammatory shift in obesity. In vivo, obesity reduces the iron content of MFe(hi) ATMs and the gene expression of iron importers as well as the iron exporter, ferroportin, suggesting an impaired ability to handle iron. In vitro, exposure of primary peritoneal macrophages to saturated fatty acids also alters iron metabolism gene expression. Finally, the impaired MFe(hi) iron handling coincides with adipocyte iron overload in obese mice. In conclusion, in obesity, iron distribution is altered both at the cellular and tissue levels, with AT playing a predominant role in this change. An increased availability of fatty acids during obesity may contribute to the observed changes in MFe(hi) ATM phenotype and their reduced capacity to handle iron.

  2. Homeostasis

    Directory of Open Access Journals (Sweden)

    Anna Negroni

    2015-01-01

    Full Text Available Intestinal epithelial cells (IECs form a physiochemical barrier that separates the intestinal lumen from the host’s internal milieu and is critical for electrolyte passage, nutrient absorption, and interaction with commensal microbiota. Moreover, IECs are strongly involved in the intestinal mucosal inflammatory response as well as in mucosal innate and adaptive immune responses. Cell death in the intestinal barrier is finely controlled, since alterations may lead to severe disorders, including inflammatory diseases. The emerging picture indicates that intestinal epithelial cell death is strictly related to the maintenance of tissue homeostasis. This review is focused on previous reports on different forms of cell death in intestinal epithelium.

  3. Obesity Promotes Alterations in Iron Recycling

    Directory of Open Access Journals (Sweden)

    Marta Citelli

    2015-01-01

    Full Text Available 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 obesity induced by a high-fat diet (HFD modifies the expression of FPN in macrophages and enterocytes, thus altering the iron bioavailability. In order to directly examine changes associated with iron metabolism in vivo, C57BL/6J mice were fed either a control or a HFD. Serum leptin levels were evaluated. The hepcidin, divalent metal transporter-1 (DMT1, FPN and ferritin genes were analyzed by real-time polymerase chain reaction. The amount of iron present in both the liver and spleen was determined by flame atomic absorption spectrometry. Ferroportin localization within reticuloendothelial macrophages was observed by immunofluorescence microscopy. Obese animals were found to exhibit increased hepcidin gene expression, while iron accumulated in the spleen and liver. They also exhibited changes in the sublocation of splenic cellular FPN and a reduction in the FPN expression in the liver and the spleen, while no changes were observed in enterocytes. Possible explanations for the increased hepcidin expression observed in HFD animals may include: increased leptin levels, the liver iron accumulation or endoplasmic reticulum (ER stress. Together, the results indicated that obesity promotes changes in iron bioavailability, since it altered the iron recycling function.

  4. The pupylation machinery is involved in iron homeostasis by targeting the iron storage protein ferritin.

    Science.gov (United States)

    Küberl, Andreas; Polen, Tino; Bott, Michael

    2016-04-26

    The balance of sufficient iron supply and avoidance of iron toxicity by iron homeostasis is a prerequisite for cellular metabolism and growth. Here we provide evidence that, in Actinobacteria, pupylation plays a crucial role in this process. Pupylation is a posttranslational modification in which the prokaryotic ubiquitin-like protein Pup is covalently attached to a lysine residue in target proteins, thus resembling ubiquitination in eukaryotes. Pupylated proteins are recognized and unfolded by a dedicated AAA+ ATPase (Mycobacterium proteasomal AAA+ ATPase; ATPase forming ring-shaped complexes). In Mycobacteria, degradation of pupylated proteins by the proteasome serves as a protection mechanism against several stress conditions. Other bacterial genera capable of pupylation such as Corynebacterium lack a proteasome, and the fate of pupylated proteins is unknown. We discovered that Corynebacterium glutamicum mutants lacking components of the pupylation machinery show a strong growth defect under iron limitation, which was caused by the absence of pupylation and unfolding of the iron storage protein ferritin. Genetic and biochemical data support a model in which the pupylation machinery is responsible for iron release from ferritin independent of degradation. PMID:27078093

  5. The Organization of Controller Motifs Leading to Robust Plant Iron Homeostasis.

    Directory of Open Access Journals (Sweden)

    Oleg Agafonov

    Full Text Available Iron is an essential element needed by all organisms for growth and development. Because iron becomes toxic at higher concentrations iron is under homeostatic control. Plants face also the problem that iron in the soil is tightly bound to oxygen and difficult to access. Plants have therefore developed special mechanisms for iron uptake and regulation. During the last years key components of plant iron regulation have been identified. How these components integrate and maintain robust iron homeostasis is presently not well understood. Here we use a computational approach to identify mechanisms for robust iron homeostasis in non-graminaceous plants. In comparison with experimental results certain control arrangements can be eliminated, among them that iron homeostasis is solely based on an iron-dependent degradation of the transporter IRT1. Recent IRT1 overexpression experiments suggested that IRT1-degradation is iron-independent. This suggestion appears to be misleading. We show that iron signaling pathways under IRT1 overexpression conditions become saturated, leading to a breakdown in iron regulation and to the observed iron-independent degradation of IRT1. A model, which complies with experimental data places the regulation of cytosolic iron at the transcript level of the transcription factor FIT. Including the experimental observation that FIT induces inhibition of IRT1 turnover we found a significant improvement in the system's response time, suggesting a functional role for the FIT-mediated inhibition of IRT1 degradation. By combining iron uptake with storage and remobilization mechanisms a model is obtained which in a concerted manner integrates iron uptake, storage and remobilization. In agreement with experiments the model does not store iron during its high-affinity uptake. As an iron biofortification approach we discuss the possibility how iron can be accumulated even during high-affinity uptake.

  6. Calcineurin signaling and membrane lipid homeostasis regulates iron mediated multidrug resistance mechanisms in Candida albicans.

    Directory of Open Access Journals (Sweden)

    Saif Hameed

    Full Text Available We previously demonstrated that iron deprivation enhances drug susceptibility of Candida albicans by increasing membrane fluidity which correlated with the lower expression of ERG11 transcript and ergosterol levels. The iron restriction dependent membrane perturbations led to an increase in passive diffusion and drug susceptibility. The mechanisms underlying iron homeostasis and multidrug resistance (MDR, however, are not yet resolved. To evaluate the potential mechanisms, we used whole genome transcriptome and electrospray ionization tandem mass spectrometry (ESI-MS/MS based lipidome analyses of iron deprived Candida cells to examine the new cellular circuitry of the MDR of this pathogen. Our transcriptome data revealed a link between calcineurin signaling and iron homeostasis. Among the several categories of iron deprivation responsive genes, the down regulation of calcineurin signaling genes including HSP90, CMP1 and CRZ1 was noteworthy. Interestingly, iron deprived Candida cells as well as iron acquisition defective mutants phenocopied molecular chaperone HSP90 and calcineurin mutants and thus were sensitive to alkaline pH, salinity and membrane perturbations. In contrast, sensitivity to above stresses did not change in iron deprived DSY2146 strain with a hyperactive allele of calcineurin. Although, iron deprivation phenocopied compromised HSP90 and calcineurin, it was independent of protein kinase C signaling cascade. Notably, the phenotypes associated with iron deprivation in genetically impaired calcineurin and HSP90 could be reversed with iron supplementation. The observed down regulation of ergosterol (ERG1, ERG2, ERG11 and ERG25 and sphingolipid biosynthesis (AUR1 and SCS7 genes followed by lipidome analysis confirmed that iron deprivation not only disrupted ergosterol biosynthesis, but it also affected sphingolipid homeostasis in Candida cells. These lipid compositional changes suggested extensive remodeling of the membranes in iron

  7. Rice-Specific Mitochondrial Iron-Regulated Gene (MIR) Plays an Important Role in Iron Homeostasis

    Institute of Scientific and Technical Information of China (English)

    Yasuhiro Ishimaru; Khurram Bashir; Masaru Fujimoto; Gynheung An; Reiko Nakanishi Itai; Nobuhiro Tsutsumi; Hiromi Nakanishi; Naoko K Nishizawa

    2009-01-01

    Mitochondria utilize iron (Fe), but the proteins involved in mitochondrial Fe regulation are not characterized in plants. We cloned and characterized a mitochondrial iron-regulated (MIR) gene in rice involved in Fe homeostasis. MIP. when expressed in tobacco BY-2 cells, was localized to the mitochondria. MIR transcripts were greatly increased in re-sponse to Fe deficiency in roots and shoot tissue. MIR is not homologous to any known protein, as homologs were not found in the rice or Arabidopsis genome databases, or in the EST database for other organisms. Growth in the MIR T-DNA knockout rice mutant (mir) was significantly impaired compared to wild-type (WT) plants when grown under Fe-deficient or-sufficient conditions. Furthermore, mir plants accumulated more than twice the amount of Fe in shoot and root tissue compared to WT plants when grown under either Fe-sufficient or-deficient conditions. Despite the high accumulation of Fe in roots and shoots, mir plants triggered the expression of Fe-deficiency-inducible genes, indicating that mir may not be able to utilize Fe for physiological functions. These results clearly suggest that MIR is a rice-specific mitochondrial protein, recently evolved, and plays a significant role in Fe homeostasis.

  8. Candida albicans specializations for iron homeostasis: from commensalism to virulence

    OpenAIRE

    Noble, Suzanne

    2013-01-01

    Candida albicans is a fungal commensal-pathogen that persistently associates with its mammalian hosts. Between the commensal and pathogenic lifestyles, this microorganism inhabits host niches that differ markedly in the levels of bioavailable iron. A number of recent studies have exposed C. albicans specializations for acquiring iron from specific host molecules in regions where iron is scarce, while also defending against iron-related toxicity in regions where iron occurs in surfeit. Togethe...

  9. PfsR is a key regulator of iron homeostasis in Synechocystis PCC 6803.

    Directory of Open Access Journals (Sweden)

    Dan Cheng

    Full Text Available Iron is an essential cofactor in numerous cellular processes. The iron deficiency in the oceans affects the primary productivity of phytoplankton including cyanobacteria. In this study, we examined the function of PfsR, a TetR family transcriptional regulator, in iron homeostasis of the cyanobacterium Synechocystis PCC 6803. Compared with the wild type, the pfsR deletion mutant displayed stronger tolerance to iron limitation and accumulated significantly more chlorophyll a, carotenoid, and phycocyanin under iron-limiting conditions. The mutant also maintained more photosystem I and photosystem II complexes than the wild type after iron deprivation. In addition, the activities of photosystem I and photosystem II were much higher in pfsR deletion mutant than in wild-type cells under iron-limiting conditions. The transcripts of pfsR were enhanced by iron limitation and inactivation of the gene affected pronouncedly expression of fut genes (encoding a ferric iron transporter, feoB (encoding a ferrous iron transporter, bfr genes (encoding bacterioferritins, ho genes (encoding heme oxygenases, isiA (encoding a chlorophyll-binding protein, and furA (encoding a ferric uptake regulator. The iron quota in pfsR deletion mutant cells was higher than in wild-type cells both before and after exposure to iron limitation. Electrophoretic mobility shift assays showed that PfsR bound to its own promoter and thereby auto-regulated its own expression. These data suggest that PfsR is a critical regulator of iron homeostasis.

  10. Liver-gut axis in the regulation of iron homeostasis

    Institute of Scientific and Technical Information of China (English)

    Deepak Darshan; Gregory J Anderson

    2007-01-01

    The human body requires about 1-2 mg of iron per day for its normal functioning, and dietary iron is the only source for this essential metal. Since humans do not possess a mechanism for the active excretion of iron,the amount of iron in the body is determined by the amount absorbed across the proximal small intestine and, consequently, intestinal iron absorption is a highly regulated process. In recent years, the liver has emerged as a central regulator of both iron absorption and iron release from other tissues. It achieves this by secreting a peptide hormone called hepcidin that acts on the small intestinal epithelium and other cells to limit iron delivery to the plasma. Hepcidin itself is regulated in response to various systemic stimuli including variations in body iron stores, the rate of erythropoiesis, inflammation and hypoxia, the same stimuli that have been known for many years to modulate iron absorption. This review will summarize recent findings on the role played by the liver and hepcidin in the regulation of body iron absorption.

  11. A multi-scale model of hepcidin promoter regulation reveals factors controlling systemic iron homeostasis.

    Directory of Open Access Journals (Sweden)

    Guillem Casanovas

    2014-01-01

    Full Text Available Systemic iron homeostasis involves a negative feedback circuit in which the expression level of the peptide hormone hepcidin depends on and controls the iron blood levels. Hepcidin expression is regulated by the BMP6/SMAD and IL6/STAT signaling cascades. Deregulation of either pathway causes iron-related diseases such as hemochromatosis or anemia of inflammation. We quantitatively analyzed how BMP6 and IL6 control hepcidin expression. Transcription factor (TF phosphorylation and reporter gene expression were measured under co-stimulation conditions, and the promoter was perturbed by mutagenesis. Using mathematical modeling, we systematically analyzed potential mechanisms of cooperative and competitive promoter regulation by the transcription factors, and experimentally validated the model predictions. Our results reveal that hepcidin cross-regulation primarily occurs by combinatorial transcription factor binding to the promoter, whereas signaling crosstalk is insignificant. We find that the presence of two BMP-responsive elements enhances the steepness of the promoter response towards the iron-sensing BMP signaling axis, which promotes iron homeostasis in vivo. IL6 co-stimulation reduces the promoter sensitivity towards the BMP signal, because the SMAD and STAT transcription factors compete for recruiting RNA polymerase to the transcription start site. This may explain why inflammatory signals disturb iron homeostasis in anemia of inflammation. Taken together, our results reveal why the iron homeostasis circuit is sensitive to perturbations implicated in disease.

  12. Heme oxygenase activity correlates with serum indices of iron homeostasis in healthy nonsmokers

    Science.gov (United States)

    Heme oxygenase (HO) catalyzes the breakdown of heme to carbon monoxide, iron, and biliverdin. While the use of genetically altered animal models in investigation has established distinct associations between HO activity and systemic iron availability, studies have not yet confirm...

  13. Involvement of the Iron Regulatory Protein from Eisenia andrei Earthworms in the Regulation of Cellular Iron Homeostasis

    OpenAIRE

    Petra Procházková; František Škanta; Radka Roubalová; Marcela Šilerová; Jiří Dvořák; Martin Bilej

    2014-01-01

    Iron homeostasis in cells is regulated by iron regulatory proteins (IRPs) that exist in different organisms. IRPs are cytosolic proteins that bind to iron-responsive elements (IREs) of the 5'- or 3'-untranslated regions (UTR) of mRNAs that encode many proteins involved in iron metabolism. In this study, we have cloned and described a new regulatory protein belonging to the family of IRPs from the earthworm Eisenia andrei (EaIRP). The earthworm IRE site in 5'-UTR of ferritin mRNA most likely f...

  14. Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice.

    Science.gov (United States)

    Viatte, Lydie; Nicolas, Gaël; Lou, Dan-Qing; Bennoun, Myriam; Lesbordes-Brion, Jeanne-Claire; Canonne-Hergaux, François; Schönig, Kai; Bujard, Hermann; Kahn, Axel; Andrews, Nancy C; Vaulont, Sophie

    2006-04-01

    We report the generation of a tetracycline-regulated (Tet ON) transgenic mouse model for acute and chronic expression of the iron regulatory peptide hepcidin in the liver. We demonstrate that short-term and long-term tetracycline-dependent activation of hepcidin in adult mice leads to hypoferremia and iron-limited erythropoiesis, respectively. This clearly establishes the key role of hepcidin in regulating the extracellular iron concentration. We previously demonstrated that, when expressed early in fetal development, constitutive transgenic hepcidin expression prevented iron accumulation in an Hfe-/- mouse model of hemochromatosis. We now explore the effect of chronic hepcidin expression in adult Hfe-/- mice that have already developed liver iron overload. We demonstrate that induction of chronic hepcidin expression in 2-month-old Hfe-/- mice alters their pattern of cellular iron accumulation, leading to increased iron in tissue macrophages and duodenal cells but less iron in hepatocytes. These hepcidin-induced changes in the pattern of cellular iron accumulation are associated with decreased expression of the iron exporter ferroportin in macrophages but no detectable alteration of ferroportin expression in the hepatocytes. We speculate that this change in iron homeostasis could offer a therapeutic advantage by protecting against damage to parenchymal cells. PMID:16339398

  15. Iron Homeostasis and Inflammatory Status in Mice Deficient for the Cystic Fibrosis Transmembrane Regulator.

    Directory of Open Access Journals (Sweden)

    Jean-Christophe Deschemin

    Full Text Available Cystic Fibrosis (CF is a frequent and lethal autosomal recessive disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR. Patients with CF suffer from chronic infections and severe inflammation, which lead to progressive pulmonary and gut diseases. Recently, an expanding body of evidence has suggested that iron homeostasis was abnormal in CF with, in particular, systemic iron deficiency and iron sequestration in the epithelium airway. The molecular mechanisms responsible for iron dysregulation and the relationship with inflammation in CF are unknown.We assessed the impact of CFTR deficiency on systemic and tissue iron homeostasis as well as inflammation in wildtype and CFTR knockout (KO mice. First, in contrast to the systemic and intestinal inflammation we observed in the CFTR KO mice, we reported the absence of lung phenotype with regards to both inflammation and iron status. Second, we showed a significant decrease of plasma ferritin levels in the KO mice, as in CF patients, likely caused by a decrease in spleen ferritin levels. However, we measured unchanged plasma iron levels in the KO mice that may be explained by increased intestinal iron absorption.These results indicate that in CF, the lung do not predominantly contributes to the systemic ferritin deficiency and we propose the spleen as the major organ responsible for hypoferritinemia in the KO mouse. These results should provide a better understanding of iron dysregulation in CF patients where treating or not iron deficiency remains a challenging question.

  16. Functional genomics of pH homeostasis in Corynebacterium glutamicum revealed novel links between pH response, oxidative stress, iron homeostasis and methionine synthesis

    Directory of Open Access Journals (Sweden)

    Persicke Marcus

    2009-12-01

    Full Text Available Abstract Background The maintenance of internal pH in bacterial cells is challenged by natural stress conditions, during host infection or in biotechnological production processes. Comprehensive transcriptomic and proteomic analyses has been conducted in several bacterial model systems, yet questions remain as to the mechanisms of pH homeostasis. Results Here we present the comprehensive analysis of pH homeostasis in C. glutamicum, a bacterium of industrial importance. At pH values between 6 and 9 effective maintenance of the internal pH at 7.5 ± 0.5 pH units was found. By DNA microarray analyses differential mRNA patterns were identified. The expression profiles were validated and extended by 1D-LC-ESI-MS/MS based quantification of soluble and membrane proteins. Regulators involved were identified and thereby participation of numerous signaling modules in pH response was found. The functional analysis revealed for the first time the occurrence of oxidative stress in C. glutamicum cells at neutral and low pH conditions accompanied by activation of the iron starvation response. Intracellular metabolite pool analysis unraveled inhibition of the TCA and other pathways at low pH. Methionine and cysteine synthesis were found to be activated via the McbR regulator, cysteine accumulation was observed and addition of cysteine was shown to be toxic under acidic conditions. Conclusions Novel limitations for C. glutamicum at non-optimal pH values were identified by a comprehensive analysis on the level of the transcriptome, proteome, and metabolome indicating a functional link between pH acclimatization, oxidative stress, iron homeostasis, and metabolic alterations. The results offer new insights into bacterial stress physiology and new starting points for bacterial strain design or pathogen defense.

  17. Simon Labbé’s work on iron and copper homeostasis

    Institute of Scientific and Technical Information of China (English)

    Simon; Labbé

    2010-01-01

    Iron and copper have a wealth of functions in biological systems,which makes them essential micronutrients for all living organisms.Defects in iron and copper homeostasis are directly responsible for diseases,and have been linked to impaired development,metabolic syndromes and fungal virulence.Consequently,it is crucial to gain a comprehensive understanding of the molecular bases of iron-and copper-dependent proteins in living systems.Simon Labbémaintains parallel programs on iron and copper homeostasis using the fission yeast Schizosaccharomyces pombe(Schiz.pombe) as a model system.The study of fission yeast transition-metal metabolism has been successful,not only in discerning the genes and pathways functioning in Schiz.pombe,but also the genes and pathways that are active in mammalian systems and for other fungi.

  18. Fenvalerate-induced Alterations in Calcium Homeostasis in Rat Ovary

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective To observe the effects of fenvalerate on calcium homeostasis in rat ovary. Methods Female SpragueDawley rats were orally given fenvalerate at daily doses of 0.00, 1.91, 9.55, and 31.80 mg/kg for four weeks. The ovary ultrastucture was observed by electron microscopy. Serum free calcium concentration was measured by atomic absorption spectrophotometry. The activities of phosphorylase a in rat ovary were evaluated by the chromatometry. The total content of calmodulin in ovary was estimated by ELISA at each stage of estrous cycle. Radioimmunoassay (RIA) was used to evaluate the level of serum progesterone. Results Histopathologically, damages of ovarian corpus luteum cells were observed. An increase in serum free calcium concentration was observed in rats treated with 31.80mg/kg fenvalerate. The activities of phosphorylase a enhanced in all treated groups, and fenvalerate increased the total content of calmodulin significantly in estrus period. Serum progesterone levels declined in fenvalerate exposed rats in diestrus. Conclusion Fenvalerate interferes with calcium homeostasis in rat ovary. Also, the inhibitory effects of fenvalerate on serum progesterone levels may be mediated partly through calcium signals.

  19. The extrahepatic role of TFR2 in iron homeostasis

    Directory of Open Access Journals (Sweden)

    Laura eSilvestri

    2014-05-01

    Full Text Available Transferrin receptor 2 (TFR2, a protein homologous to the cell iron importer transferrin receptor 1 (TFR1, is expressed in the liver and erythroid cells and is reported to bind diferric transferrin, although at lower affinity than TFR1. TFR2 gene is mutated in type 3 hemochromatosis, a disorder characterized by iron overload and inability to upregulate hepcidin in response to iron. Liver TFR2 is considered a sensor of diferric transferrin, possibly in a complex with HFE. In erythroid cells TFR2 is a partner of erythropoietin receptor (EPOR and stabilizes the receptor on the cell surface. However, Tfr2 null mice as well as TFR2 hemochromatosis patients do not show defective erythropoiesis and tolerate repeated phlebotomy. The iron deficient Tfr2-Tmprss6 double knock out mice have higher red cells count and more severe microcytosis than the liver specific Tfr2 and Tmprss6 double knock out mice. TFR2 in the bone marrow might be a sensor of iron deficiency that protects against excessive microcytosis in a way that involves EPOR, although the mechanisms remain to be worked out.

  20. Hepcidin and regulation of iron homeostasis in maintenance hemodialysis patients

    Directory of Open Access Journals (Sweden)

    Dawlat Sany

    2014-01-01

    Full Text Available Hepcidin may play a critical role in the response of patients with anemia to iron and erythropoiesis-stimulating agent therapy. To evaluate the factors affecting serum hepcidin levels and their relation to other indexes of anemia, iron metabolism and inflammation, as well as the dose of erythropoietin, we studied 80 maintenance hemodialysis (MHD patients treated with recombinant human erythropoietin and their serum hepcidin levels were specifically measured by using a competitive enzyme-linked immunosorbent assay. In linear regression analysis, ferritin was found to be a significant predictor of hepcidin levels in all the study patients. In the absence of apparent inflammation, serum hepcidin levels correlated exclusively with ferritin levels in MHD patients, and it was also an independent marker of inflammation as highly sensitive C-reactive protein.

  1. A role for amyloid precursor protein translation to restore iron homeostasis and ameliorate lead (Pb) neurotoxicity.

    Science.gov (United States)

    Rogers, Jack T; Venkataramani, Vivek; Washburn, Cecilia; Liu, Yanyan; Tummala, Vinusha; Jiang, Hong; Smith, Ann; Cahill, Catherine M

    2016-08-01

    Iron supplementation ameliorates the neurotoxicity of the environmental contaminant lead (Pb); however, the mechanism remains undefined. Iron is an essential nutrient but high levels are toxic due to the catalytic generation of destructive hydroxyl radicals. Using human neuroblastoma SH-SY5Y cells to model human neurons, we investigated the effect of Pb on proteins of iron homeostasis: the Alzheimer's amyloid precursor protein (APP), which stabilizes the iron exporter ferroportin 1; and, the heavy subunit of the iron-storage protein, ferritin (FTH). Lead (Pb(II) and Pb(IV) inhibited APP translation and raised cytosolic iron(II). Lead also increased iron regulatory protein-1 binding to the cognate 5'untranslated region-specific iron-responsive element (IRE) of APP and FTH mRNAs. Concurrent iron treatment rescued cells from Pb toxicity by specifically restoring APP synthesis, i.e. levels of the APP-related protein, APLP-2, were unchanged. Significantly, iron/IRE-independent over-expression of APP695  protected SH-SY5Y cells from Pb toxicity, demonstrating that APP plays a key role in maintaining safe levels of intracellular iron. Overall, our data support a model of neurotoxicity where Pb enhances iron regulatory protein/IRE-mediated repression of APP and FTH translation. We propose novel treatment options for Pb poisoning to include chelators and the use of small molecules to maintain APP and FTH translation. We propose the following cascade for Lead (Pb) toxicity to neurons; by targeting the interaction between Iron regulatory protein-1 and Iron-responsive elements, Pb caused translational repression of proteins that control intracellular iron homeostasis, including the Alzheimer's amyloid precursor protein (APP) that stabilizes the iron exporter ferroportin, and the ferroxidase heavy subunit of the iron-storage protein, ferritin. When unregulated, IRE-independent over-expression of APP695 protected SH-SY5Y neurons from Pb toxicity. There is a novel and key role

  2. Alterations in auxin homeostasis suppress defects in cell wall function.

    Directory of Open Access Journals (Sweden)

    Blaire J Steinwand

    Full Text Available The plant cell wall is a highly dynamic structure that changes in response to both environmental and developmental cues. It plays important roles throughout plant growth and development in determining the orientation and extent of cell expansion, providing structural support and acting as a barrier to pathogens. Despite the importance of the cell wall, the signaling pathways regulating its function are not well understood. Two partially redundant leucine-rich-repeat receptor-like kinases (LRR-RLKs, FEI1 and FEI2, regulate cell wall function in Arabidopsis thaliana roots; disruption of the FEIs results in short, swollen roots as a result of decreased cellulose synthesis. We screened for suppressors of this swollen root phenotype and identified two mutations in the putative mitochondrial pyruvate dehydrogenase E1α homolog, IAA-Alanine Resistant 4 (IAR4. Mutations in IAR4 were shown previously to disrupt auxin homeostasis and lead to reduced auxin function. We show that mutations in IAR4 suppress a subset of the fei1 fei2 phenotypes. Consistent with the hypothesis that the suppression of fei1 fei2 by iar4 is the result of reduced auxin function, disruption of the WEI8 and TAR2 genes, which decreases auxin biosynthesis, also suppresses fei1 fei2. In addition, iar4 suppresses the root swelling and accumulation of ectopic lignin phenotypes of other cell wall mutants, including procuste and cobra. Further, iar4 mutants display decreased sensitivity to the cellulose biosynthesis inhibitor isoxaben. These results establish a role for IAR4 in the regulation of cell wall function and provide evidence of crosstalk between the cell wall and auxin during cell expansion in the root.

  3. Mitochondrial ferritin in the regulation of brain iron homeostasis and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Guofen eGao

    2014-02-01

    Full Text Available Mitochondrial ferritin (FtMt is a novel iron-storage protein in mitochondria. Evidences have shown that FtMt is structurally and functionally similar to the cytosolic H-chain ferritin. It protects mitochondria from iron-induced oxidative damage presumably through sequestration of potentially harmful excess free iron. It also participates in the regulation of iron distribution between cytosol and mitochondrial contents. Unlike the ubiquitously expressed H-ferritin, FtMt is mainly expressed in testis and brain, which suggests its tissue-related roles. FtMt is involved in pathogenesis of neurodegenerative diseases, as its increased expression has been observed in Alzheimer’s disease, restless legs syndrome and Friedreich’s ataxia. Studies from our laboratory showed that in Alzheimer’s disease, FtMt overexpression attenuated the β-amyloid induced neurotoxicity, which on the other hand increased significantly when FtMt expression was knocked down. It is also found that, by maintaining mitochondrial iron homeostasis, FtMt could prevent 6-hydroxydopamine induced dopaminergic cell damage in Parkinson’s disease. These recent findings on FtMt regarding its functions in regulation of brain iron homeostasis and its protective role in pathogenesis of neurodegenerative diseases are summarized and reviewed.

  4. Variations in dietary iron alter behavior in developing rats.

    Science.gov (United States)

    Piñero, D; Jones, B; Beard, J

    2001-02-01

    Iron deficiency in children is associated with retardation in growth and cognitive development, and the effects on cognition may be irreversible, even with treatment. Excessive iron has also been associated with neurological disease, especially in reference to the increased iron content in the brains of Alzheimer's disease and Parkinson's disease patients. This study evaluated the effects of dietary iron deficiency and excess iron on physical activity in rats. The animal model used is developmentally sensitive and permits control of the timing as well as the duration of the nutritional insult. Hence, to study the effects of early, late and long-term iron deficiency or excess iron (supplementation), rats were either made iron deficient or supplemented on postnatal day (PND) 10-21, PND 21-35 and PND 10-35. Some iron-deficient rats were iron repleted between PND 21-35. Different measures of motor activity were taken at PND 14, 17, 20, 27 and 34. Iron-deficient and iron-supplemented rats showed decreased activity and stereotypic behavior; this was apparent for any onset and duration of the nutritional insult. Recovery from iron deficiency did not normalize these functional variables, showing that the deleterious effects of early iron deficiency persist despite subsequent adequate treatment. This study demonstrates that iron deficiency in early life leads to irreversible behavioral changes. The biological bases for these behavioral alterations are not readily apparent, because iron therapy rapidly reverses the iron losses in all brain regions.

  5. Matriptase-2 is essential for hepcidin repression during fetal life and postnatal development in mice to maintain iron homeostasis.

    Science.gov (United States)

    Willemetz, Alexandra; Lenoir, Anne; Deschemin, Jean-Christophe; Lopez-Otin, Carlos; Ramsay, Andrew J; Vaulont, Sophie; Nicolas, Gaël

    2014-07-17

    Iron is an essential element required for development and survival of all living organisms. In fetuses, maternofetal iron transfer across the placenta is essential for growth and development. In neonates, efficient intestinal iron absorption is required to scavenge as much iron as possible from the low-iron-content milk. During these periods, efficient iron mobilization is ensured by the downregulation of the iron regulatory hormone hepcidin by as-yet uncharacterized molecular mechanisms. Here we demonstrate that the recently described hepcidin repressor-the serine protease matriptase-2 (encoded by Tmprss6)-is responsible for this repression throughout development, with its deficiency leading to increased hepcidin levels triggering iron deficiency and anemia starting in utero. This result might have implications for a better understanding of iron homeostasis during early development in iron-refractory iron deficiency anemia patients, who present with microcytic anemia caused by hyperhepcidinemia, and of questions about the role of matriptase-2 in human neonates. PMID:24904115

  6. Involvement of the iron regulatory protein from Eisenia andrei earthworms in the regulation of cellular iron homeostasis.

    Science.gov (United States)

    Procházková, Petra; Škanta, František; Roubalová, Radka; Šilerová, Marcela; Dvořák, Jiří; Bilej, Martin

    2014-01-01

    Iron homeostasis in cells is regulated by iron regulatory proteins (IRPs) that exist in different organisms. IRPs are cytosolic proteins that bind to iron-responsive elements (IREs) of the 5'- or 3'-untranslated regions (UTR) of mRNAs that encode many proteins involved in iron metabolism. In this study, we have cloned and described a new regulatory protein belonging to the family of IRPs from the earthworm Eisenia andrei (EaIRP). The earthworm IRE site in 5'-UTR of ferritin mRNA most likely folds into a secondary structure that differs from the conventional IRE structures of ferritin due to the absence of a typically unpaired cytosine that participates in protein binding. Prepared recombinant EaIRP and proteins from mammalian liver extracts are able to bind both mammalian and Eisenia IRE structures of ferritin mRNA, although the affinity of the rEaIRP/Eisenia IRE structure is rather low. This result suggests the possible contribution of a conventional IRE structure. When IRP is supplemented with a Fe-S cluster, it can function as a cytosolic aconitase. Cellular cytosolic and mitochondrial fractions, as well as recombinant EaIRP, exhibit aconitase activity that can be abolished by the action of oxygen radicals. The highest expression of EaIRP was detected in parts of the digestive tract. We can assume that earthworms may possess an IRE/IRP regulatory network as a potential mechanism for maintaining cellular iron homeostasis, although the aconitase function of EaIRP is most likely more relevant. PMID:25279857

  7. Involvement of the iron regulatory protein from Eisenia andrei earthworms in the regulation of cellular iron homeostasis.

    Directory of Open Access Journals (Sweden)

    Petra Procházková

    Full Text Available Iron homeostasis in cells is regulated by iron regulatory proteins (IRPs that exist in different organisms. IRPs are cytosolic proteins that bind to iron-responsive elements (IREs of the 5'- or 3'-untranslated regions (UTR of mRNAs that encode many proteins involved in iron metabolism. In this study, we have cloned and described a new regulatory protein belonging to the family of IRPs from the earthworm Eisenia andrei (EaIRP. The earthworm IRE site in 5'-UTR of ferritin mRNA most likely folds into a secondary structure that differs from the conventional IRE structures of ferritin due to the absence of a typically unpaired cytosine that participates in protein binding. Prepared recombinant EaIRP and proteins from mammalian liver extracts are able to bind both mammalian and Eisenia IRE structures of ferritin mRNA, although the affinity of the rEaIRP/Eisenia IRE structure is rather low. This result suggests the possible contribution of a conventional IRE structure. When IRP is supplemented with a Fe-S cluster, it can function as a cytosolic aconitase. Cellular cytosolic and mitochondrial fractions, as well as recombinant EaIRP, exhibit aconitase activity that can be abolished by the action of oxygen radicals. The highest expression of EaIRP was detected in parts of the digestive tract. We can assume that earthworms may possess an IRE/IRP regulatory network as a potential mechanism for maintaining cellular iron homeostasis, although the aconitase function of EaIRP is most likely more relevant.

  8. Pharmacodynamic Model of Hepcidin Regulation of Iron Homeostasis in Cynomolgus Monkeys.

    Science.gov (United States)

    Krzyzanski, Wojciech; Xiao, Jim J; Sasu, Barbra; Hinkle, Beth; Perez-Ruixo, Juan Jose

    2016-05-01

    Hepcidin (H25) is a hormone peptide synthesized by the liver that binds to ferroportin and blocks iron export. In this study, H25 was inhibited by administration of single and multiple doses of an anti-H25 monoclonal antibody Ab 12B9m in cynomolgus monkeys. The objective of this analysis was to develop a pharmacodynamic model describing the role of H25 in regulating iron homeostasis and the impact of hepcidin inhibition by Ab 12B9m. Total serum H25 and Ab 12B9m were determined in each animal. Corresponding measurements of serum iron and hemoglobin (Hb) were obtained. The PD model consisted of iron pools in serum (FeS), reticuloendothelial macrophages (FeM), hemoglobin (FeHb), and liver (FeL). The iron was assumed to be transported between the FeS, FeHb, and FeM unidirectionally at rates k S, k Hb, and k M. H25 serum concentrations were described by the previously developed PK model with the parameters fixed at their estimates. The serum iron and Hb data were fitted simultaneously. The corresponding estimates of the rate constants were k S/Fe0 = 0.113 h(-1), k M = 0.00191 h(-1), and k Hb = 0.00817 h(-1). The model-based IC50 value for the H25 inhibitory effect on ferroportin activity was 0.398 nM. The PD model predicted a negligible effect of Ab 12B9m on Hb levels for the tested doses. The presented PD model adequately described the serum iron time courses following single and multiple doses of Ab 12B9m. Ab 12B9m-induced inhibition of H25 resulted in a temporal increase in serum and liver iron and a decrease in the iron stored in reticuloendothelial macrophages. PMID:26917226

  9. FIT interacts with AtbHLH38 and AtbHLH39 in regulating iron uptake gene expression for iron homeostasis in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    Youxi Yuan; Huilan Wu; Ning Wang; Jie Li; Weina Zhao; Juan Du; Daowen Wang; Hong-Qing Ling

    2008-01-01

    Iron is an essential element for plant growth and development. Iron homeostasis in plants is tightly regulated at both transcriptional and posttranscriptional level. Several bHLH transcription factors involved in iron homeostasis have been identified recently. However, their regulatory mechanisms remain unknown. In this work, we demonstrate that the transcription factor FIT interacted with AtbHLH38 and AtbHLH39 and directly conferred the expression regulation of iron uptake genes for iron homeostasis in Arabidopsis. Yeast two-hybrid analysis and transient expression in Arabidopsis protoplasts showed that AtbH LH38 or AtbHLH39 interacted with FIT, a central transcription factor involved in iron homeostasis in Arabidopsis. Expression of FIT/AtbHLH38 or FIT/AtbHLH39 in yeast cells activated GUS expression driven by ferric chelate reductase (FRO2) and ferrous transporter (IRT1) promoters. Overexpression of FIT with either AtbHLH38 or AtbHLH39 in plants converted the expression of the iron uptake genes FRO2 and IRT1 from induced to constitutive. Further analysis revealed that FR02 and IRT1 were not regulated at the posttranscriptional level in these plants because IRT1 protein accumulation and high ferric chelate reductase activity were detected in the overexpression plants under both iron deficiency and iron sufficiency. The double overexpression plants accumulated more iron in their shoots than wild type or the plants overexpressing either AtbHLH38,AtbHLH39 or FIT. Our data support that ferric-chelate reductase FRO2 and ferrous-transporter IRT1 are the targets of the three transcription factors and the transcription of FRO2 and IRT1 is directly regulated by a complex of FIT/AtbHLH38 or FIT/AtbHLH39.

  10. Quantitative Susceptibility Mapping Indicates a Disturbed Brain Iron Homeostasis in Neuromyelitis Optica – A Pilot Study

    Science.gov (United States)

    Granado, Vanessa; Rueda, Fernanda; Deistung, Andreas; Reichenbach, Juergen R.; Tukamoto, Gustavo; Gasparetto, Emerson Leandro; Schweser, Ferdinand

    2016-01-01

    Dysregulation of brain iron homeostasis is a hallmark of many neurodegenerative diseases and can be associated with oxidative stress. The objective of this study was to investigate brain iron in patients with Neuromyelitis Optica (NMO) using quantitative susceptibility mapping (QSM), a quantitative iron-sensitive MRI technique. 12 clinically confirmed NMO patients (6 female and 6 male; age 35.4y±14.2y) and 12 age- and sex-matched healthy controls (7 female and 5 male; age 33.9±11.3y) underwent MRI of the brain at 3 Tesla. Quantitative maps of the effective transverse relaxation rate (R2*) and magnetic susceptibility were calculated and a blinded ROI-based group comparison analysis was performed. Normality of the data and differences between patients and controls were tested by Kolmogorov-Smirnov and t-test, respectively. Correlation with age was studied using Spearman’s rank correlation and an ANCOVA-like analysis. Magnetic susceptibility values were decreased in the red nucleus (p0.95; between -15 and -22 ppb depending on reference region) with a trend toward increasing differences with age. R2* revealed significantly decreased relaxation in the optic radiations of five of the 12 patients (p<0.0001; -3.136±0.567 s-1). Decreased relaxation in the optic radiation is indicative for demyelination, which is in line with previous findings. Decreased magnetic susceptibility in the red nucleus is indicative for a lower brain iron concentration, a chemical redistribution of iron into less magnetic forms, or both. Further investigations are necessary to elucidate the pathological cause or consequence of this finding. PMID:27171423

  11. Comparative analysis of iron homeostasis in sub-Saharan African children with sickle cell disease and their unaffected siblings

    Directory of Open Access Journals (Sweden)

    Selma eGomez

    2016-02-01

    Full Text Available Iron is an essential trace element subject to tight regulation to ensure adequate running of biological processes. In sub-Saharan Africa where hemoglobinopathies are common, iron homeostasis is likely to be impaired by these conditions. Here we assessed and compared key serum proteins associated with iron metabolism between sub-Saharan African children with sickle cell disease (SCD and their unaffected siblings. Complete blood counts and serum concentrations of four key proteins involved in iron regulation (ferritin, transferrin, sTfR and hepcidin were measured for 73 children with SCD and 68 healthy siblings in Benin, West Africa. We found significant differences in concentration of transferrin, sTfR and ferritin between the two groups. Hepcidin concentrations were found at unusually high concentrations but did not differ among the two groups. We found a significant negative correlation between hepcidin levels and both MCH and MCV in the SCD group and report that sTfR concentrations show a correlation with MCV and MHC in opposite directions in the two groups. These results highlight the unusually high levels of hepcidin in the Beninese population and the patterns of differential iron homeostasis taking place under sickle cell disease status. These results lay the foundation for a systematic evaluation of the underlying mechanisms deregulating iron homeostasis in populations with SCD or high prevalence of iron deficiency.

  12. Altered energy homeostasis and resistance to diet-induced obesity in KRAP-deficient mice.

    Directory of Open Access Journals (Sweden)

    Takahiro Fujimoto

    Full Text Available Obesity and related metabolic disorders have become leading causes of adult morbidity and mortality. KRAP (Ki-ras-induced actin-interacting protein is a cytoskeleton-associated protein and a ubiquitous protein among tissues, originally identified as a cancer-related molecule, however, its physiological roles remain unknown. Here we demonstrate that KRAP-deficient (KRAP(-/- mice show enhanced metabolic rate, decreased adiposity, improved glucose tolerance, hypoinsulinemia and hypoleptinemia. KRAP(-/- mice are also protected against high-fat diet-induced obesity and insulin resistance despite of hyperphagia. Notably, glucose uptake in the brown adipose tissue (BAT in KRAP(-/- mice is enhanced in an insulin-independent manner, suggesting that BAT is involved in altered energy homeostasis in KRAP(-/- mice, although UCP (Uncoupling protein expressions are not altered. Of interest is the down-regulation of fatty acid metabolism-related molecules, including acetyl-CoA carboxylase (ACC-1, ACC-2 and fatty acid synthase in the liver of KRAP(-/- mice, which could in part account for the metabolic phenotype in KRAP(-/- mice. Thus, KRAP is a novel regulator in whole-body energy homeostasis and may be a therapeutic target in obesity and related diseases.

  13. Prominent pancreatic endocrinopathy and altered control of food intake disrupt energy homeostasis in prion diseases

    Science.gov (United States)

    Bailey, J.D.; Berardinelli, J.G.; Rocke, T.E.; Bessen, R.A.

    2008-01-01

    Prion diseases are fatal neurodegenerative diseases that can induce endocrinopathies. The basis of altered endocrine function in prion diseases is not well understood, and the purpose of this study was to investigate the spatiotemporal relationship between energy homeostasis and prion infection in hamsters inoculated with either the 139H strain of scrapie agent, which induces preclinical weight gain, or the HY strain of transmissible mink encephalopathy (TME), which induces clinical weight loss. Temporal changes in body weight, feed, and water intake were measured as well as both non-fasted and fasted concentrations of serum glucose, insulin, glucagon, ??-ketones, and leptin. In 139H scrapie-infected hamsters, polydipsia, hyperphagia, non-fasted hyperinsulinemia with hyperglycemia, and fasted hyperleptinemia were found at preclinical stages and are consistent with an anabolic syndrome that has similarities to type II diabetes mellitus and/or metabolic syndrome X. In HY TME-infected hamsters, hypodipsia, hypersecretion of glucagon (in both non-fasted and fasted states), increased fasted ??-ketones, fasted hypoglycemia, and suppressed non-fasted leptin concentrations were found while feed intake was normal. These findings suggest a severe catabolic syndrome in HY TME infection mediated by chronic increases in glucagon secretion. In both models, alterations of pancreatic endocrine function were not associated with PrPSc deposition in the pancreas. The results indicate that prominent endocrinopathy underlies alterations in body weight, pancreatic endocrine function, and intake of food. The prion-induced alterations of energy homeostasis in 139H scrapie- or HY TME-infected hamsters could occur within areas of the hypothalamus that control food satiety and/or within autonomic centers that provide neural outflow to the pancreas. ?? 2008 Society for Endocrinology.

  14. Partial restoration of mutant enzyme homeostasis in three distinct lysosomal storage disease cell lines by altering calcium homeostasis.

    Directory of Open Access Journals (Sweden)

    Ting-Wei Mu

    2008-02-01

    Full Text Available A lysosomal storage disease (LSD results from deficient lysosomal enzyme activity, thus the substrate of the mutant enzyme accumulates in the lysosome, leading to pathology. In many but not all LSDs, the clinically most important mutations compromise the cellular folding of the enzyme, subjecting it to endoplasmic reticulum-associated degradation instead of proper folding and lysosomal trafficking. A small molecule that restores partial mutant enzyme folding, trafficking, and activity would be highly desirable, particularly if one molecule could ameliorate multiple distinct LSDs by virtue of its mechanism of action. Inhibition of L-type Ca2+ channels, using either diltiazem or verapamil-both US Food and Drug Administration-approved hypertension drugs-partially restores N370S and L444P glucocerebrosidase homeostasis in Gaucher patient-derived fibroblasts; the latter mutation is associated with refractory neuropathic disease. Diltiazem structure-activity studies suggest that it is its Ca2+ channel blocker activity that enhances the capacity of the endoplasmic reticulum to fold misfolding-prone proteins, likely by modest up-regulation of a subset of molecular chaperones, including BiP and Hsp40. Importantly, diltiazem and verapamil also partially restore mutant enzyme homeostasis in two other distinct LSDs involving enzymes essential for glycoprotein and heparan sulfate degradation, namely alpha-mannosidosis and type IIIA mucopolysaccharidosis, respectively. Manipulation of calcium homeostasis may represent a general strategy to restore protein homeostasis in multiple LSDs. However, further efforts are required to demonstrate clinical utility and safety.

  15. Iron homeostasis and H63D mutations in alcoholics with and without liver disease

    Institute of Scientific and Technical Information of China (English)

    Mariana Verdelho Machado; Paula Ravasco; Alexandra Martins; Maria Ermelinda Camilo; Helena Cortez-Pinto; Maria Rosario Almeida

    2009-01-01

    AIM: To evaluate the prevalence of HFE gene mutation and indices of disturbed iron homeostasis in alcoholics with and without liver disease. METHODS: One hundred and fifty-three heavy drinkers (defined as alcohol consumption > 80 g/d for at least 5 years) were included in the study. These comprised 78 patients with liver disease [liver disease alcoholics (LDA)] in whom the presence of liver disease was confirmed by liver biopsy or clinical evidence of hepatic decompensation, and 75 subjects with no evidence of liver disease, determined by normal liver tests on two occasions [non-liver disease alcoholics (NLDA)], were consecutively enrolled. Serum markers of iron status and HFE C282Y and H63D mutations were determined. HFE genotyping was compared with data obtained in healthy blood donors from the same geographical area. RESULTS: Gender ratio was similar in both study groups. LDA patients were older than NLDA patients third and one fifth of the study population had serum transferrin saturation (TS) greater than 45% and 60% respectively. Serum iron levels were similar in both groups. However, LDA patients had higher TS for having liver disease with TS greater than 45% was 2.20 (95% confidence interval (CI): 1.37-3.54). There was no difference in C282Y allelic frequency between the two groups. However, H63D was more frequent in LDA patients (0.25 vs 0.16, P = 0.03). LDA patients had a greater probability of carrying at least one HFE mutation than NLDA patients (49.5% vs 31.6%, P = 0.02). The odds ratio for LDA in patients with H63D mutation was 1.57 (95% CI: 1.02-2.40).CONCLUSION: The present study confirms the presence of iron overload in alcoholics, which was more severe in the subset of subjects with liver disease,in parallel with an increased frequency of H63D HFE mutation.

  16. Alteration of brain insulin and leptin signaling promotes energy homeostasis impairment and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Taouis Mohammed

    2011-09-01

    Full Text Available The central nervous system (CNS controls vital functions, by efficiently coordinating peripheral and central cascades of signals and networks in a coordinated manner. Historically, the brain was considered to be an insulin-insensitive tissue. But, new findings demonstrating that insulin is present in different regions of themammalian brain, in particular the hypothalamus and the hippocampus. Insulin acts through specific receptors and dialogues with numerous peptides, neurotransmitters and adipokines such as leptin. The cross-talk between leptin and insulin signaling pathways at the hypothalamic level is clearly involved in the control of energy homeostasis. Both hormones are anorexigenic through their action on hypothalamic arcuate nucleus by inducing the expression of anorexigenic neuropetides such as POMC (pro-opiomelanocortin, the precursor of aMSH and reducing the expression of orexigenic neuropeptide such as NPY (Neuropeptide Y. Central defect of insulin and leptin signaling predispose to obesity (leptin-resistant state and type-2 diabetes (insulin resistant state. Obesity and type-2 diabetes are associated to deep alterations in energy homeostasis control but also to other alterations of CNS functions as the predisposition to neurodegenerative diseases such as Alzheimer’s disease (AD. AD is a neurodegenerative disorder characterized by distinct hallmarks within the brain. Postmortem observation of AD brains showed the presence of parenchymal plaques due to the accumulation of the amyloid beta (AB peptide and neurofibrillary tangles. These accumulations result from the hyperphosphorylation of tau (a mictrotubule-interacting protein. Both insulin and leptin have been described to modulate tau phosphorylation and therefore in leptin and insulin resistant states may contribute to AD. The concentrations of leptin and insulin cerebrospinal fluid are decreased type2 diabetes and obese patients. In addition, the concentration of insulin in the

  17. Alterations in the homeostasis of phospholipids and cholesterol by antitumor alkylphospholipids

    Directory of Open Access Journals (Sweden)

    Segovia Josefa L

    2010-03-01

    biosynthesis as well as the receptor-mediated uptake of cholesterol. Thus, membrane-targeted alkylphospholipids exhibit a common mechanism of action through disruption of cholesterol homeostasis. The accumulation of cholesterol within the cell and the reduction in phosphatidylcholine and sphingomyelin biosyntheses certainly alter the ratio of choline-bearing phospholipids to cholesterol, which is critical for the integrity and functionality of specific membrane microdomains such as lipid rafts. Alkylphospholipid-induced alterations in lipid homeostasis with probable disturbance of the native membrane structure could well affect signaling processes vital to cell survival and growth.

  18. Mitochondria influence CDR1 efflux pump activity, Hog1-mediated oxidative stress pathway, iron homeostasis, and ergosterol levels in Candida albicans.

    Science.gov (United States)

    Thomas, Edwina; Roman, Elvira; Claypool, Steven; Manzoor, Nikhat; Pla, Jesús; Panwar, Sneh Lata

    2013-11-01

    Mitochondrial dysfunction in Candida albicans is known to be associated with drug susceptibility, cell wall integrity, phospholipid homeostasis, and virulence. In this study, we deleted CaFZO1, a key component required during biogenesis of functional mitochondria. Cells with FZO1 deleted displayed fragmented mitochondria, mitochondrial genome loss, and reduced mitochondrial membrane potential and were rendered sensitive to azoles and peroxide. In order to understand the cellular response to dysfunctional mitochondria, genome-wide expression profiling of fzo1Δ/Δ cells was performed. Our results show that the increased susceptibility to azoles was likely due to reduced efflux activity of CDR efflux pumps, caused by the missorting of Cdr1p into the vacuole. In addition, fzo1Δ/Δ cells showed upregulation of genes involved in iron assimilation, in iron-sufficient conditions, characteristic of iron-starved cells. One of the consequent effects was downregulation of genes of the ergosterol biosynthesis pathway with a commensurate decrease in cellular ergosterol levels. We therefore connect deregulated iron metabolism to ergosterol biosynthesis pathway in response to dysfunctional mitochondria. Impaired activation of the Hog1 pathway in the mutant was the basis for increased susceptibility to peroxide and increase in reactive oxygen species, indicating the importance of functional mitochondria in controlling Hog1-mediated oxidative stress response. Mitochondrial phospholipid levels were also altered as indicated by an increase in phosphatidylserine and phosphatidylethanolamine and decrease in phosphatidylcholine in fzo1Δ/Δ cells. Collectively, these findings reinforce the connection between functional mitochondria and azole tolerance, oxidant-mediated stress, and iron homeostasis in C. albicans.

  19. ALTERATIONS OF FE HOMEOSTASIS IN RAT CARDIOVASCULAR DISEASE MODELS AND ITS CONTRIBUTION TO CARDIOPULMONARY TOXICITY

    Science.gov (United States)

    Introduction: Fe homeostasis can be disrupted in human cardiovascular diseases (CVD). We addressed how dysregulation of Fe homeostasis affected the pulmonary inflammation/oxidative stress response and disease progression after exposure to Libby amphibole (LA), an asbestifonn mine...

  20. Hiperpigmentación cutánea y homeostasis del hierro: rol de la hepcidina Cutaneous hyperpigmentation and homeostasis of iron: role of the hepcidin

    Directory of Open Access Journals (Sweden)

    C. Wolf

    2007-06-01

    Full Text Available La hiperpigmentación cutánea por melanina en zonas expuestas al sol puede estar asociada a un desequilibrio en la homeostasis del hierro. La hepcidina es un péptido responsable de la regulación negativa de la absorción del hierro en el intestino delgado y de su liberación por los macrófagos. Posee capacidad antimicrobiana. Es sintetizada en el hígado, secretada al torrente circulatorio y excretada por la orina. La sobreexpresión causa anemia y su déficit, sobrecarga de hierro (acumulación en diferentes órganos y hemocromatosis hereditaria. Los antagonistas de la hepcidina podrían utilizarse en el tratamiento de la anemia resistente a eritropoyetina, asociada a procesos crónicos. Por su parte, los agonistas o sustancias que estimulen la producción de hepcidina, podrían constituir un tratamiento en enfermedades con sobrecarga de hierro (siderosis y por consiguiente, corregir la hiperpigmentación asociada.The cutaneous hyperpigmentation by melanin in zones of the skin exposed to the sun can be associated to an imbalance in the homeostasis of the iron. The hepcidin is a peptide responsible for the negative regulation of the absorption of the iron in the small intestine and of its liberation by the macrophages. It has, in addition, antimicrobial capacity. It is synthesized in the liver, secreted to the circulatory torrent and excreted by the urine. Its overexpression causes anemia and its deficit iron overload (accumulation in different organs and hereditary hemochromatosis, The antagonists of the hepcidin, could be used in the treatment of anemia resistant to erythropoyetin associated to chronic processes. On the other hand, the agonists or substances that stimulate the hepcidin production, could constitute a treatment in diseases with overload of iron (siderosis and therefore, to correct the associate.hyperpigmentation.

  1. Insulin/IGF-1 and hypoxia signaling act in concert to regulate iron homeostasis in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Daniel Ackerman

    Full Text Available Iron plays an essential role in many biological processes, but also catalyzes the formation of reactive oxygen species (ROS, which can cause molecular damage. Iron homeostasis is therefore a critical determinant of fitness. In Caenorhabditis elegans, insulin/IGF-1 signaling (IIS promotes growth and reproduction but limits stress resistance and lifespan through inactivation of the DAF-16/FoxO transcription factor (TF. We report that long-lived daf-2 insulin/IGF-1 receptor mutants show a daf-16-dependent increase in expression of ftn-1, which encodes the iron storage protein H-ferritin. To better understand the regulation of iron homeostasis, we performed a TF-limited genetic screen for factors influencing ftn-1 gene expression. The screen identified the heat-shock TF hsf-1, the MAD bHLH TF mdl-1, and the putative histone acetyl transferase ada-2 as activators of ftn-1 expression. It also revealed that the HIFα homolog hif-1 and its binding partner aha-1 (HIFβ are potent repressors of ftn-1 expression. ftn-1 expression is induced by exposure to iron, and we found that hif-1 was required for this induction. In addition, we found that the prolyl hydroxylase EGL-9, which represses HIF-1 via the von Hippel-Lindau tumor suppressor VHL-1, can also act antagonistically to VHL-1 in regulating ftn-1. This suggests a novel mechanism for HIF target gene regulation by these evolutionarily conserved and clinically important hydroxylases. Our findings imply that the IIS and HIF pathways act together to regulate iron homeostasis in C. elegans. We suggest that IIS/DAF-16 regulation of ftn-1 modulates a trade-off between growth and stress resistance, as elevated iron availability supports growth but also increases ROS production.

  2. The Loss of Myocardial Benefit following Ischemic Preconditioning Is Associated with Dysregulation of Iron Homeostasis in Diet-Induced Diabetes.

    Science.gov (United States)

    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

  3. Arabidopsis HY1 Confers Cadmium Toleranceby Decreasing Nitric Oxide Production andImproving Iron Homeostasis

    Institute of Scientific and Technical Information of China (English)

    2014-01-01

    Up-regulation of the gene that encodes intracellular heme oxygenase 1 (HO1) benefits plants under cad-mium (Cd2+) stress; however, the molecular mechanisms remain unclear. Here, we elucidate the role of Arabidopsis HY1(AtHO1) in Cd2+ tolerance by using genetic and molecular approaches. Analysis of two HY1 null mutants, three HY1 over-expression lines, HO double or triple mutants, as well as phyA and phyB mutants revealed the specific hypersensitivityof by1 to Cd2+ stress. Supplementation with two enzymatic by-products of HY1, carbon monoxide (CO) and iron (Fe,especially), rescued the Cd2+-induced inhibition of primary root (PR) elongation in hy1-100. The mutation of HY1, whichexhibited lower glutathione content than Col-0 in root tissues, was able to induce nitric oxide (NO) overproduction,Cd2+ accumulation, and severe Fe deficiency in root tissues. However, the contrasting responses appeared in 35S:HY1-4.Additionally, reduced levels of Ferric Reduction Oxidase 2 (FRO2) and Iron-Regulated Transporter 1 (IRT1) transcripts,and increased levels of Heavy Metal ATPase 2/4 (HMA2/4) transcripts bolster the notion that HY1 up-regulation amelio-rates Fe deficiency, and might increase Cd2+ exclusion. Taken together, these results showed that HY1 plays a commonlink in Cd2+ tolerance by decreasing NO production and improving Fe homeostasis in Arabidopsis root tissues.

  4. Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia.

    Directory of Open Access Journals (Sweden)

    Tolunay Beker Aydemir

    altered in the Zip14(-/- mice and their phenotype shows defects in glucose homeostasis.

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

    Science.gov (United States)

    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

  6. Triphenyltin alters lipid homeostasis in females of the ramshorn snail Marisa cornuarietis

    Energy Technology Data Exchange (ETDEWEB)

    Lyssimachou, Angeliki [Environmental Chemistry Department, IIQAB-CSIC, Jordi Girona 18, 08034 Barcelona (Spain); Navarro, Juan Carlos [Institute of Aquaculture of Torre de la Sal, CSIC, 12595 Ribera de Cabanes, Castellon (Spain); Bachmann, Jean [Department of Ecology and Evolution-Ecotoxicology, Johann Wolfgang Goethe-University Frankfurt, D-60054 Frankfurt am Main (Germany); Porte, Cinta, E-mail: cinta.porte@cid.csic.e [Environmental Chemistry Department, IIQAB-CSIC, Jordi Girona 18, 08034 Barcelona (Spain)

    2009-05-15

    Molluscs are sensitive species to the toxic effects of organotin compounds, particularly to masculinisation. Both tributyltin (TBT) and triphenyltin (TPT) have been recently shown to bind to mollusc retinoid X receptor (RXR). If RXR is involved in lipid homeostasis, exposure to TPT would have an immediate effect on endogenous lipids. To test this hypothesis, the ramshorn snail Marisa cornuarietis was exposed to environmentally relevant concentrations of TPT (30, 125, 500 ng/L as Sn) in a semi-static water regime for 7 days. Percentage of lipids and total fatty acid content decreased significantly in TPT-exposed females while the activity of peroxisomal acyl-CoA oxidase, involved in fatty acid catabolism, increased. In addition, fatty acid profiles (carbon chain length and unsaturation degree) were significantly altered in exposed females but not in males. This work highlights the ability of TPT to disrupt lipid metabolism in M. cornuarietis at environmentally realistic concentrations and the higher susceptibility of females in comparison to males. - Short-term exposure to the fungicide TPT disrupts lipid metabolism in M. cornuarietis at environmentally realistic concentrations.

  7. Triphenyltin alters lipid homeostasis in females of the ramshorn snail Marisa cornuarietis.

    Science.gov (United States)

    Lyssimachou, Angeliki; Navarro, Juan Carlos; Bachmann, Jean; Porte, Cinta

    2009-05-01

    Molluscs are sensitive species to the toxic effects of organotin compounds, particularly to masculinisation. Both tributyltin (TBT) and triphenyltin (TPT) have been recently shown to bind to mollusc retinoid X receptor (RXR). If RXR is involved in lipid homeostasis, exposure to TPT would have an immediate effect on endogenous lipids. To test this hypothesis, the ramshorn snail Marisa cornuarietis was exposed to environmentally relevant concentrations of TPT (30, 125, 500 ng/L as Sn) in a semi-static water regime for 7 days. Percentage of lipids and total fatty acid content decreased significantly in TPT-exposed females while the activity of peroxisomal acyl-CoA oxidase, involved in fatty acid catabolism, increased. In addition, fatty acid profiles (carbon chain length and unsaturation degree) were significantly altered in exposed females but not in males. This work highlights the ability of TPT to disrupt lipid metabolism in M. cornuarietis at environmentally realistic concentrations and the higher susceptibility of females in comparison to males.

  8. Transgenic poplar expressing the pine GS1a show alterations in nitrogen homeostasis during drought.

    Science.gov (United States)

    Molina-Rueda, Juan Jesús; Kirby, Edward G

    2015-09-01

    Transgenic hybrid poplars engineered to express ectopically the heterologous pine cytosolic GS1a display a number of significant pleiotropic phenotypes including enhanced growth, enhanced nitrogen use efficiency, and resistance to drought stress. The present study was undertaken in order to assess mechanisms whereby ectopic expression of pine GS1a in transgenic poplars results in enhanced agronomic phenotypes. Microarray analysis using the Agilent Populus whole genome array has allowed identification of genes differentially expressed between wild type (WT) and GS transgenics in four tissues (sink leaves, source leaves, stems, and roots) under three growth conditions (well-watered, drought, and recovery). Analysis revealed that differentially expressed genes in functional categories related to nitrogen metabolism show a trend of significant down-regulation in GS poplars compared to the WT, including genes encoding nitrate and nitrite reductases. The down-regulation of these genes was verified using qPCR, and downstream effects were further tested using NR activity assays. Results suggest that higher glutamine levels in GS transgenics regulate nitrate uptake and reduction. Transcript levels of nitrogen-related genes in leaves, including GS/GOGAT cycle enzymes, aspartate aminotransferase, GABA shunt enzymes, photorespiration enzymes, asparagine synthetase, phenylalanine ammonia lyase, isocitrate dehydrogenase, and PII, were also assessed using qPCR revealing significant differences between GS poplars and the WT. Moreover, metabolites related to these differentially expressed genes showed alterations in levels, including higher levels of GABA, hydroxyproline, and putrescine in the GS transgenic. These alterations in nitrogen homeostasis offer insights into mechanisms accounting for drought tolerance observed in GS poplars. PMID:26113157

  9. Trypanosoma cruzi disrupts thymic homeostasis by altering intrathymic and systemic stress-related endocrine circuitries.

    Directory of Open Access Journals (Sweden)

    Ailin Lepletier

    2013-11-01

    Full Text Available We have previously shown that experimental infection caused by Trypanosoma cruzi is associated with changes in the hypothalamus-pituitary-adrenal axis. Increased glucocorticoid (GC levels are believed to be protective against the effects of acute stress during infection but result in depletion of CD4(+CD8(+ thymocytes by apoptosis, driving to thymic atrophy. However, very few data are available concerning prolactin (PRL, another stress-related hormone, which seems to be decreased during T. cruzi infection. Considering the immunomodulatory role of PRL upon the effects caused by GC, we investigated if intrathymic cross-talk between GC and PRL receptors (GR and PRLR, respectively might influence T. cruzi-induced thymic atrophy. Using an acute experimental model, we observed changes in GR/PRLR cross-activation related with the survival of CD4(+CD8(+ thymocytes during infection. These alterations were closely related with systemic changes, characterized by a stress hormone imbalance, with progressive GC augmentation simultaneously to PRL reduction. The intrathymic hormone circuitry exhibited an inverse modulation that seemed to counteract the GC-related systemic deleterious effects. During infection, adrenalectomy protected the thymus from the increase in apoptosis ratio without changing PRL levels, whereas an additional inhibition of circulating PRL accelerated the thymic atrophy and led to an increase in corticosterone systemic levels. These results demonstrate that the PRL impairment during infection is not caused by the increase of corticosterone levels, but the opposite seems to occur. Accordingly, metoclopramide (MET-induced enhancement of PRL secretion protected thymic atrophy in acutely infected animals as well as the abnormal export of immature and potentially autoreactive CD4(+CD8(+ thymocytes to the periphery. In conclusion, our findings clearly show that Trypanosoma cruzi subverts mouse thymus homeostasis by altering intrathymic and

  10. Abdominal Fat and Sarcopenia in Women Significantly Alter Osteoblasts Homeostasis In Vitro by a WNT/β-Catenin Dependent Mechanism

    Directory of Open Access Journals (Sweden)

    Francesca Wannenes

    2014-01-01

    Full Text Available Obesity and sarcopenia have been associated with mineral metabolism derangement and low bone mineral density (BMD. We investigated whether imbalance of serum factors in obese or obese sarcopenic patients could affect bone cell activity in vitro. To evaluate and characterize potential cellular and molecular changes of human osteoblasts, cells were exposed to sera of four groups of patients: (1 affected by obesity with normal BMD (O, (2 affected by obesity with low BMD (OO, (3 affected by obesity and sarcopenia (OS, and (4 affected by obesity, sarcopenia, and low BMD (OOS as compared to subjects with normal body weight and normal BMD (CTL. Patients were previously investigated and characterized for body composition, biochemical and bone turnover markers. Then, sera of different groups of patients were used to incubate human osteoblasts and evaluate potential alterations in cell homeostasis. Exposure to OO, OS, and OOS sera significantly reduced alkaline phosphatase, osteopontin, and BMP4 expression compared to cells exposed to O and CTL, indicating a detrimental effect on osteoblast differentiation. Interestingly, sera of all groups of patients induced intracellular alteration in Wnt/β-catenin molecular pathway, as demonstrated by the significant alteration of specific target genes expression and by altered β-catenin cellular compartmentalization and GSK3β phosphorylation. In conclusion our results show for the first time that sera of obese subjects with low bone mineral density and sarcopenia significantly alter osteoblasts homeostasis in vitro, indicating potential detrimental effects of trunk fat on bone formation and skeletal homeostasis.

  11. Implications of Hydrogen Sulfide in Glucose Regulation: How H2S Can Alter Glucose Homeostasis through Metabolic Hormones

    Science.gov (United States)

    Pichette, Jennifer

    2016-01-01

    Diabetes and its comorbidities continue to be a major health problem worldwide. Understanding the precise mechanisms that control glucose homeostasis and their dysregulation during diabetes are a major research focus. Hydrogen sulfide (H2S) has emerged as an important regulator of glucose homeostasis. This is achieved through its production and action in several metabolic and hormone producing organs including the pancreas, liver, and adipose. Of importance, H2S production and signaling in these tissues are altered during both type 1 and type 2 diabetes mellitus. This review first examines how H2S is produced both endogenously and by gastrointestinal microbes, with a particular focus on the altered production that occurs during obesity and diabetes. Next, the action of H2S on the metabolic organs with key roles in glucose homeostasis, with a particular focus on insulin, is described. Recent work has also suggested that the effects of H2S on glucose homeostasis goes beyond its role in insulin secretion. Several studies have demonstrated important roles for H2S in hepatic glucose output and adipose glucose uptake. The mechanism of H2S action on these metabolic organs is described. In the final part of this review, future directions examining the roles of H2S in other metabolic and glucoregulatory hormone secreting tissues are proposed. PMID:27478532

  12. Regulation of calpain activity in rat brain with altered Ca2+ homeostasis.

    Science.gov (United States)

    Averna, Monica; Stifanese, Roberto; De Tullio, Roberta; Passalacqua, Mario; Defranchi, Enrico; Salamino, Franca; Melloni, Edon; Pontremoli, Sandro

    2007-01-26

    Activation of calpain occurs as an early event in correlation with an increase in [Ca2+]i induced in rat brain upon treatment with a high salt diet for a prolonged period of time. The resulting sequential events have been monitored in the brain of normal and hypertensive rats of the Milan strain, diverging for a constitutive alteration in the level of [Ca2+]i found to be present in nerve cells of hypertensive animals. After 2 weeks of treatment, the levels of the plasma membrane Ca2+-ATPase and of native calpastatin are profoundly decreased. These degradative processes, more pronounced in the brain of hypertensive rats, are progressively and efficiently compensated in the brain of both rat strains by different incoming mechanisms. Along with calpastatin degradation, 15-kDa still-active inhibitory fragments are accumulated, capable of efficiently replacing the loss of native inhibitor molecules. A partial return to a more efficient control of Ca2+ homeostasis occurs in parallel, assured by an early increase in the expression of Ca2+-ATPase and of calpastatin, both producing, after 12 weeks of a high salt (sodium) diet, the restoration of almost original levels of the Ca2+ pump and of significant amounts of native inhibitor molecules. Thus, conservative calpastatin fragmentation, associated with an increased expression of Ca2+-ATPase and of the calpain natural inhibitor, has been demonstrated to occur in vivo in rat brain. This represents a sequential adaptive response capable of overcoming the effects of calpain activation induced by a moderate long term elevation of [Ca2+]i.

  13. Sleep duration and sleep quality are associated differently with alterations of glucose homeostasis

    DEFF Research Database (Denmark)

    Byberg, Stine; Hansen, Anne-Louise Smidt; Christensen, Dirk Lund;

    2012-01-01

    Abstract Aims  Studies suggest that inadequate sleep duration and poor sleep quality increase the risk of impaired glucose regulation and diabetes. However, associations with specific markers of glucose homeostasis are less well explained. The objective of this study was to explore possible...... associations of sleep duration and sleep quality with markers of glucose homeostasis and glucose tolerance status in a healthy population-based study sample. Methods  The study comprised 771 participants from the Danish, population-based cross-sectional ‘Health2008’ study. Sleep duration and sleep quality were......), the homeostasis model assessment of β-cell function and glucose tolerance status. Associations of sleep duration and sleep quality with markers of glucose homeostasis and tolerance were analysed by multiple linear and logistic regression. Results  A 1-h increment in sleep duration was associated with a 0.3 mmol...

  14. Anaemia and Iron Homeostasis in a Cohort of HIV-Infected Patients: A Cross-Sectional Study in Ghana

    Directory of Open Access Journals (Sweden)

    Christian Obirikorang

    2016-01-01

    Full Text Available Aim. We determined the prevalence of anaemia and evaluated markers of iron homeostasis in a cohort of HIV patients. Methods. A comparative cross-sectional study on 319 participants was carried out at the Tamale Teaching Hospital from July 2013 to December 2013, 219 patients on HAART (designated On-HAART and 100 HAART-naive patients. Data gathered include sociodemography, clinical history, and selected laboratory assays. Results. Prevalence of anaemia was 23.8%. On-HAART participants had higher CD4/CD3 lymphocyte counts, Hb, HCT/PCV, MCV, MCH, iron, ferritin, and TSAT (P<0.05. Hb, iron, ferritin, and TSAT decreased from grade 1 to grade 3 anaemia and CD4/CD3 lymphocyte count was lowest in grade 3 anaemia (P<0.05. Iron (P=0.0072 decreased with disease severity whilst transferrin (P=0.0143 and TIBC (P=0.0143 increased with disease severity. Seventy-six (23.8% participants fulfilled the criteria for anaemia, 86 (26.9% for iron deficiency, 41 (12.8% for iron deficiency anaemia, and 17 (5.3% for iron overload. The frequency of anaemia was higher amongst participants not on HAART (OR 2.6 for grade 1 anaemia; OR 3.0 for grade 3 anaemia. Conclusion. In this study population, HIV-associated anaemia is common and is related to HAART status and disease progression. HIV itself is the most important cause of anaemia and treatment of HIV should be a priority compared to iron supplementation.

  15. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women.

    Science.gov (United States)

    Wolf, Myles; Koch, Todd A; Bregman, David B

    2013-08-01

    Fibroblast growth factor 23 (FGF23) is an osteocyte-derived hormone that regulates phosphate and vitamin D homeostasis. Through unknown mechanisms, certain intravenous iron preparations induce acute, reversible increases in circulating FGF23 levels that lower serum phosphate in association with inappropriately low levels of calcitriol, similar to genetic diseases of primary FGF23 excess. In contrast, studies in wild-type mice suggest that iron deficiency stimulates fgf23 transcription but does not result in hypophosphatemia because FGF23 is cleaved within osteocytes by an unknown catabolic system. We tested the association of iron deficiency anemia with C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 55 women with a history of heavy uterine bleeding, and assessed the longitudinal biochemical response over 35 days to equivalent doses of randomly-assigned, intravenous elemental iron in the form of ferric carboxymaltose (FCM) or iron dextran. Iron deficiency was associated with markedly elevated cFGF23 (807.8 ± 123.9 relative units [RU]/mL) but normal iFGF23 (28.5 ± 1.1 pg/mL) levels at baseline. Within 24 hours of iron administration, cFGF23 levels fell by approximately 80% in both groups. In contrast, iFGF23 transiently increased in the FCM group alone, and was followed by a transient, asymptomatic reduction in serum phosphate iron dextran group. Reduced serum phosphate was accompanied by increased urinary fractional excretion of phosphate, decreased calcitriol levels, and increased parathyroid hormone levels. These findings suggest that iron deficiency increases cFGF23 levels, and that certain iron preparations temporarily increase iFGF23 levels. We propose that intravenous iron lowers cFGF23 in humans by reducing fgf23 transcription as it does in mice, whereas carbohydrate moieties in certain iron preparations may simultaneously inhibit FGF23 degradation in osteocytes leading to transient increases in iFGF23 and reduced serum phosphate.

  16. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

    NARCIS (Netherlands)

    B. Benyamin (Beben); T. Esko (Tõnu); J.S. Ried (Janina); A. Radhakrishnan (Aparna); S.H.H.M. Vermeulen (Sita); M. Traglia (Michela); M. Gögele (Martin); D. Anderson (David); L. Broer (Linda); C. Podmore (Clara); J. Luan; Z. Kutalik (Zoltán); S. Sanna (Serena); P. van der Meer (Peter); T. Tanaka (Toshiko); F. Wang (Fudi); H.J. Westra (Harm-Jan); L. Franke (Lude); E. Mihailov (Evelin); L. Milani (Lili); J. Häldin (Jonas); B. Winkelmann; T. Meitinger (Thomas); J. Thiery (Joachim); A. Peters (Annette); M. Waldenberger (Melanie); A. Rendon (Augusto); G.J. Jolley (Jason); J.G. Sambrook (Jennifer); L.A.L.M. Kiemeney (Bart); F.C. Sweep (Fred); C. Sala (Cinzia); C. Schwienbacher (Christine); I. Pichler (Irene); J. Hui (Jennie); A. Demirkan (Ayşe); A. Isaacs (Aaron); N. Amin (Najaf); M. Steri (Maristella); G. Waeber (Gérard); N. Verweij (Niek); J.E. Powell (Joseph); A.S. Dimas (Antigone); A.C. Heath (Andrew); P.A. Madden (Pamela); P.M. Visscher (Peter); M.J. Wright (Margaret); G.W. Montgomery (Grant); N.G. Martin (Nicholas); D.G. Hernandez (Dena); S. Bandinelli (Stefania); P. van der Harst (Pim); M. Uda (Manuela); P. Vollenweider (Peter); R.A. Scott (Robert A.); C. Langenberg (Claudia); N.J. Wareham (Nick); C.M. van Duijn (Cock); J. Beilby (John); P.P. Pramstaller (Peter Paul); A.A. Hicks (Andrew); W.H. Ouwehand (Willem); K. Oexle (Konrad); C. Gieger (Christian); A. Metspalu (Andres); C. Camaschella (Clara); D. Toniolo (Daniela); D.W. Swinkels (Dorine); J. Whitfield (John)

    2014-01-01

    textabstractVariation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subject

  17. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

    NARCIS (Netherlands)

    Benyamin, Beben; Esko, Tonu; Ried, Janina S.; Radhakrishnan, Aparna; Vermeulen, Sita H.; Traglia, Michela; Goegele, Martin; Anderson, Denise; Broer, Linda; Podmore, Clara; Luan, Jian'an; Kutalik, Zoltan; Sanna, Serena; van der Meer, Peter; Tanaka, Toshiko; Wang, Fudi; Westra, Harm-Jan; Franke, Lude; Mihailov, Evelin; Milani, Lili; Haeldin, Jonas; Winkelmann, Juliane; Meitinger, Thomas; Thiery, Joachim; Peters, Annette; Waldenberger, Melanie; Rendon, Augusto; Jolley, Jennifer; Sambrook, Jennifer; Kiemeney, Lambertus A.; Sweep, Fred C.; Sala, Cinzia F.; Schwienbacher, Christine; Pichler, Irene; Hui, Jennie; Demirkan, Ayse; Isaacs, Aaron; Amin, Najaf; Steri, Maristella; Waeber, Gerard; Verweij, Niek; Powell, Joseph E.; Nyholt, Dale R.; Heath, Andrew C.; Madden, Pamela A. F.; Visscher, Peter M.; Wright, Margaret J.; Montgomery, Grant W.; Martin, Nicholas G.; Hernandez, Dena; Bandinelli, Stefania; van der Harst, Pim; Uda, Manuela; Vollenweider, Peter; Scott, Robert A.; Langenberg, Claudia; Wareham, Nicholas J.; van Duijn, Cornelia; Beilby, John; Pramstaller, Peter P.; Hicks, Andrew A.; Ouwehand, Willem H.; Oexle, Konrad; Gieger, Christian; Metspalu, Andres; Camaschella, Clara; Toniolo, Daniela; Swinkels, Dorine W.; Whitfield, John B.

    2014-01-01

    Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find

  18. High dose intravenous iron, mineral homeostasis and intact FGF23 in normal and uremic rats

    DEFF Research Database (Denmark)

    Gravesen, Eva; Hofman-Bang, Jacob; Mace, Maria L.;

    2013-01-01

    High iron load might have a number of toxic effects in the organism. Recently intravenous (iv) iron has been proposed to induce elevation of fibroblast growth factor 23 (FGF23), hypophosphatemia and osteomalacia in iron deficient subjects. High levels of FGF23 are associated with increased mortal......, iron isomaltoside 1000 (IIM) and ferric carboxymaltose (FCM), on plasma levels of FGF23 and phosphate was examined in normal and uremic iron repleted rats.......High iron load might have a number of toxic effects in the organism. Recently intravenous (iv) iron has been proposed to induce elevation of fibroblast growth factor 23 (FGF23), hypophosphatemia and osteomalacia in iron deficient subjects. High levels of FGF23 are associated with increased...... mortality in the chronic kidney disease (CKD) population. CKD patients are often treated with iv iron therapy in order to maintain iron stores and erythropoietin responsiveness, also in the case of not being iron depleted. Therefore, the effect of a single high iv dose of two different iron preparations...

  19. Iron

    DEFF Research Database (Denmark)

    Hansen, Jakob Bondo; Moen, I W; Mandrup-Poulsen, T

    2014-01-01

    The interest in the role of ferrous iron in diabetes pathophysiology has been revived by recent evidence of iron as an important determinant of pancreatic islet inflammation and as a biomarker of diabetes risk and mortality. The iron metabolism in the β-cell is complex. Excess free iron is toxic......, but at the same time, iron is required for normal β-cell function and thereby glucose homeostasis. In the pathogenesis of diabetes, iron generates reactive oxygen species (ROS) by participating in the Fenton chemistry, which can induce oxidative damage and apoptosis. The aim of this review is to present...... and discuss recent evidence, suggesting that iron is a key pathogenic factor in both type 1 and type 2 diabetes with a focus on inflammatory pathways. Pro-inflammatory cytokine-induced β-cell death is not fully understood, but may include iron-induced ROS formation resulting in dedifferentiation by activation...

  20. Alteration of ROS Homeostasis and Decreased Lifespan in S. cerevisiae Elicited by Deletion of the Mitochondrial Translocator FLX1

    Directory of Open Access Journals (Sweden)

    Teresa Anna Giancaspero

    2014-01-01

    Full Text Available This paper deals with the control exerted by the mitochondrial translocator FLX1, which catalyzes the movement of the redox cofactor FAD across the mitochondrial membrane, on the efficiency of ATP production, ROS homeostasis, and lifespan of S. cerevisiae. The deletion of the FLX1 gene resulted in respiration-deficient and small-colony phenotype accompanied by a significant ATP shortage and ROS unbalance in glycerol-grown cells. Moreover, the flx1Δ strain showed H2O2 hypersensitivity and decreased lifespan. The impaired biochemical phenotype found in the flx1Δ strain might be justified by an altered expression of the flavoprotein subunit of succinate dehydrogenase, a key enzyme in bioenergetics and cell regulation. A search for possible cis-acting consensus motifs in the regulatory region upstream SDH1-ORF revealed a dozen of upstream motifs that might respond to induced metabolic changes by altering the expression of Flx1p. Among these motifs, two are present in the regulatory region of genes encoding proteins involved in flavin homeostasis. This is the first evidence that the mitochondrial flavin cofactor status is involved in controlling the lifespan of yeasts, maybe by changing the cellular succinate level. This is not the only case in which the homeostasis of redox cofactors underlies complex phenotypical behaviours, as lifespan in yeasts.

  1. Neuro-endocrine basis for altered plasma glucose homeostasis in the Fragile X mouse

    Directory of Open Access Journals (Sweden)

    El Idrissi Abdeslem

    2010-08-01

    observed in taurine-fed mice there was an increase in insulin, glucagon and somatostatin immunoreactivity in the islets of WT mice. In the KO mice however, insulin levels were not affected whereas glucagon and somatostatin levels were reduced. Exocytosis of these hormones is calcium-dependent, therefore any exacerbation of calcium homeostasis could affect hormone release. We found the expression of the voltage sensitive calcium channels (VSCC is drastically reduced in the pancreas of fragile X mice. Conclusions During early development, the VSCC play an important role in calcium-dependent gene expression. Since these channels are also involved in depolarization and calcium-mediated vesicular release of neurotransmitters and pancreatic hormones, alterations in the expression of VSCC not only will affect calcium-mediated gene expression but also hormonal and neurotransmitter release creating therefore a neuroendocrine perturbation in the fragile X that may potentially affect other organ systems. We find that in the fragile X mouse, taurine treatment may partially restore functionality of the neuro-endocrine pancreas.

  2. Alzheimer's disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis.

    Science.gov (United States)

    Bandyopadhyay, Sanghamitra; Rogers, Jack T

    2014-04-15

    The neurotoxicity of amyloid beta (Aβ), a major cleavage product of the amyloid precursor protein (APP), is enhanced by iron, as found in the amyloid plaques of Alzheimer's disease (AD) patients. By contrast, the long-known neuroprotective activity of APP is evident after α-secretase cleavage of the precursor to release sAPPα, and depends on the iron export actions of APP itself. The latter underlie its neurotrophic and protective effects in facilitating the homeostatic actions of ferroportin mediated-iron export. Thus APP-dependent iron export may alleviate oxidative stress by minimizing labile iron thus protecting neurons from iron overload during stroke and hemorrhage. Consistent with this, altered phosphorylation of iron-regulatory protein-1 (IRP1) and its signaling processes play a critical role in modulating APP translation via the 5' untranslated region (5'UTR) of its transcript. The APP 5'UTR region encodes a functional iron-responsive element (IRE) RNA stem loop that represents a potential target for modulating APP production. Targeted regulation of APP gene expression via the modulation of 5'UTR sequence function represents a novel approach for the potential treatment of AD since altering APP translation can be used to improve both the protective brain iron balance and provide anti-amyloid efficacy. Approved drugs including paroxetine and desferrioxamine and several novel compounds have been identified that suppress abnormal metal-promoted Aβ accumulation with a subset of these acting via APP 5'UTR-dependent mechanisms to modulate APP translation and cleavage to generate the non-toxic sAPPα.

  3. An iron homeostasis regulatory circuit with reciprocal roles in Candida albicans commensalism and pathogenesis

    OpenAIRE

    Chen, Changbin; Pande, Kalyan; French, Sarah D.; Tuch, Brian B.; Noble, Suzanne M.

    2011-01-01

    The mammalian gastrointestinal tract and bloodstream are highly disparate biological niches that differ in concentrations of nutrients such as iron. However, some commensal-pathogenic microorganisms, such as the yeast Candida albicans, thrive in both environments. We report the evolution of a transcription circuit in C. albicans that controls iron uptake and determines its fitness in both niches. Our analysis of DNA-binding proteins that regulate iron uptake by this organism suggests the evol...

  4. Chlordecone, a mixed pregnane X receptor (PXR) and estrogen receptor alpha (ERα) agonist, alters cholesterol homeostasis and lipoprotein metabolism in C57BL/6 mice

    OpenAIRE

    Lee, Junga; Scheri, Richard C.; Zhang, Yuan; Curtis, Lawrence R.

    2008-01-01

    Chlordecone (CD) is one of many banned organochlorine (OC) insecticides that are widespread persistent organic pollutants. OC insecticides alter lipid homeostasis in rodents at doses that are not neurotoxic or carcinogenic. Pretreatment of mice or rats with CD altered tissue distribution of a subsequent dose of [14C]CD or [14C]cholesterol (CH). Nuclear receptors regulate expression of genes important in the homeostasis of CH and other lipids. In this study, we report that CD suppresses in vit...

  5. Identification of two genes potentially associated in iron-heme homeostasis in human carotid plaque using microarray analysis

    Indian Academy of Sciences (India)

    Hanène Ayari; Giampiero Bricca

    2013-06-01

    Classic characteristics are poor predictors of the risk of thromboembolism. Thus, better markers for the carotid atheroma plaque formation and symptom causing are needed. Our objective was to study by microarray analysis gene expression of genes involved in homeostasis of iron and heme in carotid atheroma plaque from the same patient. mRNA gene expression was measured by an Affymetrix GeneChip Human Gene 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 68 specimens of endarteriectomy from 34 patients. Two genes involved in iron-heme homeostasis, CD163 and heme oxygenase (HO-1), were analysed in 34 plaques. CD163 (2.18, =1.45E−08) and HO-1 (fold-change 2.67, =2.07E−09) mRNAs were induced. We suggest that atheroma plaques show a more pronounced induction of CD163 and HO-1. Although further evidence is needed, our results support previous data. To our knowledge, this is the first report comparing gene expression between intact arterial tissue and carotid plaque using microarray analysis.

  6. Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis

    DEFF Research Database (Denmark)

    Srinivasan, Gayathri; Aitken, Jesse D; Zhang, Benyue;

    2012-01-01

    Various states of inflammation, including sepsis, are associated with hypoferremia, which limits iron availability to pathogens and reduces iron-mediated oxidative stress. Lipocalin 2 (Lcn2; siderocalin, 24p3) plays a central role in iron transport. Accordingly, Lcn2-deficient (Lcn2KO) mice exhibit...... elevated intracellular labile iron. In this study, we report that LPS induced systemic Lcn2 by 150-fold in wild-type mice at 24 h. Relative to wild-type littermates, Lcn2KO mice were markedly more sensitive to endotoxemia, exhibiting elevated indices of organ damage (transaminasemia, lactate dehydrogenase...... exhibited delayed LPS-induced hypoferremia despite normal hepatic hepcidin expression and displayed decreased levels of the tissue redox state indicators cysteine and glutathione in liver and plasma. Desferroxamine, an iron chelator, significantly protects Lcn2KO mice from LPS-induced toxicity, including...

  7. Modulation of hepcidin to treat iron deregulation: potential clinical applications

    OpenAIRE

    Blanchette, Nicole L.; Manz, David H.; Torti, Frank M.; Torti, Suzy V.

    2015-01-01

    The secreted peptide hormone hepcidin regulates systemic and local iron homeostasis through degradation of the iron exporter ferroportin. Dysregulation of hepcidin leads to altered iron homeostasis and development of pathological disorders including hemochromatosis, and iron loading and iron restrictive anemias. Therapeutic modulation of hepcidin is a promising method to ameliorate these conditions. Several approaches have been taken to enhance or reduce the effects of hepcidin in vitro and i...

  8. Oxygen glucose deprivation in rat hippocampal slice cultures results in alterations in carnitine homeostasis and mitochondrial dysfunction.

    Directory of Open Access Journals (Sweden)

    Thomas F Rau

    Full Text Available Mitochondrial dysfunction characterized by depolarization of mitochondrial membranes and the initiation of mitochondrial-mediated apoptosis are pathological responses to hypoxia-ischemia (HI in the neonatal brain. Carnitine metabolism directly supports mitochondrial metabolism by shuttling long chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Our previous studies have shown that HI disrupts carnitine homeostasis in neonatal rats and that L-carnitine can be neuroprotective. Thus, this study was undertaken to elucidate the molecular mechanisms by which HI alters carnitine metabolism and to begin to elucidate the mechanism underlying the neuroprotective effect of L-carnitine (LCAR supplementation. Utilizing neonatal rat hippocampal slice cultures we found that oxygen glucose deprivation (OGD decreased the levels of free carnitines (FC and increased the acylcarnitine (AC: FC ratio. These changes in carnitine homeostasis correlated with decreases in the protein levels of carnitine palmitoyl transferase (CPT 1 and 2. LCAR supplementation prevented the decrease in CPT1 and CPT2, enhanced both FC and the AC∶FC ratio and increased slice culture metabolic viability, the mitochondrial membrane potential prior to OGD and prevented the subsequent loss of neurons during later stages of reperfusion through a reduction in apoptotic cell death. Finally, we found that LCAR supplementation preserved the structural integrity and synaptic transmission within the hippocampus after OGD. Thus, we conclude that LCAR supplementation preserves the key enzymes responsible for maintaining carnitine homeostasis and preserves both cell viability and synaptic transmission after OGD.

  9. The Abnormal Measures of Iron Homeostasis in Pediatric Obesity Are Associated with the Inflammation of Obesity

    Directory of Open Access Journals (Sweden)

    Visintainer PaulF

    2009-08-01

    Full Text Available Objectives. To determine if the low iron state described in obese children is associated with the chronic inflammatory state seen in obesity. Study Design. Obese children age from 2 to 19 years seen at a weight management clinic were studied prospectively. Data were collected on age, gender, BMI, BMI -score, serum iron, ferritin, transferrin saturation, free erythrocyte protoporphyrin, high sensitivity creactive protein (hs-crp, and hemoglobin concentration. Results. 107 subjects were studied. Hs-crp levels correlated positively with BMI and BMI -score and negatively with serum iron . 11.2% of subjects had low serum iron. Median serum iron was significantly lower for subjects with American Heart Association high risk hs-crp values (3 mg/L compared to those with low risk hs-crp (1 mg/L, (65 mcg/dL versus 96 mcg/dL, . After adjusting for age, gender, and BMI -score, serum iron was still negatively associated with hs-crp . Conclusions. We conclude that the chronic inflammation of obesity results in the low iron state previously reported in obese children, similar to what is seen in other inflammatory diseases.

  10. The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body.

    Directory of Open Access Journals (Sweden)

    Christal A Worthen

    2014-03-01

    Full Text Available Fine tuning of body iron is required to prevent diseases such as iron-overload and anemia. The putative iron-sensor, transferrin receptor 2 (TfR2, is expressed in the liver and mutations in this protein result in the iron-overload disease Type III hereditary hemochromatosis (HH. With the loss of functional TfR2, the liver produces about two-fold less of the peptide hormone hepcidin, which is responsible for negatively regulating iron uptake from the diet. This reduction in hepcidin expression leads to the slow accumulation of iron in the liver, heart, joints, and pancreas and subsequent cirrhosis, heart disease, arthritis, and diabetes. TfR2 can bind iron-loaded transferrin in the bloodstream, and hepatocytes treated with transferrin respond with a two-fold increase in hepcidin expression through stimulation of the BMP-signaling pathway. Loss of functional TfR2 or its binding partner, the original HH protein (HFE, results in a loss of this transferrin-sensitivity. While much is known about the trafficking and regulation of TfR2, the mechanism of its transferrin-sensitivity through the BMP-signaling pathway is still not known.

  11. Methylmercury alters glutathione homeostasis by inhibiting glutaredoxin 1 and enhancing glutathione biosynthesis in cultured human astrocytoma cells.

    Science.gov (United States)

    Robitaille, Stephan; Mailloux, Ryan J; Chan, Hing Man

    2016-08-10

    Methylmercury (MeHg) is a neurotoxin that binds strongly to thiol residues on protein and low molecular weight molecules like reduced glutathione (GSH). The mechanism of its effects on GSH homeostasis particularly at environmentally relevant low doses is not fully known. We hypothesized that exposure to MeHg would lead to a depletion of reduced glutathione (GSH) and an accumulation of glutathione disulfide (GSSG) leading to alterations in S-glutathionylation of proteins. Our results showed exposure to low concentrations of MeHg (1μM) did not significantly alter GSH levels but increased GSSG levels by ∼12-fold. This effect was associated with a significant increase in total cellular glutathione content and a decrease in GSH/GSSG. Immunoblot analyses revealed that proteins involved in glutathione synthesis were upregulated accounting for the increase in cellular glutathione. This was associated an increase in cellular Nrf2 protein levels which is required to induce the expression of antioxidant genes in response to cellular stress. Intriguingly, we noted that a key enzyme involved in reversing protein S-glutathionylation and maintaining glutathione homeostasis, glutaredoxin-1 (Grx1), was inhibited by ∼50%. MeHg treatment also increased the S-glutathionylation of a high molecular weight protein. This observation is consistent with the inhibition of Grx1 and elevated H2O2 production however; contrary to our original hypothesis we found few S-glutathionylated proteins in the astrocytoma cells. Collectively, MeHg affects multiple arms of glutathione homeostasis ranging from pool management to protein S-glutathionylation and Grx1 activity. PMID:27180086

  12. Effect of natural and synthetic iron corrosion products on silicate glass alteration processes

    Science.gov (United States)

    Dillmann, Philippe; Gin, Stéphane; Neff, Delphine; Gentaz, Lucile; Rebiscoul, Diane

    2016-01-01

    Glass long term alteration in the context of high-level radioactive waste (HLW) storage is influenced by near-field materials and environmental context. As previous studies have shown, the extent of glass alteration is strongly related to the presence of iron in the system, mainly provided by the steel overpack around surrounding the HLW glass package. A key to understanding what will happen to the glass-borne elements in the geological disposal lies in the relationship between the iron-bearing phases and the glass alteration products formed. In this study, we focus on the influence of the formation conditions (synthetized or in-situ) and the age of different iron corrosion products on SON68 glass alteration. Corrosion products obtained from archaeological iron artifacts are considered here to be true analogues of the corrosion products in a waste disposal system due to the similarities in formation conditions and physical properties. These representative corrosion products (RCP) are used in the experiment along with synthetized iron anoxic corrosion products and pristine metallic iron. The model-cracks of SON68 glass were altered in cell reactors, with one of the different iron-sources inserted in the crack each time. The study was successful in reproducing most of the processes observed in the long term archaeological system. Between the different systems, alteration variations were noted both in nature and intensity, confirming the influence of the iron-source on glass alteration. Results seem to point to a lesser effect of long term iron corrosion products (RCP) on the glass alteration than that of the more recent products (SCP), both in terms of general glass alteration and of iron transport.

  13. Period2 gene mutant mice show compromised insulin-mediated endothelial nitric oxide release and altered glucose homeostasis

    Directory of Open Access Journals (Sweden)

    João Miguel Carvas

    2012-08-01

    Full Text Available Period2 (Per2 is an important component of the circadian clock. Mutation of this gene is associated with vascular endothelial dysfunction and altered glucose metabolism. The aim of this study is to further characterize whole body glucose homeostasis and endothelial NO production in response to insulin in the mPer2Brdm1 mice. We show that mPer2Brdm1 mice exhibit compromised insulin receptor activation and Akt signaling in various tissues including liver, fat, heart, and aortas with a tissue-specific heterogeneous diurnal pattern, and decreased insulin-stimulated endothelial NO release in the aortas in both active and inactive phases of the animals. As compared to wild type mice, the mPer2Brdm1 mice reveal hyperinsulinemia, hypoglycemia with lower fasting hepatic glycogen content and glycogen synthase level, no difference in glucose tolerance and insulin tolerance. The mPer2Brdm1 mice do not show increased predisposition to obesity either on normal chow or high fat diet compared to wild type controls. Thus, mice with Per2 gene mutation show altered glucose homeostasis and compromised insulin-stimulated endothelial NO release, independently of obesity.

  14. Anemia and iron homeostasis in a cohort of HIV-infected patients in Indonesia

    Directory of Open Access Journals (Sweden)

    Jusuf Hadi

    2011-08-01

    Full Text Available Abstract Background Anemia is a common clinical finding in HIV-infected patients and iron deficiency or redistribution may contribute to the development of low hemoglobin levels. Iron overload is associated with a poor prognosis in HIV and Hepatitis C virus infections. Iron redistribution may be caused by inflammation but possibly also by hepatitis C co-infection. We examined the prevalence of anemia and its relation to mortality in a cohort of HIV patients in a setting where injecting drug use (IDU is a main mode of HIV transmission, and measured serum ferritin and sTfR, in relation to anemia, inflammation, stage of HIV disease, ART and HCV infection. Methods Patient characteristics, ART history and iron parameters were recorded from adult HIV patients presenting between September 2007 and August 2009 in the referral hospital for West Java, Indonesia. Kaplan-Meier estimates and Cox's regression were used to assess factors affecting survival. Logistic regression was used to identity parameters associated with high ferritin concentrations. Results Anemia was found in 49.6% of 611 ART-naïve patients, with mild (Hb 10.5 - 12.99 g/dL for men; and 10.5 - 11.99 g/dL for women anemia in 62.0%, and moderate to severe anemia (Hb Conclusion HIV-associated anemia is common among HIV-infected patients in Indonesia and strongly related to mortality. High ferritin with low sTfR levels suggest that iron redistribution and low erythropoietic activity, rather than iron deficiency, contribute to anemia. Serum ferritin and sTfR should be used cautiously to assess iron status in patients with advanced HIV infection.

  15. CD14 deficiency impacts glucose homeostasis in mice through altered adrenal tone.

    Directory of Open Access Journals (Sweden)

    James L Young

    Full Text Available The toll-like receptors comprise one of the most conserved components of the innate immune system, signaling the presence of molecules of microbial origin. It has been proposed that signaling through TLR4, which requires CD14 to recognize bacterial lipopolysaccharide (LPS, may generate low-grade inflammation and thereby affect insulin sensitivity and glucose metabolism. To examine the long-term influence of partial innate immune signaling disruption on glucose homeostasis, we analyzed knockout mice deficient in CD14 backcrossed into the diabetes-prone C57BL6 background at 6 or 12 months of age. CD14-ko mice, fed either normal or high-fat diets, displayed significant glucose intolerance compared to wild type controls. They also displayed elevated norepinephrine urinary excretion and increased adrenal medullary volume, as well as an enhanced norepinephrine secretory response to insulin-induced hypoglycemia. These results point out a previously unappreciated crosstalk between innate immune- and sympathoadrenal- systems, which exerts a major long-term effect on glucose homeostasis.

  16. Altered Ca2+ Homeostasis and Endoplasmic Reticulum Stress in Myotonic Dystrophy Type 1 Muscle Cells

    Directory of Open Access Journals (Sweden)

    Gyorgy Szabadkai

    2013-06-01

    Full Text Available The pathogenesis of Myotonic Dystrophy type 1 (DM1 is linked to unstable CTG repeats in the DMPK gene which induce the mis-splicing to fetal/neonatal isoforms of many transcripts, including those involved in cellular Ca2+ homeostasis. Here we monitored the splicing of three genes encoding for Ca2+ transporters and channels (RyR1, SERCA1 and CACN1S during maturation of primary DM1 muscle cells in parallel with the functionality of the Excitation-Contraction (EC coupling machinery. At 15 days of differentiation, fetal isoforms of SERCA1 and CACN1S mRNA were significantly higher in DM1 myotubes compared to controls. Parallel functional studies showed that the cytosolic Ca2+ response to depolarization in DM1 myotubes did not increase during the progression of differentiation, in contrast to control myotubes. While we observed no differences in the size of intracellular Ca2+ stores, DM1 myotubes showed significantly reduced RyR1 protein levels, uncoupling between the segregated ER/SR Ca2+ store and the voltage-induced Ca2+ release machinery, parallel with induction of endoplasmic reticulum (ER stress markers. In conclusion, our data suggest that perturbed Ca2+ homeostasis, via activation of ER stress, contributes to muscle degeneration in DM1 muscle cells likely representing a premature senescence phenotype.

  17. Interference of nickel with copper and iron homeostasis contributes to metal toxicity symptoms in the nickel hyperaccumulator plant Alyssum inflatum.

    Science.gov (United States)

    Ghasemi, Rasoul; Ghaderian, S Majid; Krämer, Ute

    2009-11-01

    The divalent cations of several transition metal elements have similar chemical properties and, when present in excess, one metal can interfere with the homeostasis of another. To better understand the role of interactions between transition metals in the development of metal toxicity symptoms in plants, the effects of exposure to excess nickel (Ni) on copper (Cu) and iron (Fe) homeostasis in the Ni hyperaccumulator plant Alyssum inflatum were examined. Alyssum inflatum was hypertolerant to Ni, but not to Cu. Exposure to elevated subtoxic Ni concentrations increased Cu sensitivity, associated with enhanced Cu accumulation and enhanced root surface Cu(II)-specific reductase activity. Exposure to elevated Ni concentrations resulted in an inhibition of root-to-shoot translocation of Fe and concentration-dependent progressive Fe accumulation in root pericycle, endodermis and cortex cells of the differentiation zone. Shoot Fe concentrations, chlorophyll concentrations and Fe-dependent antioxidant enzyme activities were decreased in Ni-exposed plants when compared with unexposed controls. Foliar Fe spraying or increased Fe supply to roots ameliorated the chlorosis observed under exposure to high Ni concentrations. These results suggest that Ni interferes with Cu regulation and that the disruption of root-to-shoot Fe translocation is a major cause of nickel toxicity symptoms in A. inflatum. PMID:19691676

  18. Profile of altered brain iron acquisition in restless legs syndrome

    OpenAIRE

    Connor, James R; Ponnuru, Padmavathi; Wang, Xin-sheng; Patton, Stephanie M.; Allen, Richard P; Earley, Christopher J

    2011-01-01

    Restless legs syndrome is a neurological disorder characterized by an urgency to move the legs during periods of rest. Data from a variety of sources provide a compelling argument that the amount of iron in the brain is lower in individuals with restless legs syndrome compared with neurologically normal individuals. Moreover, a significant percentage of patients with restless legs syndrome are responsive to intravenous iron therapy. The mechanism underlying the decreased iron concentrations i...

  19. Sudden Sensorineural Hearing Loss and Polymorphisms in Iron Homeostasis Genes: New Insights from a Case-Control Study

    Directory of Open Access Journals (Sweden)

    Alessandro Castiglione

    2015-01-01

    Full Text Available Background. Even if various pathophysiological events have been proposed as explanations, the putative cause of sudden hearing loss remains unclear. Objectives. To investigate and to reveal associations (if any between the main iron-related gene variants and idiopathic sudden sensorineural hearing loss. Study Design. Case-control study. Materials and Methods. A total of 200 sudden sensorineural hearing loss patients (median age 63.65 years; range 10–92 were compared with 400 healthy control subjects. The following genetic variants were investigated: the polymorphism c.−8CG in the promoter of the ferroportin gene (FPN1; SLC40A1, the two isoforms C1 and C2 (p.P570S of the transferrin protein (TF, the amino acidic substitutions p.H63D and p.C282Y in the hereditary hemochromatosis protein (HFE, and the polymorphism c.–582AG in the promoter of the HEPC gene, which encodes the protein hepcidin (HAMP. Results. The homozygous genotype c.−8GG of the SLC40A1 gene revealed an OR for ISSNHL risk of 4.27 (CI 95%, 2.65–6.89; P=0.001, being overrepresented among cases. Conclusions. Our study indicates that the homozygous genotype FPN1 −8GG was significantly associated with increased risk of developing sudden hearing loss. These findings suggest new research should be conducted in the field of iron homeostasis in the inner ear.

  20. Chloroquine Interference with Hemoglobin Endocytic Trafficking Suppresses Adaptive Heme and Iron Homeostasis in Macrophages: The Paradox of an Antimalarial Agent

    Directory of Open Access Journals (Sweden)

    Christian A. Schaer

    2013-01-01

    Full Text Available The CD163 scavenger receptor pathway for Hb:Hp complexes is an essential mechanism of protection against the toxicity of extracellular hemoglobin (Hb, which can accumulate in the vasculature and within tissues during hemolysis. Chloroquine is a lysosomotropic agent, which has been extensively used as an antimalarial drug in the past, before parasite resistance started to limit its efficacy in most parts of the world. More recent use of chloroquine is related to its immunomodulatory activity in patients with autoimmune diseases, which may also involve hemolytic disease components. In this study we examined the effects of chloroquine on the human Hb clearance pathway. For this purpose we developed a new mass-spectrometry-based method to specifically quantify intracellular Hb peptides within the endosomal-lysosomal compartment by single reaction monitoring (SRM. We found that chloroquine exposure impairs trafficking of Hb:Hp complexes through the endosomal-lysosomal compartment after internalization by CD163. Relative quantification of intracellular Hb peptides by SRM confirmed that chloroquine blocked cellular Hb:Hp catabolism. This effect suppressed the cellular heme-oxygenase-1 (HO-1 response and shifted macrophage iron homeostasis towards inappropriately high expression of the transferrin receptor with concurrent inhibition of ferroportin expression. A functional deficiency of Hb detoxification and heme-iron recycling may therefore be an adverse consequence of chloroquine treatment during hemolysis.

  1. Polychlorinated biphenyls-induced alterations of thyroid hormone homeostasis and brain development in the rat.

    NARCIS (Netherlands)

    Morse, D.C.

    1995-01-01

    IntroductionThe work described in this thesis was undertaken to gain insight in the processes involved in the developmental neurotoxicity of polychlorinated biphenyls. It has been previously hypothesized that the alteration of thyroid hormone status by PCBs may be in part responsibl

  2. Altered glucose homeostasis and hepatic function in obese mice deficient for both kinin receptor genes.

    Directory of Open Access Journals (Sweden)

    Carlos C Barros

    Full Text Available The Kallikrein-Kinin System (KKS has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM, we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO. Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM.

  3. Arabidopsis ferritin 1 (AtFer1) gene regulation by the phosphate starvation response 1 (AtPHR1) transcription factor reveals a direct molecular link between iron and phosphate homeostasis.

    Science.gov (United States)

    Bournier, Marc; Tissot, Nicolas; Mari, Stéphane; Boucherez, Jossia; Lacombe, Eric; Briat, Jean-François; Gaymard, Frédéric

    2013-08-01

    A yeast one-hybrid screening allowed the selection of PHR1 as a factor that interacted with the AtFer1 ferritin gene promoter. In mobility shift assays, PHR1 and its close homologue PHL1 (PHR1-like 1) interact with Element 2 of the AtFer1 promoter, containing a P1BS (PHR1 binding site). In a loss of function mutant for genes encoding PHR1 and PHL1 (phr1 phl1 mutant), the response of AtFer1 to phosphate starvation was completely lost, showing that the two transcription factors regulate AtFer1 expression upon phosphate starvation. This regulation does not involve the IDRS (iron-dependent regulatory sequence) present in the AtFer1 promoter and involved in the iron-dependent regulation. The phosphate starvation response of AtFer1 is not linked to the iron status of plants and is specifically initiated by phosphate deficiency. Histochemical localization of iron, visualized by Perls DAB staining, was strongly altered in a phr1 phl1 mutant, revealing that both PHR1 and PHL1 are major factors involved in the regulation of iron homeostasis.

  4. Polychlorinated biphenyls-induced alterations of thyroid hormone homeostasis and brain development in the rat.

    OpenAIRE

    Morse, D.C.

    1995-01-01

    IntroductionThe work described in this thesis was undertaken to gain insight in the processes involved in the developmental neurotoxicity of polychlorinated biphenyls. It has been previously hypothesized that the alteration of thyroid hormone status by PCBs may be in part responsible for the developmental neurotoxicity of these compounds in humans (Rogan et al. 1986). This is a logical hypothesis, given the well-described effects of PCBs on plasma thyroid hormone levels in adult animals, and ...

  5. Deletion of the major peroxiredoxin Tsa1 alters telomere length homeostasis

    OpenAIRE

    LU, Jian; Vallabhaneni, Haritha; Yin, Jinhu; Liu, Yie

    2013-01-01

    Reactive oxygen species (ROS) are proposed to play a major role in telomere length alterations during aging. The mechanisms by which ROS disrupt telomeres remain unclear. In Saccharomyces cerevisiae, telomere DNA consists of TG(1-3) repeats, which are maintained primarily by telomerase. Telomere length maintenance can be modulated by the expression level of telomerase subunits and telomerase activity. Additionally, telomerase-mediated telomere repeat addition is negatively modulated by the le...

  6. Role of Saccharomyces cerevisiae ISA1 and ISA2 in Iron Homeostasis

    OpenAIRE

    Jensen, Laran T.; Culotta, Valeria Cizewski

    2000-01-01

    The budding yeast Saccharomyces cerevisiae contains two homologues of bacterial IscA proteins, designated Isa1p and Isa2p. Bacterial IscA is a product of the isc (iron-sulfur cluster) operon and has been suggested to participate in Fe-S cluster formation or repair. To test the function of yeast Isa1p and Isa2p, single or combinatorial disruptions were introduced in ISA1 and ISA2. The resultant isaΔ mutants were viable but exhibited a dependency on lysine and glutamate for growth and a respira...

  7. Formula feeding alters hepatic gene expression signature, iron and cholesterol homeostasis in the neonatal pig

    Science.gov (United States)

    Although the American Academy of Pediatrics recommends breast feeding for at least the first 6 months of life, formula feeding remains more popular in the US. In the current study, neonatal piglets were breast-fed or were fed commercially available milk-based formula (MF) or soy-based formula (SF) ...

  8. Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans

    Science.gov (United States)

    Chakraborty, Sudipta; Chen, Pan; Bornhorst, Julia; Schwerdtle, Tanja; Schumacher, Fabian; Kleuser, Burkhard; Bowman, Aaron B.; Aschner, Michael

    2015-01-01

    Overexposure to the essential metal manganese (Mn) can result in an irreversible condition known as manganism that shares similar pathophysiology with Parkinson’s disease (PD), including dopaminergic (DAergic) cell loss that leads to motor and cognitive impairments. However, the mechanisms behind this neurotoxicity and its relationship with PD remain unclear. Many genes confer risk for autosomal recessive, early-onset PD, including the parkin/PARK2 gene that encodes for the E3 ubiquitin ligase Parkin. Using Caenorhabditis elegans (C. elegans) as an invertebrate model that conserves the DAergic system, we previously reported significantly increased Mn accumulation in pdr-1/parkin mutants compared to wildtype (WT) animals. For the current study, we hypothesize that this enhanced accumulation is due to alterations in Mn transport in the pdr-1 mutants. While no change in mRNA expression of the major Mn importer proteins (smf-1-3) was found in pdr-1 mutants, significant downregulation in mRNA levels of the putative Mn exporter ferroportin (fpn-1.1) was observed. Using a strain overexpressing fpn-1.1 in worms lacking pdr-1, we show evidence for attenuation of several endpoints of Mn-induced toxicity, including survival, metal accumulation, mitochondrial copy number and DAergic integrity, compared to pdr-1 mutants alone. These changes suggest a novel role of pdr-1 in modulating Mn export through altered transporter expression, and provides further support of metal dyshomeostasis as a component of Parkinsonism pathophysiology. PMID:25769119

  9. Long-term mTOR inhibitors administration evokes altered calcium homeostasis and platelet dysfunction in kidney transplant patients

    Science.gov (United States)

    López, Esther; Berna-Erro, Alejandro; Bermejo, Nuria; Brull, José María; Martinez, Rocío; Garcia Pino, Guadalupe; Alvarado, Raul; Salido, Ginés María; Rosado, Juan Antonio; Cubero, Juan José; Redondo, Pedro Cosme

    2013-01-01

    The use of the mammal target of rapamycin (mTOR) inhibitors has been consolidated as the therapy of election for preventing graft rejection in kidney transplant patients, despite their immunosuppressive activity is less strong than anti-calcineurin agents like tacrolimus and cyclosporine A. Furthermore, as mTOR is widely expressed, rapamycin (a macrolide antibiotic produced by Streptomyces hygroscopicus) is recommended in patients presenting neoplasia due to its antiproliferative actions. Hence, we have investigated whether rapamycin presents side effects in the physiology of other cell types different from leucocytes, such as platelets. Blood samples were drawn from healthy volunteers and kidney transplant patients long-term medicated with rapamycin: sirolimus and everolimus. Platelets were either loaded with fura-2 or directly stimulated, and immunoassayed or fixed with Laemmli's buffer to perform the subsequent analysis of platelet physiology. Our results indicate that rapamycin evokes a biphasic time-dependent alteration in calcium homeostasis and function in platelets from kidney transplant patients under rapamycin regime, as demonstrated by the reduction in granule secretion observed and subsequent impairment of platelet aggregation in these patients compared with healthy volunteers. Platelet count was also reduced in these patients, thus 41% of patients presented thrombocytopenia. All together our results show that long-term administration of rapamycin to kidney transplant patients evokes alteration in platelet function. PMID:23577651

  10. The PICALM Protein Plays a Key Role in Iron Homeostasis and Cell Proliferation

    OpenAIRE

    Scotland, Paula B.; Heath, Jessica L.; Conway, Amanda E; Porter, Natasha B.; Armstrong, Michael B.; Walker, Jennifer A.; Mitchell L Klebig; Catherine P Lavau; Wechsler, Daniel S

    2012-01-01

    The ubiquitously expressed phosphatidylinositol binding clathrin assembly (PICALM) protein associates with the plasma membrane, binds clathrin, and plays a role in clathrin-mediated endocytosis. Alterations of the human PICALM gene are present in aggressive hematopoietic malignancies, and genome-wide association studies have recently linked the PICALM locus to late-onset Alzheimer's disease. Inactivating and hypomorphic Picalm mutations in mice cause different degrees of severity of anemia, a...

  11. Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression.

    Science.gov (United States)

    Ioannides, Zara A; Ngo, Shyuan T; Henderson, Robert D; McCombe, Pamela A; Steyn, Frederik J

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research. PMID:27400276

  12. Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats

    Directory of Open Access Journals (Sweden)

    Qinna NA

    2015-05-01

    Full Text Available Nidal A Qinna,1 Adnan A Badwan2 1Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, 2Research and Innovation Centre, The Jordanian Pharmaceutical Manufacturing Co. Plc. (JPM, Amman, Jordan Abstract: Streptozotocin (STZ is currently the most used diabetogenic agent in testing insulin and new antidiabetic drugs in animals. Due to the toxic and disruptive nature of STZ on organs, apart from pancreas, involved in preserving the body’s normal glucose homeostasis, this study aims to reassess the action of STZ in inducing different glucose response states in diabetic rats while testing insulin. Diabetic Sprague-Dawley rats induced with STZ were classified according to their initial blood glucose levels into stages. The effect of randomizing rats in such a manner was investigated for the severity of interrupting normal liver, pancreas, and kidney functions. Pharmacokinetic and pharmacodynamic actions of subcutaneously injected insulin in diabetic and nondiabetic rats were compared. Interruption of glucose homeostasis by STZ was challenged by single and repeated administrations of injected insulin and oral glucose to diabetic rats. In diabetic rats with high glucose (451–750 mg/dL, noticeable changes were seen in the liver and kidney functions compared to rats with lower basal glucose levels. Increased serum levels of recombinant human insulin were clearly indicated by a significant increase in the calculated maximum serum concentration and area under the concentration–time curve. Reversion of serum glucose levels to normal levels pre- and postinsulin and oral glucose administrations to STZ diabetic rats were found to be variable. In conclusion, diabetic animals were more responsive to insulin than nondiabetic animals. STZ was capable of inducing different levels of normal glucose homeostasis disruption in rats. Both pharmacokinetic and pharmacodynamic actions of insulin were

  13. Iron and iron-related proteins in asbestosis.

    Science.gov (United States)

    ABSTRACT: We tested the postulate that iron homeostasis is altered among patients diagnosed to have asbestosis. Lung tissue from six individuals diagnosed to have had asbestosis at autopsy was stained for iron, ferritin, divalent metal transporter 1 (DMT1), and ferroportin 1 (FP...

  14. Disordered myocardial Ca(2+) homeostasis results in substructural alterations that may promote occurrence of malignant arrhythmias.

    Science.gov (United States)

    Tribulova, N; Knezl, V; Szeiffova Bacova, B; Egan Benova, T; Viczenczova, C; Gonçalvesova, E; Slezak, J

    2016-09-19

    We aimed to determine the impact of Ca(2+)-related disorders induced in intact animal hearts on ultrastructure of the cardiomyocytes prior to occurrence of severe arrhythmias. Three types of acute experiments were performed that are known to be accompanied by disturbances in Ca(2+) handling. Langedorff-perfused rat or guinea pig hearts subjected to K(+)-deficient perfusion to induce ventricular fibrillation (VF), burst atrial pacing to induce atrial fibrillation (AF) and open chest pig heart exposed to intramyocardial noradrenaline infusion to induce ventricular tachycardia (VT). Tissue samples for electron microscopic examination were taken during basal condition, prior and during occurrence of malignant arrhythmias. Cardiomyocyte alterations preceding occurrence of arrhythmias consisted of non-uniform sarcomere shortening, disruption of myofilaments and injury of mitochondria that most likely reflected cytosolic Ca(2+) disturbances and Ca(2+) overload. These disorders were linked with non-uniform pattern of neighboring cardiomyocytes and dissociation of adhesive junctions suggesting defects in cardiac cell-to-cell coupling. Our findings identified heterogeneously distributed high [Ca(2+)](i)-induced subcellular injury of the cardiomyocytes and their junctions as a common feature prior occurrence of VT, VF or AF. In conclusion, there is a link between Ca(2+)-related disorders in contractility and coupling of the cardiomyocytes pointing out a novel paradigm implicated in development of severe arrhythmias. PMID:27643936

  15. Restraint Stress Impairs Glucose Homeostasis Through Altered Insulin Signalling in Sprague-Dawley Rat.

    Science.gov (United States)

    Morakinyo, Ayodele O; Ajiboye, Kolawole I; Oludare, Gabriel O; Samuel, Titilola A

    2016-01-01

    The study investigated the potential alteration in the level of insulin and adiponectin, as well as the expression of insulin receptors (INSR) and glucose transporter 4 GLUT-4 in chronic restraint stress rats. Sprague-Dawley rats were randomly divided into two groups: the control group and stress group in which the rats were exposed to one of the four different restraint stressors; 1 h, twice daily for a period of 7 days (S7D), 14 days (S14D) and 28 days (S28D). Glucose tolerance and insulin sensitivity were evaluated following the final stress exposure. ELISA were performed to assess the level of insulin and adiponectin as well as expression of INSR and GLUT4 protein in skeletal muscle. Plasma corticosterone level was also determined as a marker of stress exposure. Restraint stress for 7 days caused transient glucose intolerance, while S14D rats demonstrated increased glucose intolerance and insulin insensitivity. However, restraint stress for 28 days had no effect on glucose tolerance, but did cause an increase in glucose response to insulin challenge. The serum level of adiponectin was significantly (pcontrol value while insulin remained unchanged except at in S28D rats that had a significant (pcontrol counterparts. Restraint stress caused glucose intolerance and insulin insensitivity in male Sprague-Dawley rats, which becomes accommodated with prolonged exposure and was likely related to the blunted insulin signalling in skeletal muscle. PMID:27574760

  16. Postnatal growth after intrauterine growth restriction alters central leptin signal and energy homeostasis.

    Directory of Open Access Journals (Sweden)

    Bérengère Coupé

    Full Text Available Intrauterine growth restriction (IUGR is closely linked with metabolic diseases, appetite disorders and obesity at adulthood. Leptin, a major adipokine secreted by adipose tissue, circulates in direct proportion to body fat stores, enters the brain and regulates food intake and energy expenditure. Deficient leptin neuronal signalling favours weight gain by affecting central homeostatic circuitry. The aim of this study was to determine if leptin resistance was programmed by perinatal nutritional environment and to decipher potential cellular mechanisms underneath.We clearly demonstrated that 5 months old IUGR rats develop a decrease of leptin sentivity, characterized by no significant reduction of food intake following an intraperitoneal injection of leptin. Apart from the resistance to leptin injection, results obtained from IUGR rats submitted to rapid catch-up growth differed from those of IUGR rats with no catch-up since we observed, for the first group only, fat accumulation, increased appetite for food rich in fat and increased leptin synthesis. Centrally, the leptin resistant state of both groups was associated with a complex and not always similar changes in leptin receptor signalling steps. Leptin resistance in IUGR rats submitted to rapid catch-up was associated with alteration in AKT and mTOR pathways. Alternatively, in IUGR rats with no catch-up, leptin resistance was associated with low hypothalamic expression of LepRa and LepRb. This study reveals leptin resistance as an early marker of metabolic disorders that appears before any evidence of body weight increase in IUGR rats but whose mechanisms could depend of nutritional environment of the perinatal period.

  17. Whole transcriptome analysis of transgenic barley with altered cytokinin homeostasis and increased tolerance to drought stress.

    Science.gov (United States)

    Vojta, Petr; Kokáš, Filip; Husičková, Alexandra; Grúz, Jiří; Bergougnoux, Veronique; Marchetti, Cintia F; Jiskrová, Eva; Ježilová, Eliška; Mik, Václav; Ikeda, Yoshihisa; Galuszka, Petr

    2016-09-25

    Cytokinin plant hormones have been shown to play an important role in plant response to abiotic stresses. Herein, we expand upon the findings of Pospíšilová et al. [30] regarding preparation of novel transgenic barley lines overexpressing cytokinin dehydrogenase 1 gene from Arabidopsis under the control of mild root-specific promotor of maize β-glycosidase. These lines showed drought-tolerant phenotype mainly due to alteration of root architecture and stronger lignification of root tissue. A detailed transcriptomic analysis of roots of transgenic plants subjected to revitalization after drought stress revealed attenuated response through the HvHK3 cytokinin receptor and up-regulation of two transcription factors implicated in stress responses and abscisic acid sensitivity. Increased expression of several genes involved in the phenylpropanoid pathway as well as of genes encoding arogenate dehydratase/lyase participating in phenylalanine synthesis was found in roots during revitalization. Although more precursors of lignin synthesis were present in roots after drought stress, final lignin accumulation did not change compared to that in plants grown under optimal conditions. Changes in transcriptome indicated a higher auxin turnover in transgenic roots. The same analysis in leaves revealed that genes encoding putative enzymes responsible for production of jasmonates and other volatile compounds were up-regulated. Although transgenic barley leaves showed lower chlorophyll content and down-regulation of genes encoding proteins involved in photosynthesis than did wild-type plants when cultivated under optimal conditions, they did show a tendency to return to initial photochemical activities faster than did wild-type leaves when re-watered after severe drought stress. In contrast to optimal conditions, comparative transcriptomic analysis of revitalized leaves displayed up-regulation of genes encoding enzymes and proteins involved in photosynthesis, and especially

  18. Short-chain fructooligosaccharides do not alter glucose homeostasis but improve the lipid profile in obese rats

    Directory of Open Access Journals (Sweden)

    Fernanda Soares da Silva-Morita

    2015-07-01

    Full Text Available The present study investigated the effects of short-chain fructooligosaccharides (scFOS feeding on body weight, fat accumulation, glucose homeostasis and lipid profile in cafeteria (CAF obese rats. Male Wistar rats were divided randomly into two groups: control group (CTL, n = 10, which received a chow diet and water and CAF (n = 20, which received the cafeteria diet, standard chow and soda. After 30 weeks of diet, 10 animals of CAF group received scFOS in the diet (50 g kg-1 of diet over a period of 50 days, forming the CAF FOS group. Were evaluated the body weight, fat pad as well as, quantity of feces, glucose tolerance, insulin resistance (IR and serum lipids levels. Animals submitted to the CAF diet displayed obesity, hyperglycemia, glucose intolerance, hyperinsulinemia and IR. The scFOS feeding   not altered obesity, glucose intolerance, hyperinsulinemia and IR. CAF rats also presented hypertriglyceridemia and lower levels of HDL-cholesterol. The CAF FOS animals had reduced serum triglycerides (TG and increased HDL-cholesterol. Thus, the use of scFOS in the diet can be considered as a hypolipidemic agent in the obese state.

  19. Hiperpigmentación cutánea y homeostasis del hierro: rol de la hepcidina Cutaneous hyperpigmentation and homeostasis of iron: role of the hepcidin

    OpenAIRE

    Wolf, C

    2007-01-01

    La hiperpigmentación cutánea por melanina en zonas expuestas al sol puede estar asociada a un desequilibrio en la homeostasis del hierro. La hepcidina es un péptido responsable de la regulación negativa de la absorción del hierro en el intestino delgado y de su liberación por los macrófagos. Posee capacidad antimicrobiana. Es sintetizada en el hígado, secretada al torrente circulatorio y excretada por la orina. La sobreexpresión causa anemia y su déficit, sobrecarga de hierro (acumulación en ...

  20. METABOLIC CAPACITY REGULATES IRON HOMEOSTATIS IN ENDOTHELIAL CELLS

    Science.gov (United States)

    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...

  1. Aconitase post-translational modification as a key in linkage between Krebs cycle, iron homeostasis, redox signaling, and metabolism of reactive oxygen species.

    Science.gov (United States)

    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.

  2. Chlordecone, a mixed pregnane X receptor (PXR) and estrogen receptor alpha (ERα) agonist, alters cholesterol homeostasis and lipoprotein metabolism in C57BL/6 mice

    International Nuclear Information System (INIS)

    Chlordecone (CD) is one of many banned organochlorine (OC) insecticides that are widespread persistent organic pollutants. OC insecticides alter lipid homeostasis in rodents at doses that are not neurotoxic or carcinogenic. Pretreatment of mice or rats with CD altered tissue distribution of a subsequent dose of [14C]CD or [14C]cholesterol (CH). Nuclear receptors regulate expression of genes important in the homeostasis of CH and other lipids. In this study, we report that CD suppresses in vitro reporter systems for human liver X receptors (LXRs) and activates those for human farnesoid X receptor (FXR), pregnane X receptor (PXR) and estrogen receptor α (ERα) in a concentration-dependent manner (0-50 μM). Consistent with human PXR activation in vitro, three days after a single dose of CD (15 mg/kg) hepatic microsomal CYP3A11 protein increases in C57BL/6 mice. CD decreases hepatic CH ester content without altering total CH concentration. Apolipoprotein A-I (apoA-I) contents of hepatic lipoprotein-rich and microsomal fractions of CD-treated mice are higher than controls. There is a significant reduction in non-high density lipoprotein CH but not apolipoprotein B-48/100 (apoB-48/100) in plasma from CD-treated mice after a 4 h fast. At 14 days after 15 mg CD/kg apoA-I and apoB-100 proteins but not CYP3A11 protein in hepatic microsomes are similar to controls. This work indicates that altered CH homeostasis is a mode of OC insecticide action of relevance after a single dose. This at least partially explains altered CH tissue distribution in CD-pretreated mice

  3. Effect of simvastatin on the expression of farnesoid X receptor in diabetic animal models of altered glucose homeostasis

    Institute of Scientific and Technical Information of China (English)

    Wang Lulu; Huang Xianping; Hu Su; Ma Xiaoli; Wang Shaolian; Pang Shuguang

    2014-01-01

    Background Statin therapy has affected glucose homoeostasis of type 2 diabetes patients,which could be related with bile acids metabolism.Whether bile acid metabolism and the expression of farnesoid X receptor (FXR),liver X receptor-α (LXR-α) and sterol regulatory element-binding protein (Srebp)-1c is regulated by hyperglycemia,or whether simvastatin therapy led to higher glucose is related with down-regulated expression of FXR in diabetic rats remained unclear.Methods Forty male Wistar rats were randomly divided into four groups:normal control rats,insulin resistance rats,diabetic model rats,and the late simvastatin induced diabetic rats.Normal control rats were fed with standard diet,others were fed with high-fat diet.Diabetic model rats were induced by a single intraperitoneal injection of streptozotocin (STZ).The late simvastatin induced diabetic rats started simvastatin administration after STZ induced diabetic model rats.Characteristics of fasting blood glucose (FPG),lipid files and total bile acids (TBAs) were measured and the oral glucose tolerance test (OGTT) was performed after overnight fasting at the eighth weekend.RNA and protein levels of FXR,LXR-α and Srebp-1c were tested by Western blotting and reverse transcription polymerase chain reaction (RT-PCR).Results The insulin resistance rats showed higher glucose,lipid files and lower expression of FXR compared with normal control rats (P >0.05).The diabetic model rats showed significantly higher glucose,lipid files,TBA and lower expression of FXR compared with insulin resistance rats (P <0.05).The late simvastatin induced diabetic rats displayed higher glucose and TBA and lower expression of FXR compared with diabetic model rats (P <0.05).Conclusions Changes in bile acid homeostasis,including the alterations of bile acid levels and bile acid receptors,are either a cause or a consequence of the metabolic disturbances observed during diabetic models.Statin therapy induced hyperglycemia may be

  4. Silicate glass alteration enhanced by iron: origin and long-term implications

    International Nuclear Information System (INIS)

    Silicate glasses are used as containment matrices for deep geological disposal of nuclear waste arising from spent fuel reprocessing. Understanding the dissolution mechanisms of glasses in contact with iron, an element present in large amounts in the immediate environment (overpack, clay-stone, etc.) would be a major breakthrough toward predicting radionuclide release in the geosphere after disposal. Two different reacted glass-iron interfaces - a short-term nuclear system and a long-term archaeological system - were examined using a multi-scale and multi-analytical approach including, for the first time on samples of this type, STXM under synchrotron radiation. Comparisons revealed remarkable similarities between the two systems and shed light on Fe-Si interactions, including migration of iron within a porous gel layer and precipitation of Fe-silicates that locally increase short-term glass alteration and are sustainable over the long-term. (authors)

  5. Obesity and type 2 diabetes in rats are associated with altered brain glycogen and amino-acid homeostasis

    DEFF Research Database (Denmark)

    Sickmann, Helle M; Waagepetersen, Helle S; Schousboe, Arne;

    2010-01-01

    Obesity and type 2 diabetes have reached epidemic proportions; however, scarce information about how these metabolic syndromes influence brain energy and neurotransmitter homeostasis exist. The objective of this study was to elucidate how brain glycogen and neurotransmitter homeostasis are affected...... by these conditions. [1-(13)C]glucose was administered to Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rats. Sprague-Dawley (SprD), Zucker lean (ZL), and ZDF lean rats were used as controls. Several brain regions were analyzed for glycogen levels along with (13)C-labeling and content of glutamate, glutamine...... of glutamine and glutamate were decreased in the cerebellum of the ZO and the ZDF rats. Glycogen levels were also lower in this region. These results suggest that the obese and type 2 diabetic models were associated with lower brain glucose metabolism. Glucose metabolism through the TCA cycle was more...

  6. Characterization of Three New Glutaredoxin Genes in the Arbuscular Mycorrhizal Fungus Rhizophagus irregularis: Putative Role of RiGRX4 and RiGRX5 in Iron Homeostasis

    Science.gov (United States)

    Tamayo, Elisabeth; Benabdellah, Karim; Ferrol, Nuria

    2016-01-01

    Glutaredoxins (GRXs) are small ubiquitous oxidoreductases involved in the regulation of the redox state in living cells. In an attempt to identify the full complement of GRXs in the arbuscular mycorrhizal (AM) fungus Rhizophagus irregularis, three additional GRX homologs, besides the formerly characterized GintGRX1 (renamed here as RiGRX1), were identified. The three new GRXs (RiGRX4, RiGRX5 and RiGRX6) contain the CXXS domain of monothiol GRXs, but whereas RiGRX4 and RiGRX5 belong to class II GRXs, RiGRX6 belongs to class I together with RiGRX1. By using a yeast expression system, we observed that the newly identified homologs partially reverted sensitivity of the GRX deletion yeast strains to external oxidants. Furthermore, our results indicated that RiGRX4 and RiGRX5 play a role in iron homeostasis in yeast. Gene expression analyses revealed that RiGRX1 and RiGRX6 were more highly expressed in the intraradical (IRM) than in the extraradical mycelium (ERM). Exposure of the ERM to hydrogen peroxide induced up-regulation of RiGRX1, RiGRX4 and RiGRX5 gene expression. RiGRX4 expression was also up-regulated in the ERM when the fungus was grown in media supplemented with a high iron concentration. These data indicate the two monothiol class II GRXs, RiGRX4 and RiGRX5, might be involved in oxidative stress protection and in the regulation of fungal iron homeostasis. Increased expression of RiGRX1 and RiGRX6 in the IRM suggests that these GRXs should play a key role in oxidative stress protection of R. irregularis during its in planta phase. PMID:26900849

  7. Characterization of Three New Glutaredoxin Genes in the Arbuscular Mycorrhizal Fungus Rhizophagus irregularis: Putative Role of RiGRX4 and RiGRX5 in Iron Homeostasis.

    Directory of Open Access Journals (Sweden)

    Elisabeth Tamayo

    Full Text Available Glutaredoxins (GRXs are small ubiquitous oxidoreductases involved in the regulation of the redox state in living cells. In an attempt to identify the full complement of GRXs in the arbuscular mycorrhizal (AM fungus Rhizophagus irregularis, three additional GRX homologs, besides the formerly characterized GintGRX1 (renamed here as RiGRX1, were identified. The three new GRXs (RiGRX4, RiGRX5 and RiGRX6 contain the CXXS domain of monothiol GRXs, but whereas RiGRX4 and RiGRX5 belong to class II GRXs, RiGRX6 belongs to class I together with RiGRX1. By using a yeast expression system, we observed that the newly identified homologs partially reverted sensitivity of the GRX deletion yeast strains to external oxidants. Furthermore, our results indicated that RiGRX4 and RiGRX5 play a role in iron homeostasis in yeast. Gene expression analyses revealed that RiGRX1 and RiGRX6 were more highly expressed in the intraradical (IRM than in the extraradical mycelium (ERM. Exposure of the ERM to hydrogen peroxide induced up-regulation of RiGRX1, RiGRX4 and RiGRX5 gene expression. RiGRX4 expression was also up-regulated in the ERM when the fungus was grown in media supplemented with a high iron concentration. These data indicate the two monothiol class II GRXs, RiGRX4 and RiGRX5, might be involved in oxidative stress protection and in the regulation of fungal iron homeostasis. Increased expression of RiGRX1 and RiGRX6 in the IRM suggests that these GRXs should play a key role in oxidative stress protection of R. irregularis during its in planta phase.

  8. Lipopolysaccharide Increases Immune Activation and Alters T Cell Homeostasis in SHIVB'WHU Chronically Infected Chinese Rhesus Macaque

    OpenAIRE

    Gao-Hong Zhang; Run-Dong Wu; Hong-Yi Zheng; Xiao-Liang Zhang; Ming-Xu Zhang; Ren-Rong Tian; Guang-Ming Liu; Wei Pang; Yong-Tang Zheng

    2015-01-01

    Immune activation plays a significant role in the disease progression of HIV. Microbial products, especially bacterial lipopolysaccharide (LPS), contribute to immune activation. Increasing evidence indicates that T lymphocyte homeostasis disruptions are associated with immune activation. However, the mechanism by which LPS affects disruption of immune response is still not fully understood. Chronically SHIVB’WHU-infected Chinese rhesus macaques received 50 μg/kg body weight LPS in this study....

  9. Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus

    OpenAIRE

    Blossom, Sarah J.; Melnyk, Stepan; Cooney, Craig A.; Gilbert, Kathleen M.; James, S. Jill

    2012-01-01

    Previous studies have shown that continuous exposure throughout gestation until the juvenile period to environmentally-relevant doses of trichloroethylene (TCE) in the drinking water of MRL+/+ mice promoted adverse behavior associated with glutathione depletion in the cerebellum indicating increased sensitivity to oxidative stress. The purpose of this study was to extend our findings and further characterize the impact of TCE exposure on redox homeostasis and biomarkers of oxidative stress in...

  10. Oxygen Glucose Deprivation in Rat Hippocampal Slice Cultures Results in Alterations in Carnitine Homeostasis and Mitochondrial Dysfunction

    OpenAIRE

    Thomas F. Rau; Qing Lu; Shruti Sharma; Xutong Sun; Gregory Leary; Beckman, Matthew L.; Yali Hou; Wainwright, Mark S; Michael Kavanaugh; Poulsen, David J.; Black, Stephen M.

    2012-01-01

    Mitochondrial dysfunction characterized by depolarization of mitochondrial membranes and the initiation of mitochondrial-mediated apoptosis are pathological responses to hypoxia-ischemia (HI) in the neonatal brain. Carnitine metabolism directly supports mitochondrial metabolism by shuttling long chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Our previous studies have shown that HI disrupts carnitine homeostasis in neonatal rats and that L-carnitine can be neurop...

  11. Global deletion of MGL in mice delays lipid absorption and alters energy homeostasis and diet-induced obesity

    Science.gov (United States)

    Douglass, John D.; Zhou, Yin Xiu; Wu, Amy; Zadrogra, John A.; Gajda, Angela M.; Lackey, Atreju I.; Lang, Wensheng; Chevalier, Kristen M.; Sutton, Steven W.; Zhang, Sui-Po; Flores, Christopher M.; Connelly, Margery A.; Storch, Judith

    2015-01-01

    Monoacylglycerol lipase (MGL) is a ubiquitously expressed enzyme that catalyzes the hydrolysis of monoacylglycerols (MGs) to yield FFAs and glycerol. MGL contributes to energy homeostasis through the mobilization of fat stores and also via the degradation of the endocannabinoid 2-arachidonoyl glycerol. To further examine the role of MG metabolism in energy homeostasis, MGL−/− mice were fed either a 10% (kilocalories) low-fat diet (LFD) or a 45% (kilocalories) high-fat diet (HFD) for 12 weeks. Profound increases of MG species in the MGL−/− mice compared with WT control mice were found. Weight gain over the 12 weeks was blunted in both diet groups. MGL−/− mice were leaner than WT mice at both baseline and after 12 weeks of LFD feeding. Circulating lipids were decreased in HFD-fed MGL−/− mice, as were the levels of several plasma peptides involved in glucose homeostasis and energy balance. Interestingly, MGL−/− mice had markedly reduced intestinal TG secretion following an oral fat challenge, suggesting delayed lipid absorption. Overall, the results indicate that global MGL deletion leads to systemic changes that produce a leaner phenotype and an improved serum metabolic profile. PMID:25842377

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

    Science.gov (United States)

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

    2016-02-01

    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

  13. Pulmonary Toxicity and Modifications in Iron Homeostasis Following Libby Amphibole Asbestos Exposure in Rat Models of Cardiovascular Disease

    Science.gov (United States)

    Rationale: Individuals suffering from cardiovascular disease (CVD) develop iron dysregulation which may influence pulmonary toxicity and injury upon exposure to asbestos. We hypothesized spontaneously hypertensive (SH) and spontaneously hypertensive heart failure (SHHF) rats woul...

  14. Experimental and clinical studies on liver regeneration and hepatocellular carcinoma. Roles of redox proteins, iron homeostasis and multikinase inhibition.

    OpenAIRE

    Mollbrink, Annelie

    2013-01-01

    Compensatory liver regeneration is triggered by chronic liver injury or surgery and is crucial to maintain tissue homeostasis. The underlying mechanisms which include a whole battery of complex signaling events have been thoroughly studied for decades. The majority of hepatocellular carcinomas develop in a highly proliferative environment caused by underlying chronic liver disease in which lost liver tissue must be restored to meet the needs of the organism. The chronic inflammatory condition...

  15. Endoplasmic reticulum Ca2+-homeostasis is altered in small and non-small cell lung cancer cell lines

    Directory of Open Access Journals (Sweden)

    Tufman Amanda

    2009-02-01

    Full Text Available Abstract Background Knowledge of differences in the cellular physiology of malignant and non-malignant cells is a prerequisite for the development of cancer treatments that effectively kill cancer without damaging normal cells. Calcium is a ubiquitous signal molecule that is involved in the control of proliferation and apoptosis. We aimed to investigate if the endoplasmic reticulum (ER Ca2+-homeostasis is different in lung cancer and normal human bronchial epithelial (NHBE cells. Methods The intracellular Ca2+-signaling was investigated using fluorescence microscopy and the expression of Ca2+-regulating proteins was assessed using Western Blot analysis. Results In a Small Cell Lung Cancer (H1339 and an Adeno Carcinoma Lung Cancer (HCC cell line but not in a Squamous Cell Lung Cancer (EPLC and a Large Cell Lung Cancer (LCLC cell line the ER Ca2+-content was reduced compared to NHBE. The reduced Ca2+-content correlated with a reduced expression of SERCA 2 pumping calcium into the ER, an increased expression of IP3R releasing calcium from the ER, and a reduced expression of calreticulin buffering calcium within the ER. Lowering the ER Ca2+-content with CPA led to increased proliferation NHBE and lung cancer cells. Conclusion The significant differences in Ca2+-homeostasis between lung cancer and NHBE cells could represent a new target for cancer treatments.

  16. Influence of microRNA on the Maintenance of Human Iron Metabolism

    Directory of Open Access Journals (Sweden)

    Stephen Clarke

    2013-07-01

    Full Text Available Iron is an essential nutrient critical for many cellular functions including DNA synthesis, ATP generation, and cellular proliferation. Though essential, excessive iron may contribute to the generation of free radicals capable of damaging cellular lipids, proteins, and nucleic acids. As such, the maintenance and control of cellular iron homeostasis is critical to prevent either iron deficiency or iron toxicity conditions. The maintenance of cellular iron homeostasis is largely coordinated by a family of cytosolic RNA binding proteins known as Iron Regulatory Proteins (IRP that function to post-transcriptionally control the translation and/or stability of mRNA encoding proteins required for iron uptake, storage, transport, and utilization. More recently, a class of small non-coding RNA known as microRNA (miRNA has also been implicated in the control of iron metabolism. To date, miRNA have been demonstrated to post-transcriptionally regulate the expression of genes associated with iron acquisition (transferrin receptor and divalent metal transporter, iron export (ferroportin, iron storage (ferritin, iron utilization (ISCU, and coordination of systemic iron homeostasis (HFE and hemojevelin. Given the diversity of miRNA and number of potential mRNA targets, characterizing factors that contribute to alterations in miRNA expression, biogenesis, and processing will enhance our understanding of mechanisms by which cells respond to changes in iron demand and/or iron availability to control cellular iron homeostasis.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  19. Morbillivirus glycoprotein expression induces ER stress, alters Ca2+ homeostasis and results in the release of vasostatin.

    Directory of Open Access Journals (Sweden)

    Jean-Marc Brunner

    Full Text Available Although the pathology of Morbillivirus in the central nervous system (CNS is well described, the molecular basis of neurodegenerative events still remains poorly understood. As a model to explore Morbillivirus-mediated CNS dysfunctions, we used canine distemper virus (CDV that we inoculated into two different cell systems: a monkey cell line (Vero and rat primary hippocampal neurons. Importantly, the recombinant CDV used in these studies not only efficiently infects both cell types but recapitulates the uncommon, non-cytolytic cell-to-cell spread mediated by virulent CDVs in brain of dogs. Here, we demonstrated that both CDV surface glycoproteins (F and H markedly accumulated in the endoplasmic reticulum (ER. This accumulation triggered an ER stress, characterized by increased expression of the ER resident chaperon calnexin and the proapoptotic transcription factor CHOP/GADD 153. The expression of calreticulin (CRT, another ER resident chaperon critically involved in the response to misfolded proteins and in Ca(2+ homeostasis, was also upregulated. Transient expression of recombinant CDV F and H surface glycoproteins in Vero cells and primary hippocampal neurons further confirmed a correlation between their accumulation in the ER, CRT upregulation, ER stress and disruption of ER Ca(2+ homeostasis. Furthermore, CDV infection induced CRT fragmentation with re-localisation of a CRT amino-terminal fragment, also known as vasostatin, on the surface of infected and neighbouring non-infected cells. Altogether, these results suggest that ER stress, CRT fragmentation and re-localization on the cell surface may contribute to cytotoxic effects and ensuing cell dysfunctions triggered by Morbillivirus, a mechanism that might potentially be relevant for other neurotropic viruses.

  20. Effects of acute creatine supplementation on iron homeostasis and uric acid-based antioxidant capacity of plasma after wingate test

    Directory of Open Access Journals (Sweden)

    Barros Marcelo P

    2012-06-01

    Full Text Available Abstract Background Dietary creatine has been largely used as an ergogenic aid to improve strength and athletic performance, especially in short-term and high energy-demanding anaerobic exercise. Recent findings have also suggested a possible antioxidant role for creatine in muscle tissues during exercise. Here we evaluate the effects of a 1-week regimen of 20 g/day creatine supplementation on the plasma antioxidant capacity, free and heme iron content, and uric acid and lipid peroxidation levels of young subjects (23.1 ± 5.8 years old immediately before and 5 and 60 min after the exhaustive Wingate test. Results Maximum anaerobic power was improved by acute creatine supplementation (10.5 %, but it was accompanied by a 2.4-fold increase in pro-oxidant free iron ions in the plasma. However, potential iron-driven oxidative insult was adequately counterbalanced by proportional increases in antioxidant ferric-reducing activity in plasma (FRAP, leading to unaltered lipid peroxidation levels. Interestingly, the FRAP index, found to be highly dependent on uric acid levels in the placebo group, also had an additional contribution from other circulating metabolites in creatine-fed subjects. Conclusions Our data suggest that acute creatine supplementation improved the anaerobic performance of athletes and limited short-term oxidative insults, since creatine-induced iron overload was efficiently circumvented by acquired FRAP capacity attributed to: overproduction of uric acid in energy-depleted muscles (as an end-product of purine metabolism and a powerful iron chelating agent and inherent antioxidant activity of creatine.

  1. Coffee Consumption, Newly Diagnosed Diabetes, and Other Alterations in Glucose Homeostasis: A Cross-Sectional Analysis of the Longitudinal Study of Adult Health (ELSA-Brasil)

    Science.gov (United States)

    Yarmolinsky, James; Mueller, Noel T.; Duncan, Bruce B.; Bisi Molina, Maria del Carmen; Goulart, Alessandra C.; Schmidt, Maria Inês

    2015-01-01

    Introduction Observational studies have reported fairly consistent inverse associations between coffee consumption and risk of type 2 diabetes, but this association has been little investigated with regard to lesser degrees of hyperglycemia and other alterations in glucose homeostasis. Additionally, the association between coffee consumption and diabetes has been rarely investigated in South American populations. We examined the cross-sectional relationships of coffee intake with newly diagnosed diabetes and measures of glucose homeostasis, insulin sensitivity, and insulin secretion, in a large Brazilian cohort of middle-aged and elderly individuals. Methods We used baseline data from 12,586 participants of the Longitudinal Study of Adult Health (ELSA-Brasil). Logistic regression analyses were performed to examine associations between coffee consumption and newly diagnosed diabetes. Analysis of covariance was used to assess coffee intake in relation to two-hour glucose from an oral glucose tolerance test, fasting glucose, glycated hemoglobin, fasting and –2-hour postload insulin and measures of insulin sensitivity. Results We found an inverse association between coffee consumption and newly diagnosed diabetes, after adjusting for multiple covariates [23% and 26% lower odds of diabetes for those consuming coffee 2–3 and >3 times per day, respectively, compared to those reporting never or almost never consuming coffee, (p = .02)]. An inverse association was also found for 2-hour postload glucose [Never/almost never: 7.57 mmol/L, ≤1 time/day: 7.48 mmol/L, 2-3 times/day: 7.22 mmol/L, >3 times/day: 7.12 mol/L, p3 times/day: 262.2 pmol/L, p = 0.0005) but not with fasting insulin concentrations (p = .58). Conclusion Our present study provides further evidence of a protective effect of coffee on risk of adult-onset diabetes. This effect appears to act primarily, if not exclusively, through postprandial, as opposed to fasting, glucose homeostasis. PMID:25978631

  2. Iron concretions within a highly altered unit of the Berlins Porphyry, New Zealand: an abiotic or biotic story?

    Science.gov (United States)

    Cox, Toni L.; Oze, Christopher; Horton, Travis W.

    2016-09-01

    The Berlins Porphyry located on the South Island of New Zealand provides an opportunity to examine iron concretions formed in a subterranean system. Specifically, an alteration zone within the Berlins Porphyry contains iron concretions similar to sedimentary biologically-mediated iron concretions. Here, we provide evidence for two sources of dissolved Fe (II) that potentially aided in the formation of the iron concretions. Furthermore, we discuss the potential for microbial involvement in the anaerobic oxidation of Fe (II) to Fe (III) to form magnetite. Evidence in support of this hypothesis includes the low concentrations of iron and sulfur in the white hydrothermally altered porphyry outcrop and concretion cores; concentrated pyrite and magnetite mineralisation surrounding the cores; and δ13C values indicative of organic carbon (averaging -26 ‰ ± 4 ‰) within the iron cement, porphyry-core-boundary and outer weathered rinds of the concretions. Overall, these unusually preserved iron concretions could represent a new environmental niche for microorganisms and a potential analogue for microbially induced iron-oxidation. More importantly, this study illustrates the many obstacles involved in analysing and interpreting potential subterranean biosignatures.

  3. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1

    Science.gov (United States)

    Guan, Jian; Gluckman, Peter; Yang, Panzao; Krissansen, Geoff; Sun, Xueying; Zhou, Yongzhi; Wen, Jingyuan; Phillips, Gemma; Shorten, Paul R.; McMahon, Chris D.; Wake, Graeme C.; Chan, Wendy H. K.; Thomas, Mark F.; Ren, April; Moon, Steve; Liu, Dong-Xu

    2014-03-01

    The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation in cell culture suggested that cGP promoted the activity of IGF-1 when it was insufficient, but inhibited the activity of IGF-1 when it was excessive. Mathematical modelling revealed that the efficacy of cGP was a modulated IGF-1 effect via changing the binding of IGF-1 to its binding proteins, which dynamically regulates the balance between bioavailable and non-bioavailable IGF-1. Our data reveal a novel mechanism of auto-regulation of IGF-1, which has physiological and pathophysiological consequences and potential pharmacological utility.

  4. Diazeniumdiolate mediated nitrosative stress alters nitric oxide homeostasis through intracellular calcium and S-glutathionylation of nitric oxide synthetase.

    Directory of Open Access Journals (Sweden)

    Yefim Manevich

    Full Text Available BACKGROUND: PABA/NO is a diazeniumdiolate that acts as a direct nitrogen monoxide (NO donor and is in development as an anticancer drug. Its mechanism of action and effect on cells is not yet fully understood. METHODOLOGY/PRINCIPAL FINDINGS: We used HPLC and mass spectrometry to identify a primary nitroaromatic glutathione metabolite of PABA/NO and used fluorescent assays to characterize drug effects on calcium and NO homeostasis, relating these to endothelial nitric oxide synthase (eNOS activity. Unexpectedly, the glutathione conjugate was found to be a competitive inhibitor of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA presumably at the same site as thapsigargin, increasing intracellular Ca2+ release and causing auto-regulation of eNOS through S-glutathionylation. CONCLUSIONS/SIGNIFICANCE: The initial direct release of NO after PABA/NO was followed by an eNOS-mediated generation of NO as a consequence of drug-induced increase in Ca2+ flux and calmodulin (CaM activation. PABA/NO has a unique dual mechanism of action with direct intracellular NO generation combined with metabolite driven regulation of eNOS activation.

  5. General geology, alteration, and iron deposits in the Palaeoproterozoic Misi region, northern Finland

    Directory of Open Access Journals (Sweden)

    Tero Niiranen

    2003-01-01

    Full Text Available The Paleoproterozoic Misi region forms the northeastern part of the Peräpohja Schist Belt in northern Finland. The area comprises mafic volcanic and sedimentary rocks, differentiated gabbros, and late-orogenic granitoids. Three geochemically different mafic volcanic units were recognised: LREE-depleted amygdaloidal lavas, slightly LREE-enriched lavas, and mafic tuffs that have a flat REE pattern. Sedimentary rocks include arkosites, mica gneisses, dolomitic marbles, quartzites, tuffites, mica schists, calc-silicate rocks and graphite-bearing schists. Two types of gabbros wereidentified: one with a LREE-enriched pattern and another with flat REE pattern. The age of the former is according to Perttunen and Vaasjoki (2001 2117±4 Ma, whereas there is no age determination for the latter. The granitoid intrusions belong to the ca. 1800 Malate-orogenic group of the Central Lapland Granitoid Complex. The geochemistry and the stable isotope data on mafic lavas and dolomitic marbles show similarities with the mafic volcanic rocks and marbles of the lower part of the Kivalo group in the western part of Peräpohja Schist Belt. Peak metamorphic conditions in the region vary from upper-greenschist to upper-amphibolite facies. Three major stages of deformation were distinguished: N-S compressional D1 with ductile deformation, NE-SW compressional D2 with ductile to brittle-ductile deformation, and E-W compressional D3 with brittle deformation. Several magnetite occurrences are known in the region and four of those have been mined for iron. The ores are mainly composed of magnetite with minor haematite, pyrite, chalcopyrite and bornite. Besides iron, the ores contain small amounts of P, S and V aswell as trace amounts of Cu, Co, Te and Au. The magnetite bodies are hosted by skarnoids within the ca. 2220–2120 Ma dolomitic marble-quartzite sequence, and highly differentiated, intensely albitised, LREE-enriched gabbro. Multistage and -type alteration is

  6. Calcium channel blockers ameliorate iron overload-associated hepatic fibrosis by altering iron transport and stellate cell apoptosis.

    Science.gov (United States)

    Zhang, Ying; Zhao, Xin; Chang, Yanzhong; Zhang, Yuanyuan; Chu, Xi; Zhang, Xuan; Liu, Zhenyi; Guo, Hui; Wang, Na; Gao, Yonggang; Zhang, Jianping; Chu, Li

    2016-06-15

    Liver fibrosis is the principal cause of morbidity and mortality in patients with iron overload. Calcium channel blockers (CCBs) can antagonize divalent cation entry into renal and myocardial cells and inhibit fibrogenic gene expression. We investigated the potential of CCBs to resolve iron overload-associated hepatic fibrosis. Kunming mice were assigned to nine groups (n=8 per group): control, iron overload, deferoxamine, high and low dose verapamil, high and low dose nimodipine, and high and low dose diltiazem. Iron deposition and hepatic fibrosis were measured in mouse livers. Expression levels of molecules associated with transmembrane iron transport were determined by molecular biology approaches. In vitro HSC-T6 cells were randomized into nine groups (the same groups as the mice). Changes in proliferation, apoptosis, and metalloproteinase expression in cells were detected to assess the anti-fibrotic effects of CCBs during iron overload conditions. We found that CCBs reduced hepatic iron content, intracellular iron deposition, the number of hepatic fibrotic areas, collagen expression levels, and hydroxyproline content. CCBs rescued abnormal expression of α1C protein in L-type voltage-dependent calcium channel (LVDCC) and down-regulated divalent metal transporter-1 (DMT-1) expression in mouse livers. In iron-overloaded HSC-T6 cells, CCBs reduced iron deposition, inhibited proliferation, induced apoptosis, and elevated expression of matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1). CCBs are potential therapeutic agents that can be used to address hepatic fibrosis during iron overload. They resolve hepatic fibrosis probably correlated with regulating transmembrane iron transport and inhibiting HSC growth. PMID:27095094

  7. Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes.

    Science.gov (United States)

    Luz, Anthony L; Rooney, John P; Kubik, Laura L; Gonzalez, Claudia P; Song, Dong Hoon; Meyer, Joel N

    2015-01-01

    Mitochondrial dysfunction has been linked to myriad human diseases and toxicant exposures, highlighting the need for assays capable of rapidly assessing mitochondrial health in vivo. Here, using the Seahorse XFe24 Analyzer and the pharmacological inhibitors dicyclohexylcarbodiimide and oligomycin (ATP-synthase inhibitors), carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (mitochondrial uncoupler) and sodium azide (cytochrome c oxidase inhibitor), we measured the fundamental parameters of mitochondrial respiratory chain function: basal oxygen consumption, ATP-linked respiration, maximal respiratory capacity, spare respiratory capacity and proton leak in the model organism Caenhorhabditis elegans. Since mutations in mitochondrial homeostasis genes cause mitochondrial dysfunction and have been linked to human disease, we measured mitochondrial respiratory function in mitochondrial fission (drp-1)-, fusion (fzo-1)-, mitophagy (pdr-1, pink-1)-, and electron transport chain complex III (isp-1)-deficient C. elegans. All showed altered function, but the nature of the alterations varied between the tested strains. We report increased basal oxygen consumption in drp-1; reduced maximal respiration in drp-1, fzo-1, and isp-1; reduced spare respiratory capacity in drp-1 and fzo-1; reduced proton leak in fzo-1 and isp-1; and increased proton leak in pink-1 nematodes. As mitochondrial morphology can play a role in mitochondrial energetics, we also quantified the mitochondrial aspect ratio for each mutant strain using a novel method, and for the first time report increased aspect ratios in pdr-1- and pink-1-deficient nematodes. PMID:26106885

  8. Adaptogenic potential of curcumin in experimental chronic stress and chronic unpredictable stress-induced memory deficits and alterations in functional homeostasis.

    Science.gov (United States)

    Bhatia, Nitish; Jaggi, Amteshwar Singh; Singh, Nirmal; Anand, Preet; Dhawan, Ravi

    2011-07-01

    The present study was designed to investigate the role of curcumin in chronic stress and chronic unpredictable stress-induced memory deficits and alteration of functional homeostasis in mice. Chronic stress was induced by immobilizing the animal for 2 h daily for 10 days, whereas chronic unpredictable stress was induced by employing a battery of stressors of variable magnitude and time for 10 days. Curcumin was administered to drug-treated mice prior to induction of stress. Body weight, adrenal gland weight, ulcer index and biochemical levels of glucose, creatine kinase, cholesterol, corticosterone, thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) were evaluated to assess stress-induced functional changes. Memory deficits were evaluated using the elevated plus maze (EPM) model. Chronic stress and chronic unpredictable stress significantly increased the levels of corticosterone, glucose and creatine kinase and decreased cholesterol levels. Moreover, chronic stress and chronic unpredictable stress resulted in severe memory deficits along with adrenal hypertrophy, weight loss and gastric ulceration. Chronic stress and chronic unpredictable stress also increased oxidative stress assessed in terms of increase in TBARS and decrease in GSH levels. Pretreatment with curcumin (25 and 50 mg/kg p.o.) attenuated chronic stress and chronic unpredictable stress-associated memory deficits, biochemical alterations, pathological outcomes and oxidative stress. It may be concluded that curcumin-mediated antioxidant actions and decrease in corticosterone secretion are responsible for its adaptogenic and memory restorative actions in chronic and chronic unpredictable stress.

  9. Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes.

    Directory of Open Access Journals (Sweden)

    Anthony L Luz

    Full Text Available Mitochondrial dysfunction has been linked to myriad human diseases and toxicant exposures, highlighting the need for assays capable of rapidly assessing mitochondrial health in vivo. Here, using the Seahorse XFe24 Analyzer and the pharmacological inhibitors dicyclohexylcarbodiimide and oligomycin (ATP-synthase inhibitors, carbonyl cyanide 4-(trifluoromethoxy phenylhydrazone (mitochondrial uncoupler and sodium azide (cytochrome c oxidase inhibitor, we measured the fundamental parameters of mitochondrial respiratory chain function: basal oxygen consumption, ATP-linked respiration, maximal respiratory capacity, spare respiratory capacity and proton leak in the model organism Caenhorhabditis elegans. Since mutations in mitochondrial homeostasis genes cause mitochondrial dysfunction and have been linked to human disease, we measured mitochondrial respiratory function in mitochondrial fission (drp-1-, fusion (fzo-1-, mitophagy (pdr-1, pink-1-, and electron transport chain complex III (isp-1-deficient C. elegans. All showed altered function, but the nature of the alterations varied between the tested strains. We report increased basal oxygen consumption in drp-1; reduced maximal respiration in drp-1, fzo-1, and isp-1; reduced spare respiratory capacity in drp-1 and fzo-1; reduced proton leak in fzo-1 and isp-1; and increased proton leak in pink-1 nematodes. As mitochondrial morphology can play a role in mitochondrial energetics, we also quantified the mitochondrial aspect ratio for each mutant strain using a novel method, and for the first time report increased aspect ratios in pdr-1- and pink-1-deficient nematodes.

  10. Altering the structure and properties of iron oxide nanoparticles and graphene oxide/iron oxide composites by urea

    Science.gov (United States)

    Naghdi, Samira; Rhee, Kyong Yop; Jaleh, Babak; Park, Soo Jin

    2016-02-01

    Iron oxide (Fe2O3) nanoparticles were grown on graphene oxide (GO) using a simple microwave-assisted method. The effects of urea concentration on Fe2O3 nanoparticles and GO/Fe2O3 composite were examined. The as-prepared samples were characterized using X-ray powder diffraction, Raman spectroscopy, and transmission electron microscopy. The Fe2O3 nanoparticles were uniformly developed on GO sheets. The results showed that urea affects both Fe2O3 morphology and particle size. In the absence of urea, the Fe2O3 nanostructures exhibited a rod-like morphology. However, increasing urea concentration altered the morphology and decreased the particle size. The Raman results of GO/Fe2O3 showed that the intensity ratio of D band to G band (ID/IG) was decreased by addition of urea, indicating that urea can preserve the GO sheets during synthesis of the composite from exposing more defects. The surface area and thermal stability of GO/Fe2O3 and Fe2O3 were compared using the Brunauer-Emmett-Teller method and thermal gravimetric analysis, respectively. The results showed that the increased concentration of urea induced a larger surface area with more active sites in the Fe2O3 nanoparticles. However, the increase in urea concentration led to decreased thermal stability of the Fe2O3 nanoparticles. The magnetic properties of Fe2O3 nanoparticles were characterized by a vibrating sample magnetometer and results revealed that the magnetic properties of Fe2O3 nanoparticles are affected by the morphology.

  11. Iron

    Science.gov (United States)

    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 ...

  12. EFFECTS OF ADDROGRAPHIS PANICULATA (NEES. ON ARSENIC- INDUCED ALTERED GLUCOSE HOMEOSTASIS AND OXIDATIVE IMPAIRMENT IN PANCREAS OF SWISS MICE

    Directory of Open Access Journals (Sweden)

    MANDAVA V. RAO

    2007-01-01

    Full Text Available The effect of Andrographis paniculata (Nees. on arsenic-induced changes in biochemical and cellular antioxident sytem was studies in adult female mice. Daily oral administration of arsenic trioxide (0.5 and 1.0mg/kg b.w for 30days induced a significant increase in blood glucose level which was associated with impaired glucose tolrence. Arsenic treatment also resulted in elevated level panreatic tissue specific makers such as activities of amylase and lipase in serum indicating pancreatic dysfunction. Interestingly, this biochemical dysfuntion was accompanied by a marked dose related enchancement of lipid peroxidation indicating significant induction of oxidative damage. Additional evidence such as deletion in reduced gluatathione levels and alterations in enzymic antioxidant defences like superoxide dismutase, catalase and glutathione peroxidase in pancreas suggested induction of oxidative stress. Concomitant administration of Adrographis paniculata (50 mg/kg b.w. with arsenic significant restored all these parameters. These results suggest that Adrographis paniculata is capable to reducing arsenic-induce cellular oxidative and inflammatory changes in pancreas.

  13. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis.

    Science.gov (United States)

    Qian, Shu-Wen; Tang, Yan; Li, Xi; Liu, Yuan; Zhang, You-You; Huang, Hai-Yan; Xue, Rui-Dan; Yu, Hao-Yong; Guo, Liang; Gao, Hui-Di; Liu, Yan; Sun, Xia; Li, Yi-Ming; Jia, Wei-Ping; Tang, Qi-Qun

    2013-02-26

    Expression of bone morphogenetic protein 4 (BMP4) in adipocytes of white adipose tissue (WAT) produces "white adipocytes" with characteristics of brown fat and leads to a reduction of adiposity and its metabolic complications. Although BMP4 is known to induce commitment of pluripotent stem cells to the adipocyte lineage by producing cells that possess the characteristics of preadipocytes, its effects on the mature white adipocyte phenotype and function were unknown. Forced expression of a BMP4 transgene in white adipocytes of mice gives rise to reduced WAT mass and white adipocyte size along with an increased number of a white adipocyte cell types with brown adipocyte characteristics comparable to those of beige or brite adipocytes. These changes correlate closely with increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. Conversely, BMP4-deficient mice exhibit enlarged white adipocyte morphology and impaired insulin sensitivity. We identify peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as the target of BMP signaling required for these brown fat-like changes in WAT. This effect of BMP4 on WAT appears to extend to human adipose tissue, because the level of expression of BMP4 in WAT correlates inversely with body mass index. These findings provide a genetic and metabolic basis for BMP4's role in altering insulin sensitivity by affecting WAT development.

  14. A Small GTPase, OsRab6a, is Involved in the Regulation of Iron Homeostasis in Rice.

    Science.gov (United States)

    Yang, An; Zhang, Wen-Hao

    2016-06-01

    Plants have evolved two distinct strategies to acquire iron (Fe) from soils. However, the regulatory mechanisms underlying the Fe acquisition remain largely elusive. There is emerging evidence that small GTPases are involved in the responses of plants to environmental cues. Here, we identified a gene encoding a small GTPase, OsRab6a, in rice and characterized its role in Fe acquisition by generating transgenic rice plants with overexpression and knockdown of OsRab6a OsRab6a shared conserved functional domains with other known members of the Rab subfamily and localized ubiquitously in the cytoplasm and nucleus. The expression of OsRab6a was rapidly and transiently up-regulated by Fe deficiency. No differences in growth and development among the OsRab6a-overexpression, OsRab6a-RNAi (RNA interference) and wild-type plants were detected when grown in Fe-sufficient medium. However, overexpression of OsRab6a in rice plants conferred greater tolerance to Fe deficiency than RNAi and wild-type plants, as evidenced by higher seedling height, and greater biomass, Chl contents and Fe concentrations in shoots, roots and grains in the overexpression lines than wild-type and RNAi plants. Moreover, the overexpression lines exhibited larger root systems than wild-type and RNAi plants in Fe-deficient medium. Exposure to Fe-deficient medium led to up-regulation of OsIRO2, OsIRT1, OsNAS1 and OsNAS2 in both wild-type and transgenic rice plants, with the magnitude of up-regulation positively correlated with the expression levels of OsRab6a These results may suggest that OsRab6a plays an important role in the regulation of Fe acquisition in rice plants by modulating physiological processes involved in Fe acquisition and root system architecture in response to Fe-deficient medium. PMID:27257291

  15. Long term alteration of glass/iron systems in anoxic conditions: contribution of archaeological analogues to the study of mechanisms

    International Nuclear Information System (INIS)

    The knowledge of glass alteration mechanisms arouses a great interest over the last decades, particularly in the nuclear field, since vitrification is used to stabilize high-level radioactive wastes in many countries. In the French concept, these nuclear glasses would be stored in geological repositories. This multi-barrier system (glass matrix, stainless steel container, low carbon steel over-container, geological barrier) must ensure the durable confinement of radionuclides. But laboratory experiments do not permit to predict directly the behaviour of these materials over typically a million-year timescale and the extrapolation of short-term laboratory data to long time periods remains problematic. Part of the validation of the predictive models relies on natural and archaeological analogues. Here, the analogues considered are vitreous slags produced as wastes by a blast furnace working during the 16. century in the iron making site of Glinet (Normandy, France). The choice of these specific artefacts is due to the presence of particular interface between corrosion products and glass matrix inside the blocks. Thus, they can help us to understand the influence of iron corrosion products from the steel containers on the glass alteration mechanisms and kinetics. A first part of this work concerns the characterization of the archaeological artefacts especially the interfacial area between glass and corrosion products inside cracks using micro and nano-beam techniques ( Raman spectroscopy, FEG-SEM, TEM, STXM...). This study has enabled to suggest an alteration process with different geochemical steps that leads to alteration profile observed. One of these steps is the precipitation of an iron silicate phase. In a second time, leaching experiments were set up on a synthetic glass of similar composition than the archaeological one to understand the first stages of alteration with and without iron. Two phenomena can be observed: silicon sorption and precipitation of iron

  16. Geology, alteration, age, and origin of iron oxide-apatite deposits in Upper Eocene quartz monzonite, Zanjan district, NW Iran

    Science.gov (United States)

    Nabatian, Ghasem; Ghaderi, Majid; Corfu, Fernando; Neubauer, Franz; Bernroider, Manfred; Prokofiev, Vsevolod; Honarmand, Maryam

    2014-02-01

    Iron oxide-apatite deposits are present in Upper Eocene pyroxene-quartz monzonitic rocks of the Zanjan district, northwestern Iran. Mineralization occurred in five stages: (1) deposition of disseminated magnetite and apatite in the host rock; (2) mineralization of massive and banded magnetite ores in veins and stockwork associated with minor brecciation and calcic alteration of host rocks; (3) deposition of sulfide ores together with potassic alteration; (4) formation of quartz and carbonate veins and sericite, chlorite, epidote, silica, carbonate, and tourmaline alteration; and (5) supergene alteration and weathering. U-Pb dating of monazite inclusions in the apatite indicates an age of 39.99 ± 0.24 Ma, which is nearly coeval with the time of emplacement of the host quartz monzonite, supporting the genetic connection. Fluid inclusions in the apatite have homogenization temperatures of about 300 °C and oxygen isotopic compositions of the magnetite support precipitation from magmatic fluids. Late-stage quartz resulted from the introduction of a cooler, less saline, and isotopically depleted fluid. The iron oxide-apatite deposits in the Tarom area of the Zanjan district are typical of a magmatic-hydrothermal origin and are similar to the Kiruna-type deposits with respect to mineral assemblages, fabric and structure of the iron ores, occurrence of the ore bodies, and wall rock alteration.

  17. Regulative roles of glutathione reductase and four glutaredoxins in glutathione redox, antioxidant activity, and iron homeostasis of Beauveria bassiana.

    Science.gov (United States)

    Zhang, Long-Bin; Tang, Li; Ying, Sheng-Hua; Feng, Ming-Guang

    2016-07-01

    Multiple glutaredoxins (Grx) and glutathione reductase (Glr) are vital for the thiol-disulfide redox system in budding yeast but generally unexplored in filamentous fungi. Here we characterized the Beauveria bassiana redox system comprising dithiol Grx1, monothiol Grx2-4, Grx-like Grx5, and Glr orthologue. Each grx or glr deletion was compensated by increased transcripts of some other grx genes in normal cultures. Particularly, grx3 compensated the absence of grx1, grx2, grx5, or glr under oxidative stress while its absence was compensated only by undeletable grx4 under normal conditions but by most of other undeleted grx and glr genes in response to menadione. Consequently, the redox state was disturbed in Δglr more than in Δgrx3 but not in Δgrx1/2/5. Superoxide dismutases were more active in normal Δgrx1-3 cultures but less in Δgrx5 or Δglr response to menadione. Total catalase activity increased differentially in all the mutant cultures stressed with or without H2O2 while total peroxidase activity decreased more in the normal or H2O2-stressed culture of Δglr than of Δgrx3. Among the mutants, Δgrx3 showed slightly increased sensitivity to menadione or H2O2; Δglr exhibited greater sensitivity to thiol-oxidizing diamide than thiol-reducing 1-chloro-2,4-dinitrobenzene as well as increased sensitivity to the two oxidants. Intriguingly, all the mutants grew slower in a Fe(3+)-inclusive medium perhaps due to elevated transcripts of two Fe(3+) transporter genes. More or fewer phenotypes linked with biocontrol potential were altered in four deletion mutants excluding Δgrx5. All the changes were restored by targeted gene complementation. Overall, Grx3 played more critical role than other Grx homologues in the Glr-dependent redox system of the fungal entomopathogen. PMID:26969041

  18. Maternal iron deficiency alters circulating thyroid hormone levels in developing neonatal rats

    Science.gov (United States)

    Thyroid hormone insufficiency and iron deficiency (FeD) during fetal and neonatal life are both similarly deleterious to mammalian development suggesting a possible linkage between iron and thyroid hormone insufficiencies. Recent published data from our laboratory demonstrate a r...

  19. Strong iron demand during hypoxia-induced erythropoiesis is associated with down-regulation of iron-related proteins and myoglobin in human skeletal muscle

    DEFF Research Database (Denmark)

    Robach, Paul; Cairo, Gaetano; Gelfi, Cecilia;

    2007-01-01

    Iron is essential for oxygen transport because it is incorporated in the heme of the oxygen-binding proteins hemoglobin and myoglobin. An interaction between iron homeostasis and oxygen regulation is further suggested during hypoxia, in which hemoglobin and myoglobin syntheses have been reported...... to increase. This study gives new insights into the changes in iron content and iron-oxygen interactions during enhanced erythropoiesis by simultaneously analyzing blood and muscle samples in humans exposed to 7 to 9 days of high altitude hypoxia (HA). HA up-regulates iron acquisition by erythroid cells...... with increased ferroportin mRNA levels, suggesting enhanced iron export. Thus, in HA, the elevated iron requirement associated with enhanced erythropoiesis presumably elicits iron mobilization and myoglobin down-modulation, suggesting an altered muscle oxygen homeostasis....

  20. Anaerobic oxidation of methane alters sediment records of sulfur, iron and phosphorus in the Black Sea

    Science.gov (United States)

    Egger, Matthias; Kraal, Peter; Jilbert, Tom; Sulu-Gambari, Fatimah; Sapart, Célia J.; Röckmann, Thomas; Slomp, Caroline P.

    2016-09-01

    The surface sediments in the Black Sea are underlain by extensive deposits of iron (Fe)-oxide-rich lake sediments that were deposited prior to the inflow of marine Mediterranean Sea waters ca. 9000 years ago. The subsequent downward diffusion of marine sulfate into the methane-bearing lake sediments has led to a multitude of diagenetic reactions in the sulfate-methane transition zone (SMTZ), including anaerobic oxidation of methane (AOM) with sulfate. While the sedimentary cycles of sulfur (S), methane and Fe in the SMTZ have been extensively studied, relatively little is known about the diagenetic alterations of the sediment record occurring below the SMTZ.Here we combine detailed geochemical analyses of the sediment and porewater with multicomponent diagenetic modeling to study the diagenetic alterations below the SMTZ at two sites in the western Black Sea. We focus on the dynamics of Fe, S and phosphorus (P), and demonstrate that diagenesis has strongly overprinted the sedimentary burial records of these elements. In line with previous studies in the Black Sea, we show that sulfate-mediated AOM substantially enhances the downward diffusive flux of sulfide into the deep limnic deposits. During this downward sulfidization, Fe oxides, Fe carbonates and Fe phosphates (e.g., vivianite) are converted to sulfide phases, leading to an enrichment in solid-phase S and the release of phosphate to the porewater. Below the sulfidization front, high concentrations of dissolved ferrous Fe (Fe2+) lead to sequestration of downward-diffusing phosphate as authigenic vivianite, resulting in a transient accumulation of total P directly below the sulfidization front.Our model results further demonstrate that downward-migrating sulfide becomes partly re-oxidized to sulfate due to reactions with oxidized Fe minerals, fueling a cryptic S cycle and thus stimulating slow rates of sulfate-driven AOM ( ˜ 1-100 pmol cm-3 d-1) in the sulfate-depleted limnic deposits. However, this process is

  1. Hypertension secondary to early-stage kidney disease: the pathogenetic role of altered cytosolic calcium (Ca2+) homeostasis of vascular smooth muscle cells.

    Science.gov (United States)

    Schiffl, H; Fricke, H; Sitter, T

    1993-05-01

    We have examined cardiovascular pressor responsiveness to infused norepinephrine (NE) as related to endogenous plasma NE and plasma renin and to platelet free cytosolic (Ca2+) in 36 patients with early-stage kidney disease and 27 matched normal subjects. The 27 hypertensive patients and the normal subjects did not differ in blood volume, plasma renin, and NE; however, the hypertensive patients had a higher exchangeable body sodium content. Basal plasma NE levels, the relationship between plasma NE measured during NE infusion and the corresponding NE infusion rate, as well as the total plasma clearance for NE did also not differ significantly between the two study groups. In contrast, the threshold or pressor doses of infused NE significantly decreased in the patients with kidney disease. Antihypertensive pharmacotherapy with (Ca2+) channel blockers and/or loop diuretics normalized blood pressure and cardiovascular NE hyperresponsiveness and reduced blood volume, exchangeable body sodium, and platelet free cytosolic (Ca2+). In contrast, experimental digitalisation as a model for in vivo sodium/potassium adenosine triphosphatase inhibition augmented NE responsiveness and raised platelet free cytosolic (Ca2+). Incubation of platelets from normal subjects with plasma ultrafiltrate from hypertensive patients gave evidence for an endogenous factor capable to raise free cytosolic (Ca2+) and to act synergistically with digoxin. Hypertension secondary to early-stage kidney disease is related to an impairment of sodium excretion leading to an expansion of blood volume and exchangeable body sodium. This may result in increased secretion of endogenous factors, leading to alterations of cytosolic (Ca2+) homeostasis of vascular smooth muscle cells followed by elevated peripheral resistance and thus blood pressure. PMID:8494019

  2. The role of iron in pulmonary pathology.

    Science.gov (United States)

    Khiroya, Heena; Turner, Alice M

    2015-01-01

    Respiratory disease accounts for a large proportion of emergency admissions to hospital and diseaseassociated mortality. Genetic association studies demonstrate a link between iron metabolism and pulmonary disease phenotypes. IREB2 is a gene that produces iron regulatory protein 2 (IRP2), which has a key role in iron homeostasis. This review addresses pathways involved in iron metabolism, particularly focusing on the role of IREB2. In addition to this, environmental factors also influence phenotypic variation in respiratory disease, for example inhaled iron from cigarette smoke is deposited in the lung and causes tissue damage by altering iron homeostasis. The effects of cigarette smoke are detailed in this article, particularly in relation to lung conditions that favour the upper lobes, such as emphysema and lung cancer. Clinical applications of iron homeostasis are also discussed in this review, especially looking at the pathophysiology of chronic obstructive pulmonary disease, lung cancer, pulmonary infections and acute respiratory distress syndrome. Promising new treatments involving iron are also covered. PMID:26629341

  3. Melanopsin as a sleep modulator: circadian gating of the direct effects of light on sleep and altered sleep homeostasis in Opn4(-/- mice.

    Directory of Open Access Journals (Sweden)

    Jessica W Tsai

    2009-06-01

    other light-encoding pathways such as rod and cones. Our study, furthermore, demonstrates that lack of melanopsin alters sleep homeostasis. These findings call for a reevaluation of the role of light on mammalian physiology and behavior.

  4. Proteomic analysis reveals that iron availability alters the metabolic status of the pathogenic fungus Paracoccidioides brasiliensis.

    Directory of Open Access Journals (Sweden)

    Ana F A Parente

    Full Text Available 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.

  5. Iron and exercise induced alterations in antioxidant status. Protection by dietary milk proteins.

    Science.gov (United States)

    Zunquin, Gautier; Rouleau, Vincent; Bouhallab, Said; Bureau, Francois; Theunynck, Denis; Rousselot, Pierre; Arhan, Pierre; Bougle, Dominique

    2006-05-01

    Lipid peroxidation stress induced by iron supplementation can contribute to the induction of gut lesions. Intensive sports lead to ischemia reperfusion, which increases free radical production. Athletes frequently use heavy iron supplementation, whose effects are unknown. On the other hand, milk proteins have in vitro antioxidant properties, which could counteract these potential side effects. The main aims of the study were: (1) to demonstrate the effects of combined exercise training (ET) and iron overload on antioxidant status; (2) to assess the protective properties of casein in vivo; (3) to study the mechanisms involved in an in vitro model. Antioxidant status was assessed by measuring the activity of antioxidant enzymes (superoxide dismutase (SOD); glutathione peroxidase (GSH-Px)), and on the onset of aberrant crypts (AC) in colon, which can be induced by lipid peroxidation. At day 30, all ET animals showed an increase in the activity of antioxidant enzymes, in iron concentration in colon mucosa and liver and in the number of AC compared to untrained rats. It was found that Casein's milk protein supplementation significantly reduced these parameters. Additional information on protective effect of casein was provided by measuring the extent of TBARS formation during iron/ascorbate-induced oxidation of liposomes. Free casein and casein bound to iron were found to significantly reduce iron-induced lipid peroxidation. The results of the overall study suggest that Iron supplementation during intensive sport training would decrease anti-oxidant status. Dietary milk protein supplementation could at least partly prevent occurrence of deleterious effects to tissue induced by iron overload. PMID:17390518

  6. Iron Prochelator BSIH Protects Retinal Pigment Epithelial Cells against Cell Death Induced by Hydrogen Peroxide

    OpenAIRE

    Charkoudian, Louise K.; Dentchev, Tzvete; Lukinova, Nina; Wolkow, Natalie; Dunaief, Joshua L.; Franz, Katherine J.

    2008-01-01

    Dysregulation of localized iron homeostasis is implicated in several degenerative diseases, including Parkinson’s, Alzheimer’s, and age-related macular degeneration, wherein iron-mediated oxidative stress is hypothesized to contribute to cell death. Inhibiting toxic iron without altering normal metal-dependent processes presents significant challenges for standard small molecule chelating agents. We previously introduced BSIH (isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl...

  7. Liver iron transport

    Institute of Scientific and Technical Information of China (English)

    Ross M Graham; Anita CG Chua; Carly E Herbison; John K Olynyk; Debbie Trinder

    2007-01-01

    The liver plays a central role in iron metabolism. It is the major storage site for iron and also expresses a complex range of molecules which are involved in iron transport and regulation of iron homeostasis. An increasing number of genes associated with hepatic iron transport or regulation have been identified. These include transferrin receptors (TFR1 and 2), a ferrireductase (STEAP3), the transporters divalent metal transporter-1 (DMT1) and ferroportin (FPN) as well as the haemochromatosis protein, HFE and haemojuvelin (HJV),which are signalling molecules. Many of these genes also participate in iron regulatory pathways which focus on the hepatic peptide hepcidin. However, we are still only beginning to understand the complex interactions between liver iron transport and iron homeostasis. This review outlines our current knowledge of molecules of iron metabolism and their roles in iron transport and regulation of iron homeostasis.

  8. Perinatal Polyunstaurated Fatty Acids Supplementation Causes Alterations in Fuel Homeostasis in Adult Male Rats but does not Offer Resistance Against STZ-induced Diabetes

    NARCIS (Netherlands)

    van Dijk, G.; Kacsandi, A.; Kobor-Nyakas, D. E.; Hogyes, E.; Nyakas, C.; Hőgyes, E.

    2011-01-01

    Maternal factors can have major imprinting effects on homeostatic mechanisms in the developing fetus and newborn. Here we studied whether supplemented perinatal polyunsaturated fatty acids (PUFAs) influence energy balance and fuel homeostasis later in life. Between day 10 after conception and day 10

  9. Diagenetic alteration of iron and phosphorus records below the sulfate-methane-transition-zone in Black Sea sediments

    Science.gov (United States)

    Egger, Matthias; Kraal, Peter; Jilbert, Tom; Sulu-Gambari, Fatimah; Slomp, Caroline

    2016-04-01

    The sediments of the Black Sea are characterized by vast deposits of iron oxide-rich lake sediments below the current marine sediments. The lake sediments were deposited until ca. 9000 years ago when the former giant lake became connected to the Mediterranean Sea through post-glacial sea level rise. The subsequent downward diffusion of marine sulfate into the methane-bearing lake sediments has led to a multitude of diagenetic reactions in the sulfate-methane-transition zone (SMTZ), including anaerobic oxidation of methane (AOM) with sulfate. While the cycles of sulfur, methane and iron in the SMTZ have been extensively studied (e.g. Jorgensen et al., 2004), relatively little is known about the diagenetic alterations of the sediment record occurring directly below the SMTZ. Here, we combine detailed geochemical analyses of the sediment and pore water with multicomponent diagenetic modeling to study the diagenetic alterations below the SMTZ at two sites in the Black Sea. We focus on the dynamics of iron and phosphorus and demonstrate that downward sulfidization leads to dissolution of Fe-oxide bound P, Fe-carbonate and vivianite in the lake sediments. Below the sulfidization front, downward diffusing phosphate is bound again in vivianite. Trends in total sediment P with depth are significantly altered highlighting that diagenesis may strongly overprint burial records of P below a lake-marine transition. We also demonstrate that cryptic sulfur cycling cannot explain the observed release of dissolved Fe below the SMTZ. Instead, we suggest that organoclastic Fe-oxide reduction and/or AOM coupled to the reduction of Fe-oxides are the key processes explaining the high concentrations of dissolved Fe at depth in the sediment. Reference Jørgensen, B. B., Böttcher, M. E., Lüschen, H., Neretin, L. N. and Volkov, I. I.: Anaerobic methane oxidation and a deep H2S sink generate isotopically heavy sulfides in Black Sea sediments, Geochim. Cosmochim. Acta, 68(9), 2095-2118, 2004.

  10. Alteration by irradiation and storage at amount of heme iron in poultry meat

    International Nuclear Information System (INIS)

    Studies of irradiation and storage effects in chicken were carried out to discover the influence in iron heme, non-heme amount, color and total pigments. Chicken thighs and chicken breast were studied. These were irradiated to 0, 1 and 2 kGy stored by 14 days to 4 deg C in refrigerator. Determining the heme content and non-heme of meat was done using the colorimeter method and the Ferrozine reagent. The values of iron heme were influenced both by the irradiation and the storage, reducing the amount throughout the course of time. The iron non-heme was also influenced by the doses and the storage time, however the values increased throughout the course of time, because of the conversion of iron heme in non-heme. The color did not show that it was influenced by the studied doses, except for the storage, and the total number of pigments was affected by the irradiation and the time, reducing the values with the increase of storage. Irradiation was shown to be a good method to conserve iron. (author)

  11. Alteration by irradiation and storage at amount of heme iron in poultry meat

    International Nuclear Information System (INIS)

    Studies of irradiation and storage effects in chicken were carried out to discover the influence in iron heme, non-heme amount, color and total pigments. Chicken thighs and chicken breast were studied. These were irradiated to 0, 1 and 2 kGy stored by 14 days to 4 °C in refrigerator. Determining the heme content and non-heme of meat was done using the colorimeter method and the Ferrozine reagent. The values of iron heme were influenced both by the irradiation and the storage, reducing the amount throughout the course of time. The iron non-heme was also influenced by the doses and the storage time, however the values increased throughout the course of time, because of the conversion of iron heme in non-heme. The color did not show that it was influenced by the studied doses, except for the storage, and the total number of pigments was affected by the irradiation and the time, reducing the values with the increase of storage. Irradiation was shown to be a good method to conserve iron. (author)

  12. Serum iron test

    Science.gov (United States)

    ... of iron homeostasis: iron deficiency and overload. In: Hoffman R, Benz EJ Jr, Silberstein LE, et al, ... EJ, Gardner LB. Anemia of chronic diseases. In: Hoffman R, Benz EJ Jr, Silberstein LE, et al, ...

  13. Dysregulation of Iron Metabolism in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Satoru Oshiro

    2011-01-01

    Full Text Available Dysregulation of iron metabolism has been observed in patients with neurodegenerative diseases (NDs. Utilization of several importers and exporters for iron transport in brain cells helps maintain iron homeostasis. Dysregulation of iron homeostasis leads to the production of neurotoxic substances and reactive oxygen species, resulting in iron-induced oxidative stress. In Alzheimer's disease (AD and Parkinson's disease (PD, circumstantial evidence has shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation. Several genetic studies have revealed mutations in genes associated with increased iron uptake, increased oxidative stress, and an altered inflammatory response in amyotrophic lateral sclerosis (ALS. Here, we review the recent findings on brain iron metabolism in common NDs, such as AD, PD, and ALS. We also summarize the conventional and novel types of iron chelators, which can successfully decrease excess iron accumulation in brain lesions. For example, iron-chelating drugs have neuroprotective effects, preventing neural apoptosis, and activate cellular protective pathways against oxidative stress. Glial cells also protect neurons by secreting antioxidants and antiapoptotic substances. These new findings of experimental and clinical studies may provide a scientific foundation for advances in drug development for NDs.

  14. 2,3,7,8-Tetrachlorodibenzo-p-dioxin promotes BHV-1 infection in mammalian cells by interfering with iron homeostasis regulation.

    Directory of Open Access Journals (Sweden)

    Filomena Fiorito

    Full Text Available Mammalian cells require iron to satisfy metabolic needs or to accomplish specialized functions, and DNA viruses, like bovine herpesvirus 1 (BHV-1, require an iron-replete host to efficiently replicate, so that iron bioavailability is an important component of viral virulence. Cellular iron metabolism is coordinately controlled by the Iron Regulatory Proteins (IRP1 and IRP2, whose activity is affected by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, a current and persistent environmental contaminant. Considering that TCDD enhances BHV-1 replication, herein we analyzed the effects of TCDD on iron metabolism during BHV-1 infection in MDBK cells, and presented evidences of a divergent modulation of IRP1 and IRP2 RNA-binding capacity. Moreover, an up-regulation of transferrin receptor 1 (TfR1 and a concomitant down-regulation of ferritin were observed. This scenario led to an expansion of the labile iron pool (LIP and induces a significant enhance of viral titer, as confirmed by increased levels of BHV-1 infected cell protein 0 (bICP0, the major transcriptional regulatory protein of BHV-1. Taken together, our data suggest that TCDD increases the free intracellular iron availability thereby promoting the onset of BHV-1 infection and rendering bovine cells more vulnerable to the virus.

  15. Serum Albumin Alters the Expression of Pseudomonas Aeruginosa Iron Controlled Genes

    Science.gov (United States)

    The objectives of this study were to examine the effect serum on global transcription within P. aeruginosa at different phases of growth and the role of iron in this regulation. Results presented in this study suggest a novel mechanism through which serum regulates the expression of different P. ae...

  16. Acute hypoxic exercise does not alter post-exercise iron metabolism in moderately trained endurance athletes

    NARCIS (Netherlands)

    Govus, A.D.; Abbiss, C.R.; Garvican-Lewis, L.A.; Swinkels, D.W.; Laarakkers, C.M.; Gore, C.J.; Peeling, P.

    2014-01-01

    PURPOSE: This study measured the influence of acute hypoxic exercise on Interleukin-6 (IL-6), hepcidin, and iron biomarkers in athletes. METHODS: In a repeated measures design, 13 moderately trained endurance athletes performed 5 x 4 min intervals at 90 % of their peak oxygen consumption velocity (v

  17. Microarray analysis of rat pancreas reveals altered expression of Alox15 and regenerating islet-derived genes in response to iron deficiency and overload.

    Directory of Open Access Journals (Sweden)

    Richard Coffey

    Full Text Available It is well known that iron overload can result in pancreatic iron deposition, beta-cell destruction, and diabetes in humans. Recent studies in animals have extended the link between iron status and pancreatic function by showing that iron depletion confers protection against beta-cell dysfunction and diabetes. The aim of the present study was to identify genes in the pancreas that are differentially expressed in response to iron deficiency or overload. Weanling male Sprague-Dawley rats (n = 6/group were fed iron-deficient, iron-adequate, or iron-overloaded diets for 3 weeks to alter their iron status. Total RNA was isolated from the pancreases and pooled within each group for microarray analyses in which gene expression levels were compared to those in iron-adequate controls. In iron-deficient pancreas, a total of 66 genes were found to be differentially regulated (10 up, 56 down, whereas in iron-overloaded pancreas, 164 genes were affected (82 up, 82 down. The most up-regulated transcript in iron-deficient pancreas was arachidonate 15-lipoxygenase (Alox15, which has been implicated in the development of diabetes. In iron-overloaded pancreas, the most upregulated transcripts were Reg1a, Reg3a, and Reg3b belonging to the regenerating islet-derived gene (Reg family. Reg expression has been observed in response to pancreatic stress and is thought to facilitate pancreatic regeneration. Subsequent qRT-PCR validation indicated that Alox15 mRNA levels were 4 times higher in iron-deficient than in iron-adequate pancreas and that Reg1a, Reg3a, and Reg3b mRNA levels were 17-36 times higher in iron-overloaded pancreas. The elevated Alox15 mRNA levels in iron-deficient pancreas were associated with 8-fold higher levels of Alox15 protein as indicated by Western blotting. Overall, these data raise the possibility that Reg expression may serve as a biomarker for iron-related pancreatic stress, and that iron deficiency may adversely affect the risk of

  18. A Thyroid Hormone Challenge in Hypothyroid Rats Identifies T3 Regulated Genes in the Hypothalamus and in Models with Altered Energy Balance and Glucose Homeostasis

    OpenAIRE

    Herwig, Annika; Campbell, Gill; Mayer, Claus-Dieter; Boelen, Anita; Richard A. Anderson; Alexander W Ross; Mercer, Julian G.; Barrett, Perry

    2014-01-01

    Background: The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms.

  19. Research advances of iron homeostasis regulatory networks in Candida albicans%白念珠菌铁稳态调控网络研究进展

    Institute of Scientific and Technical Information of China (English)

    徐宁; 程欣欣; 喻其林; 邢来君; 李明春

    2012-01-01

    Iron is an essential element that is required for the growth and normal metabolism in most organisms. However, despite its much abundance in the Earth's crust, the bioavailable form of iron is very poor. To obtain iron in the environment, Candida albicans, as a common opportunistic human fugal pathogen, has evolved the iron regulatory networks to respond to the fluctuations in iron availability, which is associated with the adaptation to the hostile environment. As well as our study, this paper reviews the research advances of iron regulatory networks in recent years, focusing on the iron acquisition and regulatory strategies exhibited by C. Albicans when it responds to iron deprivation. This review also provides an insight into the mechanisms that how cellssense, transport, store and utilize iron.%铁是绝大多数生物生长和代谢过程中必需的营养元素.尽管自然界中铁元素含量非常丰富,但是其生物可利用性却很低.作为一种人体常见的条件致病真菌,白念珠菌在漫长的进化过程中形成了复杂的铁稳态调控网络,能够应答环境中铁浓度的变化,增强菌株对环境的适应力.结合课题组研究工作,简要综述近几年关于铁代谢表达调控途径的研究进展,主要关注白念珠菌在环境铁匮乏条件下铁获得和调控策略,揭示白念珠菌体内铁离子摄取、转运、储存和利用机制.

  20. Association Studies of HFE C282Y and H63D Variants with Oral Cancer Risk and Iron Homeostasis Among Whites and Blacks

    Directory of Open Access Journals (Sweden)

    Nathan R. Jones

    2015-12-01

    Full Text Available Background: Polymorphisms in the hemochromatosis (HFE gene are associated with excessive iron absorption from the diet, and pro-oxidant effects of iron accumulation are thought to be a risk factor for several types of cancer. Methods: The C282Y (rs1800562 and H63D (rs1799945 polymorphisms were genotyped in 301 oral cancer cases and 437 controls and analyzed in relation to oral cancer risk, and serum iron biomarker levels from a subset of 130 subjects. Results: Individuals with the C282Y allele had lower total iron binding capacity (TIBC (321.2 ± 37.2 µg/dL vs. 397.7 ± 89.0 µg/dL, p = 0.007 and higher percent transferrin saturation (22.0 ± 8.7 vs. 35.6 ± 22.9, p = 0.023 than wild type individuals. Iron and ferritin levels approached significantly higher levels for the C282Y allele (p = 0.0632 and p = 0.0588, respectively. Conclusions: Iron biomarker levels were elevated by the C282Y allele, but neither (rs1800562 nor (rs1799945 was associated with oral cancer risk in blacks and whites.

  1. Association Studies of HFE C282Y and H63D Variants with Oral Cancer Risk and Iron Homeostasis Among Whites and Blacks

    Science.gov (United States)

    Jones, Nathan R.; Ashmore, Joseph H.; Lee, Sang Y.; Richie, John P.; Lazarus, Philip; Muscat, Joshua E.

    2015-01-01

    Background: Polymorphisms in the hemochromatosis (HFE) gene are associated with excessive iron absorption from the diet, and pro-oxidant effects of iron accumulation are thought to be a risk factor for several types of cancer. Methods: The C282Y (rs1800562) and H63D (rs1799945) polymorphisms were genotyped in 301 oral cancer cases and 437 controls and analyzed in relation to oral cancer risk, and serum iron biomarker levels from a subset of 130 subjects. Results: Individuals with the C282Y allele had lower total iron binding capacity (TIBC) (321.2 ± 37.2 µg/dL vs. 397.7 ± 89.0 µg/dL, p = 0.007) and higher percent transferrin saturation (22.0 ± 8.7 vs. 35.6 ± 22.9, p = 0.023) than wild type individuals. Iron and ferritin levels approached significantly higher levels for the C282Y allele (p = 0.0632 and p = 0.0588, respectively). Conclusions: Iron biomarker levels were elevated by the C282Y allele, but neither (rs1800562) nor (rs1799945) was associated with oral cancer risk in blacks and whites. PMID:26690219

  2. What the Erythrocytic Nuclear Alteration Frequencies Could Tell Us about Genotoxicity and Macrophage Iron Storage?

    Science.gov (United States)

    Gomes, Juliana M. M.; Ribeiro, Heder J.; Procópio, Marcela S.; Alvarenga, Betânia M.; Castro, Antônio C. S.; Dutra, Walderez O.; da Silva, José B. B.; Corrêa Junior, José D.

    2015-01-01

    Erythrocytic nuclear alterations have been considered as an indicative of organism’s exposure to genotoxic agents. Due to their close relationship among their frequencies and DNA damages, they are considered excellent markers of exposure in eukaryotes. However, poor data has been found in literature concerning their genesis, differential occurrence and their life span. In this study, we use markers of cell viability; genotoxicity and cellular turn over in order to shed light to these events. Tilapia and their blood were exposed to cadmium in acute exposure and in vitro assays. They were analyzed using flow cytometry for oxidative stress and membrane disruption, optical microscopy for erythrocytic nuclear alteration, graphite furnace atomic absorption spectrometry for cadmium content in aquaria water, blood and cytochemical and analytical electron microscopy techniques for the hemocateretic aspects. The results showed a close relationship among the total nuclear alterations and cadmium content in the total blood and melanomacrophage centres area, mismatching reactive oxygen species and membrane damages. Moreover, nuclear alterations frequencies (vacuolated, condensed and blebbed) showed to be associated to cadmium exposure whereas others (lobed and bud) were associated to depuration period. Decrease on nuclear alterations frequencies was also associated with hemosiderin increase inside spleen and head kidney macrophages mainly during depurative processes. These data disclosure in temporal fashion the main processes that drive the nuclear alterations frequencies and their relationship with some cellular and systemic biomarkers. PMID:26619141

  3. Iron

    Science.gov (United States)

    ... as recommended by an obstetrician or other health care provider. Infants and toddlers Iron deficiency anemia in infancy can lead to delayed psychological development, social withdrawal, and less ability to pay attention. By age 6 to 9 months, full-term infants could ...

  4. Long-term alteration of bentonite in the presence of metallic iron

    Energy Technology Data Exchange (ETDEWEB)

    Kumpulainen, Sirpa; Kiviranta, Leena (BandTech Oy (Finland)); Carlsson, Torbjoern; Muurinen, Arto (VTT (Finland)); Svensson, Daniel (Svensk Kaernbraenslehantering AB (Sweden)); Sasamoto, Hiroshi; Yui, Mikatzu (JAEA (Japan)); Wersin, Paul; Rosch, Dominic (Gruner Ltd (Switzerland))

    2010-05-15

    According to the KBS-3H concept, each copper canister containing spent nuclear fuel will be surrounded by a bentonite buffer and a perforated steel cylinder. Since steel is unstable in wet bentonite, it will corrode and the corrosion products will interact with the surrounding bentonite in ways that are not fully understood. Such interaction may seriously impair the bentonite's functioning as a buffer material, e.g. by lowering its CEC or decreasing its swelling capacity. This report presents results from two iron-bentonite experiments carried out under quite different conditions at VTT (Finland) and JAEA (Japan). Both studies focused on long-term iron-bentonite interactions under anaerobic conditions. The study at VTT comprised eight years long experiments focused on diffusive based interactions between solid cast-iron and compacted MX-80 bentonite (dry density 1.5-1.6 g/cm3) in contact with an aqueous 0.5 M NaCl solution. The study at JAEA comprised ten years long batch experiments, each involving a mixture of metallic iron powder (25 g), an industrially refined Na bentonite, Kunipia F, which contains more than 99% montmorillonite (25 g), and an aqueous solution (250 mL). Samples were sent to B+Tech in airtight steel vessels filled with N{sub 2} and subsequently analyzed at various laboratories in Finland and Sweden. The JAEA samples differed with regard to the initial solution chemistry, which was either distilled water, 0.3 M NaCl, 0.6 M NaCl, 0.1 M NaHCO{sub 3}, or 0.05 M Na{sub 2}SO{sub 4}. The analyses of the MX-80 bentonite samples were carried out on samples containing a cast iron cylinder and also on corresponding background samples with no cast iron. In addition, the external solution and gas phase in contact with the bentonite were analyzed. Briefly, the gas contained H{sub 2}, most possibly caused by corrosion of the cast iron, and CO{sub 2}, mainly as a result of carbonate dissolution. The eight years old external solution exhibited, inter alia

  5. Long-term alteration of bentonite in the presence of metallic iron

    International Nuclear Information System (INIS)

    According to the KBS-3H concept, each copper canister containing spent nuclear fuel will be surrounded by a bentonite buffer and a perforated steel cylinder. Since steel is unstable in wet bentonite, it will corrode and the corrosion products will interact with the surrounding bentonite in ways that are not fully understood. Such interaction may seriously impair the bentonite's functioning as a buffer material, e.g. by lowering its CEC or decreasing its swelling capacity. This report presents results from two iron-bentonite experiments carried out under quite different conditions at VTT (Finland) and JAEA (Japan). Both studies focused on long-term iron-bentonite interactions under anaerobic conditions. The study at VTT comprised eight years long experiments focused on diffusive based interactions between solid cast-iron and compacted MX-80 bentonite (dry density 1.5-1.6 g/cm3) in contact with an aqueous 0.5 M NaCl solution. The study at JAEA comprised ten years long batch experiments, each involving a mixture of metallic iron powder (25 g), an industrially refined Na bentonite, Kunipia F, which contains more than 99% montmorillonite (25 g), and an aqueous solution (250 mL). Samples were sent to B+Tech in airtight steel vessels filled with N2 and subsequently analyzed at various laboratories in Finland and Sweden. The JAEA samples differed with regard to the initial solution chemistry, which was either distilled water, 0.3 M NaCl, 0.6 M NaCl, 0.1 M NaHCO3, or 0.05 M Na2SO4. The analyses of the MX-80 bentonite samples were carried out on samples containing a cast iron cylinder and also on corresponding background samples with no cast iron. In addition, the external solution and gas phase in contact with the bentonite were analyzed. Briefly, the gas contained H2, most possibly caused by corrosion of the cast iron, and CO2, mainly as a result of carbonate dissolution. The eight years old external solution exhibited, inter alia, reducing conditions, a pH of around eight

  6. Exposure to Bisphenol-A during Pregnancy Partially Mimics the Effects of a High-Fat Diet Altering Glucose Homeostasis and Gene Expression in Adult Male Mice

    OpenAIRE

    Marta García-Arevalo; Paloma Alonso-Magdalena; Junia Rebelo Dos Santos; Ivan Quesada; Carneiro, Everardo M.; Angel Nadal

    2014-01-01

    Bisphenol-A (BPA) is one of the most widespread EDCs used as a base compound in the manufacture of polycarbonate plastics. The aim of our research has been to study how the exposure to BPA during pregnancy affects weight, glucose homeostasis, pancreatic β-cell function and gene expression in the major peripheral organs that control energy flux: white adipose tissue (WAT), the liver and skeletal muscle, in male offspring 17 and 28 weeks old. Pregnant mice were treated with a subcutaneous injec...

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

    Science.gov (United States)

    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

  8. Iron Dextran Increases Hepatic Oxidative Stress and Alters Expression of Genes Related to Lipid Metabolism Contributing to Hyperlipidaemia in Murine Model

    Directory of Open Access Journals (Sweden)

    Maísa Silva

    2015-01-01

    Full Text Available 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.

  9. Long-term alteration of bentonite in the presence of metallic iron

    Energy Technology Data Exchange (ETDEWEB)

    Kumpulainen, S.; Kiviranta, L. [B and Tech Oy, Helsinki (Finland); Carlsson, T.; Muurinen, A. [VTT Technical Research Centre of Finland, Espoo (Finland); Svensson, D. [Svensk Kaernbraenslehantering AB (SKB), Stockholm (Sweden); Sasamoto, Hiroshi; Yui, Mikatzu [Japan Atomic Energy Agency (JAEA) (Japan); Wersin, P.; Rosch, D. [Gruner Ltd, Basel (Switzerland)

    2011-12-15

    According to the KBS-3H concept, each copper canister containing spent nuclear fuel will be surrounded by a bentonite buffer and a perforated steel cylinder. Since steel is unstable in wet bentonite, it will corrode and the corrosion products will interact with the surrounding bentonite in ways that are not fully understood. Such interaction may seriously impair the bentonite's functioning as a buffer material, e.g. by lowering its CEC or decreasing its swelling capacity. This report presents results from two ironbentonite experiments carried out under quite different conditions at VTT (Finland) and JAEA (Japan). Both studies focused on long-term iron-bentonite interactions under anaerobic conditions. The study at VTT comprised eight years long experiments focused on diffusive based interactions between solid cast-iron and compacted MX-80 bentonite (dry density 1.5- 1.6 g/cm{sup 3}) in contact with an aqueous 0.5 M NaCl solution. The study at JAEA comprised ten years long batch experiments, each involving a mixture of metallic iron powder (25 g), an industrially refined Na bentonite, Kunipia F, which contains more than 99% montmorillonite (25 g), and an aqueous solution (250 mL). Samples were sent to B and Tech in airtight steel vessels filled with N{sub 2} and subsequently analyzed at various laboratories in Finland and Sweden. The JAEA samples differed with regard to the initial solution chemistry, which was either distilled water, 0.3 M NaCl, 0.6 M NaCl, 0.1 M NaHCO{sub 3}, or 0.05 M Na{sub 2}SO{sub 4}. The analyses of the MX-80 bentonite samples were carried out on samples containing a cast iron cylinder and also on corresponding background samples with no cast iron. In addition, the external solution and gas phase in contact with the bentonite were analyzed. Briefly, the gas contained H{sub 2}, most possibly caused by corrosion of the cast iron, and CO{sub 2}, mainly as a result of carbonate dissolution. The eight years old external solution exhibited

  10. Long-term alteration of bentonite in the presence of metallic iron

    International Nuclear Information System (INIS)

    According to the KBS-3H concept, each copper canister containing spent nuclear fuel will be surrounded by a bentonite buffer and a perforated steel cylinder. Since steel is unstable in wet bentonite, it will corrode and the corrosion products will interact with the surrounding bentonite in ways that are not fully understood. Such interaction may seriously impair the bentonite's functioning as a buffer material, e.g. by lowering its CEC or decreasing its swelling capacity. This report presents results from two ironbentonite experiments carried out under quite different conditions at VTT (Finland) and JAEA (Japan). Both studies focused on long-term iron-bentonite interactions under anaerobic conditions. The study at VTT comprised eight years long experiments focused on diffusive based interactions between solid cast-iron and compacted MX-80 bentonite (dry density 1.5- 1.6 g/cm3) in contact with an aqueous 0.5 M NaCl solution. The study at JAEA comprised ten years long batch experiments, each involving a mixture of metallic iron powder (25 g), an industrially refined Na bentonite, Kunipia F, which contains more than 99% montmorillonite (25 g), and an aqueous solution (250 mL). Samples were sent to B and Tech in airtight steel vessels filled with N2 and subsequently analyzed at various laboratories in Finland and Sweden. The JAEA samples differed with regard to the initial solution chemistry, which was either distilled water, 0.3 M NaCl, 0.6 M NaCl, 0.1 M NaHCO3, or 0.05 M Na2SO4. The analyses of the MX-80 bentonite samples were carried out on samples containing a cast iron cylinder and also on corresponding background samples with no cast iron. In addition, the external solution and gas phase in contact with the bentonite were analyzed. Briefly, the gas contained H2, most possibly caused by corrosion of the cast iron, and CO2, mainly as a result of carbonate dissolution. The eight years old external solution exhibited, inter alia, reducing conditions, a pH of around

  11. Manganese Disturbs Metal and Protein Homeostasis in Caenorhabditis elegans

    Science.gov (United States)

    Angeli, Suzanne; Barhydt, Tracy; Jacobs, Ross; Killilea, David W.; Lithgow, Gordon J.; Andersen, Julie K.

    2014-01-01

    Parkinson's disease (PD) is a debilitating motor and cognitive neurodegenerative disorder for which there is no cure. While aging is the major risk factor for developing PD, clear environmental risks have also been identified. Environmental exposure to the metal manganese (Mn) is a prominent risk factor for developing PD and occupational exposure to high levels of Mn can cause a syndrome known as manganism, which has symptoms that closely resemble PD. In this study, we developed a model of manganism in the environmentally tractable nematode, Caenorhabditis elegans. We find that, in addition to previously described modes of Mn toxicity, which primarily include mitochondrial dysfunction and oxidative stress, Mn exposure also significantly antagonizes protein homeostasis, another key pathological feature associated with PD and many age-related neurodegenerative diseases. Mn treatment activates the ER unfolded protein response, severely exacerbates toxicity in a disease model of protein misfolding, and alters aggregate solubility. Further, aged animals, which have previously been shown to exhibit decreased protein homeostasis, are particularly susceptible to Mn toxicity when compared to young animals, indicating the aging process sensitizes animals to metal toxicity. Mn exposure also significantly alters iron (Fe) and calcium (Ca) homeostasis, which are important for mitochondrial and ER health and which may further compound toxicity. These finding indicate that modeling manganism in C. elegans can provide a useful platform for identifying therapeutic interventions for ER stress, proteotoxicity, and age-dependent susceptibilities, key pathological features of PD and other related neurodegenerative diseases. PMID:25057947

  12. Alcohol disrupts sleep homeostasis.

    Science.gov (United States)

    Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep

    2015-06-01

    Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired

  13. Iron Mineralogy and Aqueous Alteration on Mars from the MER Moessbauer Spectrometers. Chapter 15

    Science.gov (United States)

    Morris, Richard V.; Klingelhoefer, Goestar

    2007-01-01

    The twin Mars Exploration Rovers Spirit (Gusev crater) and Opportunity (Meridiani Planum) used MIMOS II Moessbauer spectrometers to analyze martian surface materials in the first application of extraterrestrial Moessbauer spectroscopy. The instruments acquired spectra that identified the speciation of Fe according to oxidation state, coordination state, and mineralogical composition and provided quantitative information about the distribution of Fe among oxidation states, coordination states, and Fe-bearing phases. A total of 12 unique Fe-bearing phases were identified: Fe(2+) in olivine, pyroxene, and ilmenite; Fe(2+) and Fe(3+) in magnetite and chromite; Fe(3+) in nanophase ferric oxide (npOx), hematite, goethite, jarosite, an unassigned Fe3+ sulfate, and an unassigned Fe(3+) phase associated with jarosite; and Fe(0) in kamacite. Weakly altered basalts at Gusev crater (SO3 = 2.5 +/- 1.4 wt.% and Fe(3+)/Fe(sub T) = 0.24 +/- 0.11) are widespread on the Gusev plains and occur in less abundance on West Spur and Husband Hill in the Columbia Hills. Altered low-S rocks (SO3 = 5.2 +/- 2.0 wt.% and Fe(3+)/Fe(sub T) = 0.63 +/- 0.18) are the most common type of rock in the Columbia Hills. Ilm-bearing, weakly altered basalts were detected only in the Columbia Hills, as was the only occurrence of chromite in an altered low-S rock named Assemblee. Altered high-S rocks (SO3 > 14.2 wt.% and Fe(3+)/Fe(sub T) = 0.83 +/- 0.05) are the outcrop rocks of the ubiquitous Burns formation at Meridiani Planum. Two Fe(0)-bearing rocks at Meridiani Planum (Barberton and Heat Shield Rock) are meteorites. Laguna Class soil is weakly altered (SO3 = 6 +/- 2 wt.% and Fe(3+)/Fe(sub T) = 0.29 +/- 0.08) and widely distributed at both Gusev crater and Meridiani Planum, implying efficient global mixing processes or a global distribution of precursor rocks with comparable Fe mineralogical compositions. Paso Robles Class soil is heavily altered (SO3 approx. 31 wt.% and Fe(3+)/Fe(sub T) = 0.83 +/- 0

  14. Evidence for mechanical and chemical alteration of iron-nickel meteorites on Mars: Process insights for Meridiani Planum

    Science.gov (United States)

    Ashley, James W.; Golombek, M.P.; Christensen, P.R.; Squyres, S. W.; McCoy, T.J.; Schroder, C.; Fleischer, I.; Johnson, J. R.; Herkenhoff, K. E.; Parker, T.J.

    2011-01-01

    The weathering of meteorites found on Mars involves chemical and physical processes that can provide clues to climate conditions at the location of their discovery. Beginning on sol 1961, the Opportunity rover encountered three large iron meteorites within a few hundred meters of each other. In order of discovery, these rocks have been assigned the unofficial names Block Island, Shelter Island, and Mackinac Island. Each rock presents a unique but complimentary set of features that increase our understanding of weathering processes at Meridiani Planum. Significant morphologic characteristics interpretable as weathering features include (1) a large pit in Block Island, lined with delicate iron protrusions suggestive of inclusion removal by corrosive interaction; (2) differentially eroded kamacite and taenite lamellae in Block Island and Shelter Island, providing relative timing through crosscutting relationships with deposition of (3) an iron oxide-rich dark coating; (4) regmaglypted surfaces testifying to regions of minimal surface modification, with other regions in the same meteorites exhibiting (5) large-scale, cavernous weathering (in Shelter Island and Mackinac Island). We conclude that the current size of the rocks is approximate to their original postfall contours. Their morphology thus likely results from a combination of atmospheric interaction and postfall weathering effects. Among our specific findings is evidence supporting (1) at least one possible episode of aqueous acidic exposure for Block Island; (2) ripple migration over portions of the meteorites; (3) a minimum of two separate episodes of wind abrasion; alternating with (4) at least one episode of coating-forming chemical alteration, most likely at subzero temperatures. Copyright 2011 by the American Geophysical Union.

  15. In male rats with concurrent iron and (n-3) fatty acid deficiency, provision of either iron or (n-3) fatty acids alone alters monoamine metabolism and exacerbates the cognitive deficits associated with combined deficiency

    NARCIS (Netherlands)

    Baumgartner, J.; Smuts, C.M.; Malan, L.; Arnold, M.; Yee, B.K.; Bianco, L.E.; Boekschoten, M.V.; Muller, M.R.; Langhans, W.; Hurrell, R.F.; Zimmermann, M.B.

    2012-01-01

    Concurrent deficiencies of iron (Fe) (ID) and (n-3) fatty acids [(n-3)FAD)] in rats can alter brain monoamine pathways and impair learning and memory. We examined whether repletion with Fe and DHA/EPA, alone and in combination, corrects the deficits in brain monoamine activity (by measuring monoamin

  16. Impacto da inflamação na regulação do ferro e deficiência funcional de ferro Importance of inflammation on iron homeostasis and functional iron deficiency

    Directory of Open Access Journals (Sweden)

    Maria Stella Figueiredo

    2010-06-01

    Full Text Available Deficiência funcional de ferro (Fe pode ser definida como o desbalanço entre a quantidade necessária de Fe para a síntese de hemoglobina e o seu suprimento. Ela ocorre na ausência de estoque de Fe, característica da anemia ferropênica (AF, e na presença de bloqueio da homeostasia do Fe, como na anemia da inflamação (AI. Na AI, citocinas e células do sistema retículo-endotelial induzem alterações que interferem em diferentes vias da eritropoese levando à anemia. O bloqueio na mobilização do Fe de estoque pela hepcidina, embora não único, é o mecanismo etiológico mais evidente da AI. A hepcidina, regulador negativo da entrada de Fe no plasma, atua ligando-se à ferroportina, induzindo sua internalização e degradação. Embora a diferenciação entre AF e AI seja relativamente tranquila, pacientes com AI podem cursar com deficiência de Fe associada. O diagnóstico diferencial entre AI e AI com deficiência de Fe tem evidente importância clínica, e novas técnicas laboratoriais têm sido sugeridas para auxiliar neste diagnóstico.Functional iron deficiency can be defined as an imbalance between the iron needs of the erythroid marrow and iron supply. Iron deficiency occurs in the absence of iron deposits, as in the case of iron deficiency anemia (IDA, or when there is an impaired iron mobilization, such as in anemia of inflammation (AI. Cytokines and cells of the reticuloendothelial system can induce changes in several pathways, interfering in erythropoiesis and causing anemia. The retention of iron within cells of the reticuloendothelial system is due to hepcidin. Although this is not the only mechanism evolved in AI, it is the most important. Hepcidin is a negative regulator of iron entry into the plasma. Hepcidin binds to ferroportin, inducing its internalization and degradation. Differentiation between IDA and AI is relatively easy, but patients with AI can have the association of true iron deficiency. The differential

  17. Hemojuvelin在铁稳态平衡中的关键作用%The critical role of Hemojuvelin in iron homeostasis

    Institute of Scientific and Technical Information of China (English)

    陈文杰; 王福俤

    2012-01-01

    Hepcidin, a peptide hormone secreted by the liver, regulates systemic iron metabolism by changing the levels of ferroportin on the cell membrane. Ferroportin, the only known mammalian cellular iron exporter, is expressed on the basolateral membrane of small intestinal enterocytes and the plasma membrane of macrophages. Hepcidin binding of ferroportin leads to internalization and degradation of ferroportin in lysosomes, which decreases iron absorption from the diet and iron release from macrophages that recycle iron from senescent erythrocytes. Hemojuvelin (HJV), a glycosylphosphatidyl inositol (GPI) -linked membrane protein, acts as a bone morphogenetic protein (BMP) co-receptor to activate hepcidin expression through a SMAD signaling pathway in hepatocytes. In addition to residing on the cell membrane, hemojuvelin can be cleaved and secreted from cells in a soluble form. Soluble hemojuvelin, produced after cleavage by furin, can selectively bind to BMP ligands and inhibit endogenous and BMP-induced hepcidin expression. TMPRSS6 has been shown to cleave hemojuvelin on the cell membrane and affect hepcidin expression. Most recent studies suggest HJV may be involved in the regulation of iron metabolism by adipose tissue. This review summarizes the current understanding of the mechanism by which membrane HJV and soluble HJV regulate hepcidin expression and iron metabolism. We also discuss gaps in the knowledge that will need to be filled by future research.%铁调素(hepcidin)是由肝脏分泌的一种肽类激素,它通过改变细胞膜上ferroportin的水平而调节全身铁代谢.Ferroportin是唯一已知的哺乳动物中的铁外排通道,它表达在小肠细胞的基底外侧膜和巨噬细胞的质膜上.铁调素结合ferroportin导致其在溶酶体内降解,从而减少铁从饮食的吸收和巨噬细胞铁的释放.Hemojuvelin (HJV)是一种glycosylphosphatidyl inositol (GPI)相连的膜蛋白,它作为骨形态发生蛋白(BMP)的共受体可以激

  18. Four weeks of normobaric "live high-train low" do not alter muscular or systemic capacity for maintaining pH and K+ homeostasis during intense exercise

    DEFF Research Database (Denmark)

    Nordsborg, Nikolai B; Siebenmann, C; Jacobs, R A;

    2012-01-01

    was double-blind and placebo controlled. Mean power during 30-s all-out cycling was similar before and immediately after LHTL (650 ± 31 vs. 628 ± 32 W; n = 10) and placebo exposure (658 ± 22 vs. 660 ± 23 W; n = 6). Supporting the performance data, arterial plasma pH, lactate, and K(+) during submaximal......It was investigated if athletes subjected to 4 wk of living in normobaric hypoxia (3,000 m; 16 h/day) while training at 800-1,300 m ["live high-train low" (LHTL)] increase muscular and systemic capacity for maintaining pH and K(+) homeostasis as well as intense exercise performance. The design...... and maximal exercise were also unaffected by the intervention in both groups. In addition, muscle buffer capacity (in mmol H(+)·kg dry wt(-1)·pH(-1)) was similar before and after in both the LHTL (140 ± 12 vs. 140 ± 16) and placebo group (145 ± 2 vs. 140 ± 3). The expression of sarcolemmal H(+) transporters...

  19. The role of miR-126 in embryonic angiogenesis, adult vascular homeostasis, and vascular repair and its alterations in atherosclerotic disease.

    Science.gov (United States)

    Chistiakov, Dimitry A; Orekhov, Alexander N; Bobryshev, Yuri V

    2016-08-01

    Expression of microRNA (miR)-126 is enriched in endothelial cells (ECs) and endothelial progenitor cells (EPCs). MiR-126 is considered a master regulator of physiological angiogenesis. In embryonic vasculogenesis, this miRNA is involved in induction of angiogenic signaling, supports differentiation of embryonic stem cells to EPCs and ECs, and promotes EC maturation. However, in mature ECs and adult EPCs, miR-126 contributes to vascular homeostasis by inhibiting angiogenesis and maintaining the quiescent endothelial phenotype associated with increased vascular integrity and inhibited proliferation and motility. In a case of vessel injury and/or hypoxia, miR-126 up-regulation activates EPCs and ECs and contributes to vascular healing and neovessel formation. Indeed, miR-126 exhibits vasculoprotective and atheroprotective properties. The promising regenerative and proangiogenic potential of this miRNA will be helpful for development of cardioprotective strategies and cardiovascular repair therapies of myocardial infarction, heart failure, and other cardiovascular pathology. PMID:27180261

  20. Impairment of interrelated iron- and copper homeostatic mechanisms in brain contributes to the pathogenesis of neurodegenerative disorders

    DEFF Research Database (Denmark)

    Skjørringe, Tina; Møller, Lisbeth Birk; Moos, Torben

    2012-01-01

    is strictly regulated, and concordantly protective barriers, i.e., the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCB) have evolved to separate the brain environment from the circulation. The uptake mechanisms of the two metals interact. Both iron deficiency and overload lead......Iron and copper are important co-factors for a number of enzymes in the brain, including enzymes involved in neurotransmitter synthesis and myelin formation. Both shortage and an excess of iron or copper will affect the brain. The transport of iron and copper into the brain from the circulation...... to altered copper homeostasis in the brain. Similarly, changes in dietary copper affect the brain iron homeostasis. Moreover, the uptake routes of iron and copper overlap each other which affect the interplay between the concentrations of the two metals in the brain. The divalent metal transporter-1 (DMT1...

  1. The Role of the Cytoplasmic Heme-binding Protein (PhuS) of Pseudomonas aeruginosa in Intracellular Heme Trafficking and Iron Homeostasis*S⃞

    OpenAIRE

    Kaur, Ajinder P.; Lansky, Ila B.; Wilks, Angela

    2009-01-01

    The cytoplasmic heme-binding protein PhuS, encoded within the Fur-regulated Pseudomonas heme utilization (phu) operon, has previously been shown to traffic heme to the iron-regulated heme oxygenase (HO). We further investigate the role of PhuS in heme trafficking to HO on disruption of the phuS and hemO genes in a Pseudomonas aeruginosa siderophore-deficient and wild-type background. Previous studies have shown that deletion of hemO prevents the cells from utilizin...

  2. Exposure to bisphenol-A during pregnancy partially mimics the effects of a high-fat diet altering glucose homeostasis and gene expression in adult male mice.

    Directory of Open Access Journals (Sweden)

    Marta García-Arevalo

    Full Text Available Bisphenol-A (BPA is one of the most widespread EDCs used as a base compound in the manufacture of polycarbonate plastics. The aim of our research has been to study how the exposure to BPA during pregnancy affects weight, glucose homeostasis, pancreatic β-cell function and gene expression in the major peripheral organs that control energy flux: white adipose tissue (WAT, the liver and skeletal muscle, in male offspring 17 and 28 weeks old. Pregnant mice were treated with a subcutaneous injection of 10 µg/kg/day of BPA or a vehicle from day 9 to 16 of pregnancy. One month old offspring were divided into four different groups: vehicle treated mice that ate a normal chow diet (Control group; BPA treated mice that also ate a normal chow diet (BPA; vehicle treated animals that had a high fat diet (HFD and BPA treated animals that were fed HFD (HFD-BPA. The BPA group started to gain weight at 18 weeks old and caught up to the HFD group before week 28. The BPA group as well as the HFD and HFD-BPA ones presented fasting hyperglycemia, glucose intolerance and high levels of non-esterified fatty acids (NEFA in plasma compared with the Control one. Glucose stimulated insulin release was disrupted, particularly in the HFD-BPA group. In WAT, the mRNA expression of the genes involved in fatty acid metabolism, Srebpc1, Pparα and Cpt1β was decreased by BPA to the same extent as with the HFD treatment. BPA treatment upregulated Pparγ and Prkaa1 genes in the liver; yet it diminished the expression of Cd36. Hepatic triglyceride levels were increased in all groups compared to control. In conclusion, male offspring from BPA-treated mothers presented symptoms of diabesity. This term refers to a form of diabetes which typically develops in later life and is associated with obesity.

  3. A magnetic-dependent protein corona of tailor-made superparamagnetic iron oxides alters their biological behaviors

    Science.gov (United States)

    Liu, Ziyao; Zhan, Xiaohui; Yang, Minggang; Yang, Qi; Xu, Xianghui; Lan, Fang; Wu, Yao; Gu, Zhongwei

    2016-03-01

    In recent years, it is becoming increasingly evident that once nanoparticles come into contact with biological fluids, a protein corona surely forms and critically affects the biological behaviors of nanoparticles. Herein, we investigate whether the formation of protein corona on the surface of superparamagnetic iron oxides (SPIOs) is influenced by static magnetic field. Under static magnetic field, there is no obvious variation in the total amount of protein adsorption, but the proportion of adsorbed proteins significantly changes. Noticeably, certain proteins including apolipoproteins, complement system proteins and acute phase proteins, increase in the protein corona of SPIOs in the magnetic field. More importantly, the magnetic-dependent protein corona of SPIOs enhances the cellular uptake of SPIOs into the normal cell line (3T3 cells) and tumor cell line (HepG2 cells), due to increased adsorption of apolipoprotein. In addition, SPIOs with the magnetic-dependent protein corona cause high cytotoxicity to 3T3 cells and HepG2 cells. This work discloses that superparamagnetism as a key feature of SPIOs affects the composition of protein corona to a large extent, which further alters the biological behaviors of SPIOs.In recent years, it is becoming increasingly evident that once nanoparticles come into contact with biological fluids, a protein corona surely forms and critically affects the biological behaviors of nanoparticles. Herein, we investigate whether the formation of protein corona on the surface of superparamagnetic iron oxides (SPIOs) is influenced by static magnetic field. Under static magnetic field, there is no obvious variation in the total amount of protein adsorption, but the proportion of adsorbed proteins significantly changes. Noticeably, certain proteins including apolipoproteins, complement system proteins and acute phase proteins, increase in the protein corona of SPIOs in the magnetic field. More importantly, the magnetic-dependent protein

  4. Impairment of interrelated iron- and copper homeostatic mechanisms in brain contributes to the pathogenesis of neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Tina eSkjørringe

    2012-09-01

    Full Text Available Iron and copper are important co-factors for a number of enzymes in the brain, including enzymes involved in neurotransmitter synthesis and myelin formation. Both shortage and an excess of iron or copper will affect the brain. The transport of iron and copper into the brain from the circulation is strictly regulated, and concordantly protective barriers i.e. the blood-brain barrier (BBB and the blood-cerebrospinal fluid (CSF barrier (BCB have evolved to separate the brain environment from the circulation. The uptake mechanisms of the two metals interact. Both iron deficiency and overload lead to altered copper homeostasis in the brain. Similarly, changes in dietary copper affect the brain-iron homeostasis. Moreover, the uptake routes of iron and copper overlap each other which affect the interplay between the concentrations of the two metals in the brain. The divalent metal transporter-1 (DMT1 is involved in the uptake of both iron and copper. Furthermore, copper is an essential co-factor in numerous proteins that are vital for iron homeostasis and affects the binding of iron-response proteins to iron-response elements in the mRNA of the transferrin receptor, DMT1 and ferroportin, all highly involved in iron transport. Iron and copper are mainly taken up at the BBB, but the BCB also plays a vital role in the homeostasis of the two metals, in terms of sequestering, uptake and efflux of iron and copper from the brain. Inside the brain, iron and copper are taken up by neurons and glia cells that express various transporters

  5. Alterations of systemic and muscle iron metabolism in human subjects treated with low-dose recombinant erythropoietin

    DEFF Research Database (Denmark)

    Robach, Paul; Recalcati, Stefania; Girelli, Domenico;

    2009-01-01

    The high iron demand associated with enhanced erythropoiesis during high-altitude hypoxia leads to skeletal muscle iron mobilization and decrease in myoglobin protein levels. To investigate the effect of enhanced erythropoiesis on systemic and muscle iron metabolism under nonhypoxic conditions, 8...

  6. Iron oxide nanoparticles induced alterations in haematological, biochemical and ionoregulatory responses of an Indian major carp Labeo rohita

    Energy Technology Data Exchange (ETDEWEB)

    Saravanan, M.; Suganya, R.; Ramesh, M., E-mail: mathanramesh@yahoo.com; Poopal, R. K. [Bharathiar University, Unit of Toxicology, Department of Zoology, School of Life Sciences (India); Gopalan, N. [Bharathiar University, DRDO-BU (India); Ponpandian, N. [Bharathiar University, Department of Nanoscience and Technology (India)

    2015-06-15

    The wide use of iron oxide nanoparticles (Fe{sub 2}O{sub 3} NPs) in various applications has raised great concerns worldwide. In this work, we measured the potential harmful effects of Fe{sub 2}O{sub 3} NP (<50 nm) at concentrations of 1 and 25 mg/L on haematological, biochemical, and ionoregulatory responses in an Indian major carp, Labeo rohita for a short-term period of 96 h. The results revealed significant (P < 0.05) decreases in haemoglobin, haematocrit, mean cellular volume, mean cellular haemoglobin, protein, sodium (Na{sup +}), potassium (K{sup +}), chloride (Cl{sup −}) and gill Na{sup +}/K{sup +}-ATPase levels in both the concentrations. White blood cell, mean cellular haemoglobin concentration and glucose levels were significantly (P < 0.05) increased in response to both concentrations during the study period. However, no significant changes in red blood cell count and gill Na{sup +}/K{sup +}-ATPase (25 mg/L) activity were noticed compared to those of the respective control groups. Based on this study, it was found that the Fe{sub 2}O{sub 3} NPs do have prominent effects on freshwater fish L. rohita. Our data suggest that the alterations of these parameters can be used as nonspecific biomarkers to monitor the environmental risks arising from nanoparticles in aquatic ecosystem and also regulate the use, production and release of nanoparticles.

  7. The presence of serum alters the properties of iron oxide nanoparticles and lowers their accumulation by cultured brain astrocytes

    International Nuclear Information System (INIS)

    Iron oxide nanoparticles (IONPs) are considered for various diagnostic and therapeutic applications. Such particles are able to cross the blood–brain barrier and are taken up into brain cells. To test whether serum components affect the properties of IONPs and/or their uptake into brain cells, we have incubated dimercaptosuccinate-coated magnetic IONPs without and with fetal calf serum (FCS) and have exposed cultured brain astrocytes with IONPs in the absence or presence of FCS. Incubation with FCS caused a concentration-dependent increase in the average hydrodynamic diameter of the particles and of their zeta-potential. In the presence of 10 % FCS, the diameter of the IONPs increased from 57 ± 2 to 107 ± 6 nm and the zeta-potential of the particles from −22 ± 5 to −9 ± 1 mV. FCS affected also strongly the uptake of IONPs by cultured astrocytes. The efficient time- and temperature-dependent cellular accumulation of IONPs was lowered with increasing concentration of FCS by up to 90 %. In addition, in the absence of serum, endocytosis inhibitors did not alter the IONP accumulation by astrocytes, while chlorpromazine or wortmannin lowered significantly the accumulation of IONPs in the presence of FCS, suggesting that clathrin-mediated endocytosis and macropinocytosis are involved in astrocytic IONP uptake from serum-containing medium. These data demonstrate that the presence of FCS strongly affects the properties of IONPs as well as their accumulation by cultured brain cells.

  8. A magnetic-dependent protein corona of tailor-made superparamagnetic iron oxides alters their biological behaviors.

    Science.gov (United States)

    Liu, Ziyao; Zhan, Xiaohui; Yang, Minggang; Yang, Qi; Xu, Xianghui; Lan, Fang; Wu, Yao; Gu, Zhongwei

    2016-04-14

    In recent years, it is becoming increasingly evident that once nanoparticles come into contact with biological fluids, a protein corona surely forms and critically affects the biological behaviors of nanoparticles. Herein, we investigate whether the formation of protein corona on the surface of superparamagnetic iron oxides (SPIOs) is influenced by static magnetic field. Under static magnetic field, there is no obvious variation in the total amount of protein adsorption, but the proportion of adsorbed proteins significantly changes. Noticeably, certain proteins including apolipoproteins, complement system proteins and acute phase proteins, increase in the protein corona of SPIOs in the magnetic field. More importantly, the magnetic-dependent protein corona of SPIOs enhances the cellular uptake of SPIOs into the normal cell line (3T3 cells) and tumor cell line (HepG2 cells), due to increased adsorption of apolipoprotein. In addition, SPIOs with the magnetic-dependent protein corona cause high cytotoxicity to 3T3 cells and HepG2 cells. This work discloses that superparamagnetism as a key feature of SPIOs affects the composition of protein corona to a large extent, which further alters the biological behaviors of SPIOs.

  9. The presence of serum alters the properties of iron oxide nanoparticles and lowers their accumulation by cultured brain astrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Geppert, Mark; Petters, Charlotte [University of Bremen, Centre for Biomolecular Interactions Bremen (Germany); Thiel, Karsten [Fraunhofer Institute for Manufacturing Technology and Advanced Materials (Germany); Dringen, Ralf, E-mail: ralf.dringen@uni-bremen.de [University of Bremen, Centre for Biomolecular Interactions Bremen (Germany)

    2013-01-15

    Iron oxide nanoparticles (IONPs) are considered for various diagnostic and therapeutic applications. Such particles are able to cross the blood-brain barrier and are taken up into brain cells. To test whether serum components affect the properties of IONPs and/or their uptake into brain cells, we have incubated dimercaptosuccinate-coated magnetic IONPs without and with fetal calf serum (FCS) and have exposed cultured brain astrocytes with IONPs in the absence or presence of FCS. Incubation with FCS caused a concentration-dependent increase in the average hydrodynamic diameter of the particles and of their zeta-potential. In the presence of 10 % FCS, the diameter of the IONPs increased from 57 {+-} 2 to 107 {+-} 6 nm and the zeta-potential of the particles from -22 {+-} 5 to -9 {+-} 1 mV. FCS affected also strongly the uptake of IONPs by cultured astrocytes. The efficient time- and temperature-dependent cellular accumulation of IONPs was lowered with increasing concentration of FCS by up to 90 %. In addition, in the absence of serum, endocytosis inhibitors did not alter the IONP accumulation by astrocytes, while chlorpromazine or wortmannin lowered significantly the accumulation of IONPs in the presence of FCS, suggesting that clathrin-mediated endocytosis and macropinocytosis are involved in astrocytic IONP uptake from serum-containing medium. These data demonstrate that the presence of FCS strongly affects the properties of IONPs as well as their accumulation by cultured brain cells.

  10. In male rats with concurrent iron and (n-3) fatty acid deficiency, provision of either iron or (n-3) fatty acids alone alters monoamine metabolism and exacerbates the cognitive deficits associated with combined deficiency 1-3

    OpenAIRE

    Baumgartner, Jeannine; Smuts, Cornelius M.; Malan, Linda; Arnold, Myrtha; Yee, Benjamin K.

    2012-01-01

    Concurrent deficiencies of iron (Fe) (ID) and (n-3) fatty acids [(n-3)FAD)] in rats can alter brain monoamine pathways and impair learning and memory. We examined whether repletion with Fe and DHA/EPA, alone and in combination, corrects the deficits in brain monoamine activity (by measuring monoamines and related gene expression) and spatial working and reference memory [by Morris water maze (MWM) testing] associated with deficiency. Using a 2 × 2 design, male rats with concurrent ID and (n-3...

  11. Iron metabolism in the mononuclear phagocyte system

    Institute of Scientific and Technical Information of China (English)

    Weina Kong; Xianglin Duan; Zhenhua Shi; Yanzhong Chang

    2008-01-01

    The maintenance of body iron homeostasis requires the coordination of multiple regulatory mechanisms of iron metabolism.The mononuclear phagocyte system (MPS,composed of monocytes,macrophages,and their precursor cells) is crucial in the maintenance of iron homeostasis.Recycling of iron is carried out by specialized macrophages via engulfment of aged erythrocytes.The iron stores of macrophages depend on the levels of recovered and exported iron.However,the molecular mechanisms underlying iron homeostasis in macrophages are poorly understood.Recent studies characterizing the function and regulation of natural resistance-associated macrophage protein 1 (Nrampl),divalent metal transporter 1 (DMTI),HLA-linked hemechromatosis gene (HFE),ferroportin 1 (FPN1),and hepcidin are rapidly expanding our knowledge on the molecular level of MPS iron handling.These studies are deepening our understanding about the molecular mechanism of iron homeostasis and iron-related diseases.

  12. of Energy Homeostasis

    Directory of Open Access Journals (Sweden)

    Xian Liu

    2015-01-01

    Full Text Available Sex differences exist in the complex regulation of energy homeostasis that utilizes central and peripheral systems. It is widely accepted that sex steroids, especially estrogens, are important physiological and pathological components in this sex-specific regulation. Estrogens exert their biological functions via estrogen receptors (ERs. ERα, a classic nuclear receptor, contributes to metabolic regulation and sexual behavior more than other ER subtypes. Physiological and molecular studies have identified multiple ERα-rich nuclei in the hypothalamus of the central nervous system (CNS as sites of actions that mediate effects of estrogens. Much of our understanding of ERα regulation has been obtained using transgenic models such as ERα global or nuclei-specific knockout mice. A fundamental question concerning how ERα is regulated in wild-type animals, including humans, in response to alterations in steroid hormone levels, due to experimental manipulation (i.e., castration and hormone replacement or physiological stages (i.e., puberty, pregnancy, and menopause, lacks consistent answers. This review discusses how different sex hormones affect ERα expression in the hypothalamus. This information will contribute to the knowledge of estrogen action in the CNS, further our understanding of discrepancies in correlation of altered sex hormone levels with metabolic disturbances when comparing both sexes, and improve health issues in postmenopausal women.

  13. Iron economy in Chlamydomonas reinhardtii

    Science.gov (United States)

    Glaesener, Anne G.; Merchant, Sabeeha S.; Blaby-Haas, Crysten E.

    2013-01-01

    While research on iron nutrition in plants has largely focused on iron-uptake pathways, photosynthetic microbes such as the unicellular green alga Chlamydomonas reinhardtii provide excellent experimental systems for understanding iron metabolism at the subcellular level. Several paradigms in iron homeostasis have been established in this alga, including photosystem remodeling in the chloroplast and preferential retention of some pathways and key iron-dependent proteins in response to suboptimal iron supply. This review presents our current understanding of iron homeostasis in Chlamydomonas, with specific attention on characterized responses to changes in iron supply, like iron-deficiency. An overview of frequently used methods for the investigation of iron-responsive gene expression, physiology and metabolism is also provided, including preparation of media, the effect of cell size, cell density and strain choice on quantitative measurements and methods for the determination of metal content and assessing the effect of iron supply on photosynthetic performance. PMID:24032036

  14. C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

    Science.gov (United States)

    Dafinca, Ruxandra; Scaber, Jakub; Ababneh, Nida'a; Lalic, Tatjana; Weir, Gregory; Christian, Helen; Vowles, Jane; Douglas, Andrew G.L.; Fletcher‐Jones, Alexandra; Browne, Cathy; Nakanishi, Mahito; Turner, Martin R.; Wade‐Martins, Richard

    2016-01-01

    Abstract An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40% of familial cases and 7% of sporadic ALS in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of patients carrying C9orf72 hexanucleotide expansions, differentiated these to functional motor and cortical neurons, and performed an extensive phenotypic characterization. In C9orf72 iPSC‐derived motor neurons, decreased cell survival is correlated with dysfunction in Ca2+ homeostasis, reduced levels of the antiapoptotic protein Bcl‐2, increased endoplasmic reticulum (ER) stress, and reduced mitochondrial membrane potential. Furthermore, C9orf72 motor neurons, and also cortical neurons, show evidence of abnormal protein aggregation and stress granule formation. This study is an extensive characterization of iPSC‐derived motor neurons as cellular models of ALS carrying C9orf72 hexanucleotide repeats, which describes a novel pathogenic link between C9orf72 mutations, dysregulation of calcium signaling, and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia. Stem Cells 2016;34:2063–2078 PMID:27097283

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

    Directory of Open Access Journals (Sweden)

    Sowbiya Muneer

    2014-04-01

    Full Text Available 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.

  16. Cardiac protection by preconditioning is generated via an iron-signal created by proteasomal degradation of iron proteins.

    Directory of Open Access Journals (Sweden)

    Baruch E Bulvik

    Full Text Available Ischemia associated injury of the myocardium is caused by oxidative damage during reperfusion. Myocardial protection by ischemic preconditioning (IPC was shown to be mediated by a transient 'iron-signal' that leads to the accumulation of apoferritin and sequestration of reactive iron released during the ischemia. Here we identified the source of this 'iron signal' and evaluated its role in the mechanisms of cardiac protection by hypoxic preconditioning. Rat hearts were retrogradely perfused and the effect of proteasomal and lysosomal protease inhibitors on ferritin levels were measured. The iron-signal was abolished, ferritin levels were not increased and cardiac protection was diminished by inhibition of the proteasome prior to IPC. Similarly, double amounts of ferritin and better recovery after ex vivo ischemia-and-reperfusion (I/R were found in hearts from in vivo hypoxia pre-conditioned animals. IPC followed by normoxic perfusion for 30 min ('delay' prior to I/R caused a reduced ferritin accumulation at the end of the ischemia phase and reduced protection. Full restoration of the IPC-mediated cardiac protection was achieved by employing lysosomal inhibitors during the 'delay'. In conclusion, proteasomal protein degradation of iron-proteins causes the generation of the 'iron-signal' by IPC, ensuing de-novo apoferritin synthesis and thus, sequestering reactive iron. Lysosomal proteases are involved in subsequent ferritin breakdown as revealed by the use of specific pathway inhibitors during the 'delay'. We suggest that proteasomal iron-protein degradation is a stress response causing an expeditious cytosolic iron release thus, altering iron homeostasis to protect the myocardium during I/R, while lysosomal ferritin degradation is part of housekeeping iron homeostasis.

  17. Iron regulation by hepatocytes and free radicals

    OpenAIRE

    Takami, Taro; Sakaida, Isao

    2011-01-01

    Iron is an essential metallic microelement for life. However, iron overload is toxic. The liver serves an important role as a storehouse for iron in the body. About 20–25 mg of iron is required each day for hemoglobin synthesis. To maintain iron homeostasis, transferrin and transferrin receptors are primarily involved in the uptake of iron into hepatocytes, ferritin in its storage, and ferroportin in its export. Moreover, hepcidin controls ferroportin and plays a central role in the iron meta...

  18. Regulating Subcellular Metal Homeostasis: The Key to Crop Improvement.

    Science.gov (United States)

    Bashir, Khurram; Rasheed, Sultana; Kobayashi, Takanori; Seki, Motoaki; Nishizawa, Naoko K

    2016-01-01

    Iron (Fe), zinc (Zn), manganese (Mn), and copper (Cu) are essential micronutrient mineral elements for living organisms, as they regulate essential cellular processes, such as chlorophyll synthesis and photosynthesis (Fe, Cu, and Mn), respiration (Fe and Cu), and transcription (Zn). The storage and distribution of these minerals in various cellular organelles is strictly regulated to ensure optimal metabolic rates. Alteration of the balance in uptake, distribution, and/or storage of these minerals severely impairs cellular metabolism and significantly affects plant growth and development. Thus, any change in the metal profile of a cellular compartment significantly affects metabolism. Different subcellular compartments are suggested to be linked through complex retrograde signaling networks to regulate cellular metal homeostasis. Various genes regulating cellular and subcellular metal distribution have been identified and characterized. Understanding the role of these transporters is extremely important to elaborate the signaling between various subcellular compartments. Moreover, modulation of the proteins involved in cellular metal homeostasis may help in the regulation of metabolism, adaptability to a diverse range of environmental conditions, and biofortification. Here, we review progress in the understanding of different subcellular metal transport components in plants and discuss the prospects of regulating cellular metabolism and strategies to develop biofortified crop plants. PMID:27547212

  19. Asthma as a disruption in iron homeostasis

    Science.gov (United States)

    Over several decades, asthma has evolved from being recognized as a single disease to include a diverse group of phenotypes with dissimilar natural histories, pathophysiologies, responses to treatment, and distinctive molecular pathways. With the application of Occam’s raz...

  20. High-Iron Consumption Impairs Growth and Causes Copper-Deficiency Anemia in Weanling Sprague-Dawley Rats.

    Science.gov (United States)

    Ha, Jung-Heun; Doguer, Caglar; Wang, Xiaoyu; Flores, Shireen R; Collins, James F

    2016-01-01

    Iron-copper interactions were described decades ago; however, molecular mechanisms linking the two essential minerals remain largely undefined. Investigations in humans and other mammals noted that copper levels increase in the intestinal mucosa, liver and blood during iron deficiency, tissues all important for iron homeostasis. The current study was undertaken to test the hypothesis that dietary copper influences iron homeostasis during iron deficiency and iron overload. We thus fed weanling, male Sprague-Dawley rats (n = 6-11/group) AIN-93G-based diets containing high (~8800 ppm), adequate (~80) or low (~11) iron in combination with high (~183), adequate (~8) or low (~0.9) copper for 5 weeks. Subsequently, the iron- and copper-related phenotype of the rats was assessed. Rats fed the low-iron diets grew slower than controls, with changes in dietary copper not further influencing growth. Unexpectedly, however, high-iron (HFe) feeding also impaired growth. Furthermore, consumption of the HFe diet caused cardiac hypertrophy, anemia, low serum and tissue copper levels and decreased circulating ceruloplasmin activity. Intriguingly, these physiologic perturbations were prevented by adding extra copper to the HFe diet. Furthermore, higher copper levels in the HFe diet increased serum nonheme iron concentration and transferrin saturation, exacerbated hepatic nonheme iron loading and attenuated splenic nonheme iron accumulation. Moreover, serum erythropoietin levels, and splenic erythroferrone and hepatic hepcidin mRNA levels were altered by the dietary treatments in unanticipated ways, providing insight into how iron and copper influence expression of these hormones. We conclude that high-iron feeding of weanling rats causes systemic copper deficiency, and further, that copper influences the iron-overload phenotype. PMID:27537180

  1. Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice.

    Science.gov (United States)

    Stroh, Matthew A; Winter, Michelle K; Swerdlow, Russell H; McCarson, Kenneth E; Zhu, Hao

    2016-08-01

    Iron dyshomeostasis has been implicated in many diseases, including a number of neurological conditions. Cytosolic NADH cytochrome b5 oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues and is capable of reducing ferric iron in vitro. We previously reported that global gene ablation of NCB5OR resulted in early-onset diabetes and altered iron homeostasis in mice. To further investigate the specific effects of NCB5OR deficiency on neural tissue without contributions from known phenotypes, we generated a conditional knockout (CKO) mouse that lacks NCB5OR only in the cerebellum and midbrain. Assessment of molecular markers in the cerebellum of CKO mice revealed changes in pathways associated with cellular and mitochondrial iron homeostasis. (59)Fe pulse-feeding experiments revealed cerebellum-specific increased or decreased uptake of iron by 7 and 16 weeks of age, respectively. Additionally, we characterized behavioral changes associated with loss of NCB5OR in the cerebellum and midbrain in the context of dietary iron deprivation-evoked generalized iron deficiency. Locomotor activity was reduced and complex motor task execution was altered in CKO mice treated with an iron deficient diet. A sucrose preference test revealed that the reward response was intact in CKO mice, but that iron deficient diet consumption altered sucrose preference in all mice. Detailed gait analysis revealed locomotor changes in CKO mice associated with dysfunctional proprioception and locomotor activation independent of dietary iron deficiency. Finally, we demonstrate that loss of NCB5OR in the cerebellum and midbrain exacerbated harmaline-induced tremor activity. Our findings suggest an essential role for NCB5OR in maintaining both iron homeostasis and the proper functioning of various locomotor pathways in the mouse cerebellum and midbrain. PMID:27188291

  2. Iron regulation by hepcidin

    OpenAIRE

    Zhao, Ningning; Zhang, An-Sheng; Enns, Caroline A

    2013-01-01

    Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulati...

  3. Superparamagnetic iron oxide nanoparticles alter expression of obesity and T2D-associated risk genes in human adipocytes

    NARCIS (Netherlands)

    Sharifi, S.; Daghighi, S.; Motazacker, M. M.; Badlou, B.; Sanjabi, B.; Akbarkhanzadeh, A.; Rowshani, A. T.; Laurent, S.; Peppelenbosch, M. P.; Rezaee, F.

    2013-01-01

    Adipocytes hypertrophy is the main cause of obesity and its affliction such as type 2 diabetes (T2D). Since superparamagnetic iron oxide nanoparticles (SPIONs) are used for a wide range of biomedical/medical applications, we aimed to study the effect of SPIONs on 22 and 29 risk genes (Based on gene

  4. Depletion of cellular iron by curcumin leads to alteration in histone acetylation and degradation of Sml1p in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Gajendra Kumar Azad

    Full Text Available Curcumin, a naturally occurring polyphenolic compound, is known to possess diverse pharmacological properties. There is a scarcity of literature documenting the exact mechanism by which curcumin modulates its biological effects. In the present study, we have used yeast as a model organism to dissect the mechanism underlying the action of curcumin. We found that the yeast mutants of histone proteins and chromatin modifying enzymes were sensitive to curcumin and further supplementation of iron resulted in reversal of the changes induced by curcumin. Additionally, treatment of curcumin caused the iron starvation induced expression of FET3, FRE1 genes. We also demonstrated that curcumin induces degradation of Sml1p, a ribonucleotide reductase inhibitor involved in regulating dNTPs production. The degradation of Sml1p was mediated through proteasome and vacuole dependent protein degradation pathways. Furthermore, curcumin exerts biological effect by altering global proteome profile without affecting chromatin architecture. These findings suggest that the medicinal properties of curcumin are largely contributed by its cumulative effect of iron starvation and epigenetic modifications.

  5. Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION

    Directory of Open Access Journals (Sweden)

    Neenu Singh

    2010-09-01

    Full Text Available Superparamagnetic iron oxide nanoparticles (SPION are being widely used for various biomedical applications, for example, magnetic resonance imaging, targeted delivery of drugs or genes, and in hyperthermia. Although, the potential benefits of SPION are considerable, there is a distinct need to identify any potential cellular damage associated with these nanoparticles. Besides focussing on cytotoxicity, the most commonly used determinant of toxicity as a result of exposure to SPION, this review also mentions the importance of studying the subtle cellular alterations in the form of DNA damage and oxidative stress. We review current studies and discuss how SPION, with or without different surface coating, may cause cellular perturbations including modulation of actin cytoskeleton, alteration in gene expression profiles, disturbance in iron homeostasis and altered cellular responses such as activation of signalling pathways and impairment of cell cycle regulation. The importance of protein–SPION interaction and various safety considerations relating to SPION exposure are also addressed.

  6. Homeostasis in anorexia nervosa

    OpenAIRE

    Södersten, Per; Bergh, Cecilia; Zandian, Modjtaba; Ioakimidis, Ioannis

    2014-01-01

    Brainstem and hypothalamic “orexigenic/anorexigenic” networks are thought to maintain body weight homeostasis in response to hormonal and metabolic feedback from peripheral sites. This approach has not been successful in managing over- and underweight patients. It is suggested that concept of homeostasis has been misinterpreted; rather than exerting control, the brain permits eating in proportion to the amount of physical activity necessary to obtain food. In support, animal experiments have ...

  7. Homeostasis in anorexia nervosa

    OpenAIRE

    Per eSodersten; Cecilia eBergh; Modjtaba eZandian; Ioannis eIoakimidis

    2014-01-01

    Brainstem and hypothalamic orexigenic/anorexigenic networks are thought to maintain body weight homeostasis in response to hormonal and metabolic feedback from peripheral sites. This approach has not been successful in managing over- and underweight patients. It is suggested that concept of homeostasis has been misinterpreted; rather than exerting control, the brain permits eating in proportion to the amount of physical activity necessary to obtain food. In support, animal experiments have sh...

  8. The Role of Hepcidin in Iron Metabolism

    OpenAIRE

    Nemeth, Elizabeta; Ganz, Tomas

    2009-01-01

    Hepcidin is the central regulator of systemic iron homeostasis. Dysregulation of hepcidin production results in a variety of iron disorders. Hepcidin deficiency is the cause of iron overload in hereditary hemochromatosis, iron-loading anemias, and hepatitis C. Hepcidin excess is associated with anemia of inflammation, chronic kidney disease and iron-refractory iron deficiency anemia. Diagnostic and therapeutic applications of this new knowledge are beginning to emerge. Dr. Ernest Beutler play...

  9. Geochemistry, Paragenesis, and Wall-Rock Alteration of the Qatruyeh Iron Deposits, Southwest of Iran: Implications for a Hydrothermal-Metasomatic Genetic Model

    Directory of Open Access Journals (Sweden)

    Sina Asadi

    2014-01-01

    Full Text Available The Qatruyeh iron deposits, located on the eastern border of the NW-SE trending Sanandaj-Sirjan metamorphic zone, southwest of Iran, are hosted by a late Proterozoic to early Paleozoic sequence dominated by metamorphosed carbonate rocks. The magnetite ores occurred as layered to massive bodies, with lesser amounts of disseminated magnetite and hematite-bearing veins. Textural evidences, along with geochemical analyses of the high field strengths (HFSEs, large ion lithophiles (LILEs, and rare earth elements (REEs, indicate that the main mineralization stage occurred as low-grade layered magnetite ores due to high-temperature hydrothermal fluids accompanied by Na-Ca alteration. Most of the main ore-stage minerals precipitated from an aqueous-carbonic fluid (3.5–15 wt.% NaCl equiv. at temperatures ranging between 300° and 410°C during fluid mixing process, CO2 effervescence, cooling, and increasing of pH. Low-temperature hydrothermal activity subsequently produced hematite ores associated with propylitic alteration. The metacarbonate host rocks are LILE-depleted and HFSE-enriched due to metasomatic alteration.

  10. Alteration of proteins and pigments influence the function of photosystem I under iron deficiency from Chlamydomonas reinhardtii.

    Directory of Open Access Journals (Sweden)

    Venkateswarlu Yadavalli

    Full Text Available BACKGROUND: Iron is an essential micronutrient for all organisms because it is a component of enzyme cofactors that catalyze redox reactions in fundamental metabolic processes. Even though iron is abundant on earth, it is often present in the insoluble ferric [Fe (III] state, leaving many surface environments Fe-limited. The haploid green alga Chlamydomonas reinhardtii is used as a model organism for studying eukaryotic photosynthesis. This study explores structural and functional changes in PSI-LHCI supercomplexes under Fe deficiency as the eukaryotic photosynthetic apparatus adapts to Fe deficiency. RESULTS: 77K emission spectra and sucrose density gradient data show that PSI and LHCI subunits are affected under iron deficiency conditions. The visible circular dichroism (CD spectra associated with strongly-coupled chlorophyll dimers increases in intensity. The change in CD signals of pigments originates from the modification of interactions between pigment molecules. Evidence from sucrose gradients and non-denaturing (green gels indicates that PSI-LHCI levels were reduced after cells were grown for 72 h in Fe-deficient medium. Ultrafast fluorescence spectroscopy suggests that red-shifted pigments in the PSI-LHCI antenna were lost during Fe stress. Further, denaturing gel electrophoresis and immunoblot analysis reveals that levels of the PSI subunits PsaC and PsaD decreased, while PsaE was completely absent after Fe stress. The light harvesting complexes were also susceptible to iron deficiency, with Lhca1 and Lhca9 showing the most dramatic decreases. These changes in the number and composition of PSI-LHCI supercomplexes may be caused by reactive oxygen species, which increase under Fe deficiency conditions. CONCLUSIONS: Fe deficiency induces rapid reduction of the levels of photosynthetic pigments due to a decrease in chlorophyll synthesis. Chlorophyll is important not only as a light-harvesting pigment, but also has a structural role

  11. The influence of combined magnesium and vanadate administration on the level of some elements in selected rat organs: V-Mg interactions and the role of iron-essential protein (DMT-1) in the mechanism underlying altered tissues iron level.

    Science.gov (United States)

    Scibior, Agnieszka; Adamczyk, Agnieszka; Gołębiowska, Dorota; Niedźwiecka, Irmina; Fornal, Emilia

    2014-04-01

    The effect of 12 week co-administration of sodium metavanadate (SMV) and magnesium sulfate (MS) on the levels of some elements in selected rats' organs and an attempt to elucidate a role of divalent metal transporter 1 (DMT-1) in the mechanism(s) of the SMV-induced disorders in some tissue Fe homeostasis were studied. SMV taken up separately or in combination with MS may pose a risk of the rise and shortage of the total hepatic and splenic Fe and Cu contents, respectively, cerebral Fe deficiency, splenic Ca deposition, and the hepatic, renal, and cerebral DMT-1 down-regulation. When administered alone, SMV may also cause the decrease in the total renal Fe and Cu contents. A visible protective effect of Mg against the renal and cerebral V accumulation and the decrease in the renal Fe and Cu contents during the SMV-MS co-administration together with our previous findings suggest a beneficial role of Mg at SMV exposure. Further, the SMV-induced fall in total iron binding capacity (TIBC), reported previously, and its correlations with the hepatic, splenic, and cerebral Fe levels allow us to suggest that diminished TIBC could be partly involved in the mechanism(s) responsible for the dramatic redistribution of Fe in those tissues. Finally, DMT-1, which potentially could participate in the hepatic non-transferrin Fe-bound uptake, does not play a significant role in this process indicating the need for studying other Fe transporters to more precisely elucidate molecular mechanism(s) underlying the hepatic Fe loading in our experimental conditions.

  12. [Iron-refractory iron deficiency anemia].

    Science.gov (United States)

    Kawabata, Hiroshi

    2016-02-01

    The major causes of iron deficiency anemia (IDA) include iron loss due to bleeding, increased iron requirements, and decreased iron absorption by the intestine. The most common cause of IDA in Japanese women is iron loss during menstruation. Autoimmune atrophic gastritis and Helicobacter pylori infection can also cause IDA by reducing intestinal iron absorption. In addition to these common etiologies, germline mutations of TMPRSS6 can cause iron-refractory IDA (IRIDA). TMPRSS6 encodes matriptase-2, a membrane-bound serine protease primarily expressed in the liver. Functional loss of matriptase-2 due to homozygous mutations results in an increase in the expression of hepcidin, which is the key regulator of systemic iron homeostasis. The serum hepcidin increase in turn leads to a decrease in iron supply from the intestine and macrophages to erythropoietic cells. IRIDA is microcytic and hypochromic, but decreased serum ferritin is not observed as in IDA. IRIDA is refractory to oral iron supplementation, but does respond to intravenous iron supplementation to some extent. Because genetic testing is required for the diagnoses of IRIDA, a considerable number of cases may go undiagnosed and may thus be overlooked. PMID:26935626

  13. [Iron-refractory iron deficiency anemia].

    Science.gov (United States)

    Kawabata, Hiroshi

    2016-02-01

    The major causes of iron deficiency anemia (IDA) include iron loss due to bleeding, increased iron requirements, and decreased iron absorption by the intestine. The most common cause of IDA in Japanese women is iron loss during menstruation. Autoimmune atrophic gastritis and Helicobacter pylori infection can also cause IDA by reducing intestinal iron absorption. In addition to these common etiologies, germline mutations of TMPRSS6 can cause iron-refractory IDA (IRIDA). TMPRSS6 encodes matriptase-2, a membrane-bound serine protease primarily expressed in the liver. Functional loss of matriptase-2 due to homozygous mutations results in an increase in the expression of hepcidin, which is the key regulator of systemic iron homeostasis. The serum hepcidin increase in turn leads to a decrease in iron supply from the intestine and macrophages to erythropoietic cells. IRIDA is microcytic and hypochromic, but decreased serum ferritin is not observed as in IDA. IRIDA is refractory to oral iron supplementation, but does respond to intravenous iron supplementation to some extent. Because genetic testing is required for the diagnoses of IRIDA, a considerable number of cases may go undiagnosed and may thus be overlooked.

  14. Iron and Mechanisms of Emotional Behavior

    OpenAIRE

    Kim, Jonghan; Wessling-Resnick, Marianne

    2014-01-01

    Iron is required for appropriate behavioral organization. Iron deficiency results in poor brain myelination and impaired monoamine metabolism. Glutamate and GABA homeostasis is modified by changes in brain iron status. Such changes not only produce deficits in memory/learning capacity and motor skills, but also emotional and psychological problems. An accumulating body of evidence indicates that both energy metabolism and neurotransmitter homeostasis influence emotional behavior, and both fun...

  15. Studies of petrography, metasomatic alteration, and genesis of Kamtal iron-copper skarn, northeast of Kharvana, East-Azarbaijan

    Directory of Open Access Journals (Sweden)

    Rasool Ferdowsi

    2012-04-01

    Full Text Available Kamtal skarn is located 15 km northeast of Kharvana, East-Azarbaijan. A quartz-monzonitic stock of Oligocene age intruded the upper Cretaceous sedimentary sequence (claystone, limestone, marl, and siltstone developing noticeable metamorphic (marble, hornfels and metasomatic (skarn alteration zones along the contact. Kamtal skarn is of calcic type and consists of both endoskarn and exoskarn zones. Exoskarn includes two zones of garnet skarn and epidote skarn. Skarnification processes are divided mainly in two major stages (1 prograde and (2 retrograde. During prograde stage, the emplacement of intrusive body caused isochemical metamorphism of the wall rocks and developed marble and hornfels units in enclosing rocks. Crystallization of intrusive body led to evolvement of hydrothermal fluid phase which infiltrated into enclosing rocks. Reaction of these fluids with the early-formed metamorphosed wall rocks brought about extensive progressive metasomatic alteration characterized by the formation of anhydrous calc-silicate minerals such as garnets and pyroxenes at a temperature range of 420-550°C and ¦O2=10-22-10-25. Retrograde stage was accompanied by some physicochemical changes (decrease in temperature to <420°C and increase in ¦S2 which caused the alteration of pre-existing anhydrous calc-silicates to hydrous calc-silicates (epidote, and tremolite-actinolite, silicates (quartz, chlorites, and other clay minerals, oxides (magnetite and hematite, sulfides (pyrite, chalcopyrite, and tetrahedrite, and carbonate (calcite. Comparison of Kamtal skarn with some other ones of corresponding type from Iran and other countries shows that Kamtal skarn well resembles to Anjerd and Pahnavar skarns in East-Azarbaijan.

  16. Superparamagnetic iron oxide nanoparticles alter expression of obesity and T2D-associated risk genes in human adipocytes

    Science.gov (United States)

    Sharifi, S.; Daghighi, S.; Motazacker, M. M.; Badlou, B.; Sanjabi, B.; Akbarkhanzadeh, A.; Rowshani, A. T.; Laurent, S.; Peppelenbosch, M. P.; Rezaee, F.

    2013-07-01

    Adipocytes hypertrophy is the main cause of obesity and its affliction such as type 2 diabetes (T2D). Since superparamagnetic iron oxide nanoparticles (SPIONs) are used for a wide range of biomedical/medical applications, we aimed to study the effect of SPIONs on 22 and 29 risk genes (Based on gene wide association studies) for obesity and T2D in human adipocytes. The mRNA expression of lipid and glucose metabolism genes was changed upon the treatment of human primary adipocytes with SPIONs. mRNA of GULP1, SLC30A8, NEGR1, SEC16B, MTCH2, MAF, MC4R, and TMEM195 were severely induced, whereas INSIG2, NAMPT, MTMR9, PFKP, KCTD15, LPL and GNPDA2 were down-regulated upon SPIONs stimulation. Since SEC16B gene assist the phagocytosis of apoptotic cells and this gene were highly expressed upon SPIONs treatment in adipocytes, it is logic to assume that SPIONs may play a crucial role in this direction, which requires more consideration in the future.

  17. Heme Iron Content in Lamb Meat Is Differentially Altered upon Boiling, Grilling, or Frying as Assessed by Four Distinct Analytical Methods

    Directory of Open Access Journals (Sweden)

    Azin Pourkhalili

    2013-01-01

    Full Text Available Lamb meat is regarded as an important source of highly bioavailable iron (heme iron in the Iranians diet. The main objective of this study is to evaluate the effect of traditional cooking methods on the iron changes in lamb meat. Four published experimental methods for the determination of heme iron were assessed analytically and statistically. Samples were selected from lambs' loin. Standard methods (AOAC were used for proximate analysis. For measuring heme iron, the results of four experimental methods were compared regarding their compliance to Ferrozine method which was used for the determination of nonheme iron. Among three cooking methods, the lowest total iron and heme iron were found in boiling method. The heme iron proportions to the total iron in raw, boiled lamb meat and grilled, were counted as 65.70%, 67.75%, and 76.01%, receptively. Measuring the heme iron, the comparison of the methods in use showed that the method in which heme extraction solution was composed of 90% acetone, 18% water, and 2% hydrochloric acid was more appropriate and more correlated with the heme iron content calculated by the difference between total iron and nonheme iron.

  18. Hepcidin, a new iron regulatory peptide.

    Science.gov (United States)

    Nicolas, Gaël; Viatte, Lydie; Bennoun, Myriam; Beaumont, Carole; Kahn, Axel; Vaulont, Sophie

    2002-01-01

    Maintaining normal iron homeostasis is essential for the organism, as both iron deficiency and iron excess are associated with cellular dysfunction. Recently, several lines of evidence have suggested that hepcidin, a peptide mainly produced by the liver, plays a major role in the control of body iron homeostasis. The subject of this paper is to summarize the advances toward the understanding of function and regulation of hepcidin in iron metabolism and to provide new data on the regulation of hepcidin gene expression by erythropoietin, the major regulator of mammalian erythropoiesis. PMID:12547223

  19. Hepcidin in iron overload disorders

    OpenAIRE

    Papanikolaou, George; Tzilianos, Michalis; Christakis, John I.; Bogdanos, Dionisios; Tsimirika, Konstantina; MacFarlane, Julie; Goldberg, Y. Paul; Sakellaropoulos, Nikos; Ganz, Tomas; Nemeth, Elizabeta

    2005-01-01

    Hepcidin is the principal regulator of iron absorption in humans. The peptide inhibits cellular iron efflux by binding to the iron export channel ferroportin and inducing its internalization and degradation. Either hepcidin deficiency or alterations in its target, ferroportin, would be expected to result in dysregulated iron absorption, tissue maldistribution of iron, and iron overload. Indeed, hepcidin deficiency has been reported in hereditary hemochromatosis and attributed to mutations in ...

  20. Iron and immunity: immunological consequences of iron deficiency and overload

    OpenAIRE

    Cherayil, Bobby J.

    2010-01-01

    The influence of iron on immune function has been long appreciated. However, the molecular basis for this interaction is less well understood. Recently, there have been several important advances that have shed light on the mechanisms that regulate mammalian iron metabolism. The new insights provide a conceptual framework for understanding and manipulating the cross-talk between iron homeostasis and the immune system. This article will review what is currently known about how disturbances of ...

  1. Water Homeostasis: Evolutionary Medicine

    OpenAIRE

    Zeidel, Mark L.

    2012-01-01

    As a major component of homeostasis, all organisms regulate the water composition of various compartments. Through the selective use of barrier membranes and surface glycoproteins, as well as aquaporin water channels, organisms ranging from Archaebacteria to humans can vary water permeabilities across their cell membranes by 4 to 5 orders of magnitude. In barrier epithelia the outer, or exofacial, leaflet acts as the main resistor to water flow; this leaflet restricts water flow by minimizing...

  2. The Hepcidin Circuits Act: Balancing Iron and Inflammation

    OpenAIRE

    Maliken, Bryan D.; Nelson, James E.; Kowdley, Kris V.

    2011-01-01

    Hepcidin is a peptide hormone that regulates iron homeostasis and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the trans...

  3. Blockage of mitochondrial calcium uniporter prevents iron accumulation in a model of experimental subarachnoid hemorrhage.

    Science.gov (United States)

    Yan, Huiying; Hao, Shuangying; Sun, Xiaoyan; Zhang, Dingding; Gao, Xin; Yu, Zhuang; Li, Kuanyu; Hang, Chun-Hua

    2015-01-24

    Previous studies have shown that iron accumulation is involved in the pathogenesis of brain injury following subarachnoid hemorrhage (SAH) and chelation of iron reduced mortality and oxidative DNA damage. We previously reported that blockage of mitochondrial calcium uniporter (MCU) provided benefit in the early brain injury after experimental SAH. This study was undertaken to identify whether blockage of MCU could ameliorate iron accumulation-associated brain injury following SAH. Therefore, we used two reagents ruthenium red (RR) and spermine (Sper) to inhibit MCU. Sprague-Dawley (SD) rats were randomly divided into four groups including sham, SAH, SAH+RR, and SAH+Sper. Biochemical analysis and histological assays were performed. The results confirmed the iron accumulation in temporal lobe after SAH. Interestingly, blockage of MCU dramatically reduced the iron accumulation in this area. The mechanism was revealed that inhibition of MCU reversed the down-regulation of iron regulatory protein (IRP) 1/2 and increase of ferritin. Iron-sulfur cluster dependent-aconitase activity was partially conserved when MCU was blocked. In consistence with this and previous report, ROS levels were notably reduced and ATP supply was rescued; levels of cleaved caspase-3 dropped; and integrity of neurons in temporal lobe was protected. Taken together, our results indicated that blockage of MCU could alleviate iron accumulation and the associated injury following SAH. These findings suggest that the alteration of calcium and iron homeostasis be coupled and MCU be considered to be a therapeutic target for patients suffering from SAH.

  4. Iron deficiency and cognition

    OpenAIRE

    Hulthén, Lena

    2003-01-01

    Iron deficiency is the most prevalent nutritional disorder in the world. One of the most worrying consequences of iron deficiency in children is the alteration of behaviour and cognitive performance. In iron-deficient children, striking behavioural changes are observed, such as reduced attention span, reduced emotional responsiveness and low scores on tests of intelligence. Animal studies on nutritional iron deficiency show effects on learning ability that parallel the human studies. Despite ...

  5. Iron and Iron Metabolism

    OpenAIRE

    Melike Sezgin Evim; Birol Baytan; Adalet Meral Güneş

    2012-01-01

    Iron is an essential element for almost all living organisms except some bacteria. A great number of new articles related to the iron metabolism have been published in recent years explaining new findings. Hepsidine, a peptide hormon, that is recently found, regulates iron methabolism by effecting iron absorbsion from gut, secreting iron from hepatic store and flows iron from macrophages. Hepsidin blockes to effluxe iron from cells by bounding to ferroportin and by inducing ferroportin destru...

  6. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.

    Science.gov (United States)

    Nicolas, G; Bennoun, M; Devaux, I; Beaumont, C; Grandchamp, B; Kahn, A; Vaulont, S

    2001-07-17

    We previously reported the disruption of the murine gene encoding the transcription factor USF2 and its consequences on glucose-dependent gene regulation in the liver. We report here a peculiar phenotype of Usf2(-/-) mice that progressively develop multivisceral iron overload; plasma iron overcomes transferrin binding capacity, and nontransferrin-bound iron accumulates in various tissues including pancreas and heart. In contrast, the splenic iron content is strikingly lower in knockout animals than in controls. To identify genes that may account for the abnormalities of iron homeostasis in Usf2(-/-) mice, we used suppressive subtractive hybridization between livers from Usf2(-/-) and wild-type mice. We isolated a cDNA encoding a peptide, hepcidin (also referred to as LEAP-1, for liver-expressed antimicrobial peptide), that was very recently purified from human blood ultrafiltrate and from urine as a disulfide-bonded peptide exhibiting antimicrobial activity. Accumulation of iron in the liver has been recently reported to up-regulate hepcidin expression, whereas our data clearly show that a complete defect in hepcidin expression is responsible for progressive tissue iron overload. The striking similarity of the alterations in iron metabolism between HFE knockout mice, a murine model of hereditary hemochromatosis, and the Usf2(-/-) hepcidin-deficient mice suggests that hepcidin may function in the same regulatory pathway as HFE. We propose that hepcidin acts as a signaling molecule that is required in conjunction with HFE to regulate both intestinal iron absorption and iron storage in macrophages. PMID:11447267

  7. Homeostasis Hombre-Naturaleza

    Directory of Open Access Journals (Sweden)

    Stephano Betancourt

    2016-06-01

    Full Text Available La tendencia al equilibrio en la naturaleza y el flujo energético entre los organismos y suambiente; resulta de vital importancia para la supervivencia de estos últimos. Cuando seda una mirada antropocéntrica a esta interacción, se genera un enfoque reduccionista de losfactores que influyen para mantener la tendencia al equilibrio. Por consiguiente, el sostenerlo inteligible de las interacciones de los elementos que conforman nuestra existencia es unpunto clave de la compleja relación, entre el ser humano y su entorno, para poder permitiruna homeostasis entre ellos.

  8. Acid-Base Homeostasis.

    Science.gov (United States)

    Hamm, L Lee; Nakhoul, Nazih; Hering-Smith, Kathleen S

    2015-12-01

    Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and function. The importance of this regulation is evidenced by a variety of physiologic derangements that occur when plasma pH is either high or low. The kidneys have the predominant role in regulating the systemic bicarbonate concentration and hence, the metabolic component of acid-base balance. This function of the kidneys has two components: reabsorption of virtually all of the filtered HCO3(-) and production of new bicarbonate to replace that consumed by normal or pathologic acids. This production or generation of new HCO3(-) is done by net acid excretion. Under normal conditions, approximately one-third to one-half of net acid excretion by the kidneys is in the form of titratable acid. The other one-half to two-thirds is the excretion of ammonium. The capacity to excrete ammonium under conditions of acid loads is quantitatively much greater than the capacity to increase titratable acid. Multiple, often redundant pathways and processes exist to regulate these renal functions. Derangements in acid-base homeostasis, however, are common in clinical medicine and can often be related to the systems involved in acid-base transport in the kidneys.

  9. Homeostasis in anorexia nervosa

    Directory of Open Access Journals (Sweden)

    Per eSodersten

    2014-08-01

    Full Text Available Brainstem and hypothalamic orexigenic/anorexigenic networks are thought to maintain body weight homeostasis in response to hormonal and metabolic feedback from peripheral sites. This approach has not been successful in managing over- and underweight patients. It is suggested that concept of homeostasis has been misinterpreted; rather than exerting control, the brain permits eating in proportion to the amount of physical activity necessary to obtain food. In support, animal experiments have shown that while a hypothalamic orexigen excites eating when food is abundant, it inhibits eating and stimulates foraging when food is in short supply. As the physical price of food approaches zero, eating and body weight increase without constraints. Conversely, in anorexia nervosa body weight is homeostatically regulated, the high level of physical activity in anorexia is displaced hoarding for food that keeps body weight constantly low. A treatment based on this point of view, providing patients with computerized mealtime support to re-establish normal eating behavior, has brought 75% of patients with eating disorders into remission, reduced the rate of relapse to 10%, and eliminated mortality.

  10. Ageing and water homeostasis

    Science.gov (United States)

    Robertson, David; Jordan, Jens; Jacob, Giris; Ketch, Terry; Shannon, John R.; Biaggioni, Italo

    2002-01-01

    This review outlines current knowledge concerning fluid intake and volume homeostasis in ageing. The physiology of vasopressin is summarized. Studies have been carried out to determine orthostatic changes in plasma volume and to assess the effect of water ingestion in normal subjects, elderly subjects, and patients with dysautonomias. About 14% of plasma volume shifts out of the vasculature within 30 minutes of upright posture. Oral ingestion of water raises blood pressure in individuals with impaired autonomic reflexes and is an important source of noise in blood pressure trials in the elderly. On the average, oral ingestion of 16 ounces (473ml) of water raises blood pressure 11 mmHg in elderly normal subjects. In patients with autonomic impairment, such as multiple system atrophy, strikingly exaggerated pressor effects of water have been seen with blood pressure elevations greater than 75 mmHg not at all uncommon. Ingestion of water is a major determinant of blood pressure in the elderly population. Volume homeostasis is importantly affected by posture and large changes in plasma volume may occur within 30 minutes when upright posture is assumed.

  11. Global transcriptional response to Hfe deficiency and dietary iron overload in mouse liver and duodenum.

    Directory of Open Access Journals (Sweden)

    Alejandra Rodriguez

    Full Text Available Iron is an essential trace element whose absorption is usually tightly regulated in the duodenum. HFE-related hereditary hemochromatosis (HH is characterized by abnormally low expression of the iron-regulatory hormone, hepcidin, which results in increased iron absorption. The liver is crucial for iron homeostasis as it is the main production site of hepcidin. The aim of this study was to explore and compare the genome-wide transcriptome response to Hfe deficiency and dietary iron overload in murine liver and duodenum. Illumina arrays containing over 47,000 probes were used to study global transcriptional changes. Quantitative RT-PCR (Q-RT-PCR was used to validate the microarray results. In the liver, the expression of 151 genes was altered in Hfe(-/- mice while dietary iron overload changed the expression of 218 genes. There were 173 and 108 differentially expressed genes in the duodenum of Hfe(-/- mice and mice with dietary iron overload, respectively. There was 93.5% concordance between the results obtained by microarray analysis and Q-RT-PCR. Overexpression of genes for acute phase reactants in the liver and a strong induction of digestive enzyme genes in the duodenum were characteristic of the Hfe-deficient genotype. In contrast, dietary iron overload caused a more pronounced change of gene expression responsive to oxidative stress. In conclusion, Hfe deficiency caused a previously unrecognized increase in gene expression of hepatic acute phase proteins and duodenal digestive enzymes.

  12. The role of iron in pulmonary pathology

    OpenAIRE

    Khiroya, Heena; Turner, Alice M

    2015-01-01

    Respiratory disease accounts for a large proportion of emergency admissions to hospital and diseaseassociated mortality. Genetic association studies demonstrate a link between iron metabolism and pulmonary disease phenotypes. IREB2 is a gene that produces iron regulatory protein 2 (IRP2), which has a key role in iron homeostasis. This review addresses pathways involved in iron metabolism, particularly focusing on the role of IREB2. In addition to this, environmental factors also influence phe...

  13. Autophagy and intestinal homeostasis.

    Science.gov (United States)

    Patel, Khushbu K; Stappenbeck, Thaddeus S

    2013-01-01

    Nutrient absorption is the basic function that drives mammalian intestinal biology. To facilitate nutrient uptake, the host's epithelial barrier is composed of a single layer of cells. This constraint is problematic, as a design of this type can be easily disrupted. The solution during the course of evolution was to add numerous host defense mechanisms that can help prevent local and systemic infection. These mechanisms include specialized epithelial cells that produce a physiochemical barrier overlying the cellular barrier, robust and organized adaptive and innate immune cells, and the ability to mount an inflammatory response that is commensurate with a specific threat level. The autophagy pathway is a critical cellular process that strongly influences all these functions. Therefore, a fundamental understanding of the components of this pathway and their influence on inflammation, immunity, and barrier function will facilitate our understanding of homeostasis in the gastrointestinal tract. PMID:23216414

  14. Iron Absorption in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Fanis Missirlis

    2013-05-01

    Full Text Available The way in which Drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. To describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export and how intestinal epithelial cells sense and respond to iron availability. Here we review studies on the Divalent Metal Transporter-1 homolog Malvolio (iron import, the recent discovery that Multicopper Oxidase-1 has ferroxidase activity (iron export and the role of ferritin in the process of iron acquisition (iron storage. We also describe what is known about iron regulation in insect cells. We then draw upon knowledge from mammalian iron homeostasis to identify candidate genes in flies. Questions arise from the lack of conservation in Drosophila for key mammalian players, such as ferroportin, hepcidin and all the components of the hemochromatosis-related pathway. Drosophila and other insects also lack erythropoiesis. Thus, systemic iron regulation is likely to be conveyed by different signaling pathways and tissue requirements. The significance of regulating intestinal iron uptake is inferred from reports linking Drosophila developmental, immune, heat-shock and behavioral responses to iron sequestration.

  15. Iron Absorption in Drosophila melanogaster

    Science.gov (United States)

    Mandilaras, Konstantinos; Pathmanathan, Tharse; Missirlis, Fanis

    2013-01-01

    The way in which Drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. To describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export and how intestinal epithelial cells sense and respond to iron availability. Here we review studies on the Divalent Metal Transporter-1 homolog Malvolio (iron import), the recent discovery that Multicopper Oxidase-1 has ferroxidase activity (iron export) and the role of ferritin in the process of iron acquisition (iron storage). We also describe what is known about iron regulation in insect cells. We then draw upon knowledge from mammalian iron homeostasis to identify candidate genes in flies. Questions arise from the lack of conservation in Drosophila for key mammalian players, such as ferroportin, hepcidin and all the components of the hemochromatosis-related pathway. Drosophila and other insects also lack erythropoiesis. Thus, systemic iron regulation is likely to be conveyed by different signaling pathways and tissue requirements. The significance of regulating intestinal iron uptake is inferred from reports linking Drosophila developmental, immune, heat-shock and behavioral responses to iron sequestration. PMID:23686013

  16. Iron overload and immunity

    Institute of Scientific and Technical Information of China (English)

    Gra(c)a Porto; Maria De Sousa

    2007-01-01

    Progress in the characterization of genes involved in the control of iron homeostasis in humans and in mice has improved the definition of iron overload and of the cells affected by it. The cell involved in iron overload with the greatest effect on immunity is the macrophage.Intriguing evidence has emerged, however, in the last 12 years indicating that parenchymal iron overload is linked to genes classically associated with the immune system. This review offers an update of the genes and proteins relevant to iron metabolism expressed in cells of the innate immune system, and addresses the question of how this system is affected in clinical situations of iron overload. The relationship between iron and the major cells of adaptive immunity, the T lymphocytes,will also be reviewed. Most studies addressing this last question in humans were performed in the clinical model of Hereditary Hemochromatosis. Data will also be reviewed demonstrating how the disruption of molecules essentially involved in adaptive immune responses result in the spontaneous development of iron overload and how they act as modifiers of iron overload.

  17. Bitter taste receptors influence glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    Cedrick D Dotson

    Full Text Available TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca(2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1, an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease.

  18. Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1.

    Science.gov (United States)

    Lelliott, Patrick M; McMorran, Brendan J; Foote, Simon J; Burgio, Gaetan

    2015-11-01

    The treatment of iron deficiency in areas of high malaria transmission is complicated by evidence which suggests that iron deficiency anemia protects against malaria, while iron supplementation increases malaria risk. Iron deficiency anemia results in an array of pathologies, including reduced systemic iron bioavailability and abnormal erythrocyte physiology; however, the mechanisms by which these pathologies influence malaria infection are not well defined. In the present study, the response to malaria infection was examined in a mutant mouse line, Tfrc(MRI24910), identified during an N-ethyl-N-nitrosourea (ENU) screen. This line carries a missense mutation in the gene for transferrin receptor 1 (TFR1). Heterozygous mice exhibited reduced erythrocyte volume and density, a phenotype consistent with dietary iron deficiency anemia. However, unlike the case in dietary deficiency, the erythrocyte half-life, mean corpuscular hemoglobin concentration, and intraerythrocytic ferritin content were unchanged. Systemic iron bioavailability was also unchanged, indicating that this mutation results in erythrocytic iron deficiency without significantly altering overall iron homeostasis. When infected with the rodent malaria parasite Plasmodium chabaudi adami, mice displayed increased parasitemia and succumbed to infection more quickly than their wild-type littermates. Transfusion of fluorescently labeled erythrocytes into malaria parasite-infected mice demonstrated an erythrocyte-autonomous enhanced survival of parasites within mutant erythrocytes. Together, these results indicate that TFR1 deficiency alters erythrocyte physiology in a way that is similar to dietary iron deficiency anemia, albeit to a lesser degree, and that this promotes intraerythrocytic parasite survival and an increased susceptibility to malaria in mice. These findings may have implications for the management of iron deficiency in the context of malaria.

  19. Ndfip2 is a potential regulator of the iron transporter DMT1 in the liver

    Science.gov (United States)

    Foot, Natalie J.; Gembus, Kelly M.; Mackenzie, Kimberly; Kumar, Sharad

    2016-01-01

    The regulation of divalent metal ion transporter DMT1, the primary non-heme iron importer in mammals, is critical for maintaining iron homeostasis. Previously we identified ubiquitin-dependent regulation of DMT1 involving the Nedd4 family of ubiquitin ligases and the Ndfip1 and Ndfip2 adaptors. We also established the in vivo function of Ndfip1 in the regulation of DMT1 in the duodenum of mice. Here we have studied the function of Ndfip2 using Ndfip2-deficient mice. The DMT1 protein levels in the duodenum were comparable in wild type and Ndfip2−/− mice, as was the transport activity of isolated enterocytes. A complete blood examination showed no significant differences between wild type and Ndfip2−/− mice in any of the hematological parameters measured. However, when fed a low iron diet, female Ndfip2−/− mice showed a decrease in liver iron content, although they maintained normal serum iron levels and transferrin saturation, compared to wild type female mice that showed a reduction in serum iron and transferrin saturation. Ndfip2−/− female mice also showed an increase in DMT1 expression in the liver, with no change in male mice. We suggest that Ndfip2 controls DMT1 in the liver with female mice showing a greater response to altered dietary iron than the male mice. PMID:27048792

  20. Pregnancy and maternal iron deficiency stimulate hepatic CRBPII expression in rats.

    Science.gov (United States)

    Cottin, Sarah C; Gambling, Lorraine; Hayes, Helen E; Stevens, Valerie J; McArdle, Harry J

    2016-06-01

    Iron deficiency impairs vitamin A (VA) metabolism in the rat but the mechanisms involved are unknown and the effect during development has not been investigated. We investigated the effect of pregnancy and maternal iron deficiency on VA metabolism in the mother and fetus. 54 rats were fed either a control or iron deficient diet for 2weeks prior to mating and throughout pregnancy. Another 15 female rats followed the same diet and were used as non-pregnant controls. Maternal liver, placenta and fetal liver were collected at d21 for total VA, retinol and retinyl ester (RE) measurement and VA metabolic gene expression analysis. Iron deficiency increased maternal hepatic RE (PRE (P<.05), and decreased placenta total VA (P<.05). Pregnancy increased Cellular Retinol Binding Protein (CRBP)-II gene expression by 7 fold (P=.001), decreased VA levels (P=.0004) and VA metabolic gene expression (P<.0001) in the liver. Iron deficiency increased hepatic CRBPII expression by a further 2 fold (P=.044) and RBP4 by~20% (P=.005), increased RBPR2 and decreased CRBPII, LRAT, and TTR in fetal liver, while it had no effect on VA metabolic gene expression in the placenta. Hepatic CRBPII expression is increased by pregnancy and further increased by iron deficiency, which may play an important role in VA metabolism and homeostasis. Maternal iron deficiency also alters VA metabolism in the fetus, which is likely to have consequences for development.

  1. Plant transporters involved in heavy metal homeostasis

    Directory of Open Access Journals (Sweden)

    Dorina Podar

    2010-12-01

    Full Text Available Transition metal ions (predominately manganese, iron, cobalt, nickel, copper and zinc havean array of catalytic and regulatory roles in the growth and development of all living organisms.However, an excess of these metal ions can also be toxic to any life form and therefore every cell andwhole organism needs to maintain the concentration of these essential nutrient metals within a narrowrange: a process known as metal homeostasis. Heavy metal ions are taken up into cells by selectivetransporters and as they cannot be degraded, the “desired” levels of metal ions are achieved by anumber of strategies that involve: chelation, sequestration and export out of the cell. Cation DiffusionFacilitators (CDF is a large family of transporters involved in maintaining the cytosolic metalconcentration. They transport different heavy metal divalent ions, but exhibit main affinity for zinc, ironand manganese. Metal Tolerance Proteins (MTPs are a subfamily of the Cation Diffusion Facilitator (CDFfamily found in plants. There has been much interest in these heavy metal transporters in order toprovide an insight into plant metal homeostasis, which has significant implications in human health andphytoremediation. Although data regarding the CDFs/MTPs mechanism is gathering there is still littleinformation with respect to metal selectivity determinants.

  2. Iron accumulates in the lavage and explanted lungs of cystic fibrosis patients.

    Science.gov (United States)

    Abstract Oxidative stress participates in the pathophysiology of cystic fibrosis (CF). An underlying disruption in iron homeostasis can frequently be demonstrated in injuries and diseases associated with an oxidative stress. We tested the hypothesis that iron accumulation and ...

  3. Redox homeostasis: The Golden Mean of healthy living

    Directory of Open Access Journals (Sweden)

    Fulvio Ursini

    2016-08-01

    Full Text Available The notion that electrophiles serve as messengers in cell signaling is now widely accepted. Nonetheless, major issues restrain acceptance of redox homeostasis and redox signaling as components of maintenance of a normal physiological steady state. The first is that redox signaling requires sudden switching on of oxidant production and bypassing of antioxidant mechanisms rather than a continuous process that, like other signaling mechanisms, can be smoothly turned up or down. The second is the misperception that reactions in redox signaling involve “reactive oxygen species” rather than reaction of specific electrophiles with specific protein thiolates. The third is that hormesis provides protection against oxidants by increasing cellular defense or repair mechanisms rather than by specifically addressing the offset of redox homeostasis. Instead, we propose that both oxidant and antioxidant signaling are main features of redox homeostasis. As the redox shift is rapidly reversed by feedback reactions, homeostasis is maintained by continuous signaling for production and elimination of electrophiles and nucleophiles. Redox homeostasis, which is the maintenance of nucleophilic tone, accounts for a healthy physiological steady state. Electrophiles and nucleophiles are not intrinsically harmful or protective, and redox homeostasis is an essential feature of both the response to challenges and subsequent feedback. While the balance between oxidants and nucleophiles is preserved in redox homeostasis, oxidative stress provokes the establishment of a new radically altered redox steady state. The popular belief that scavenging free radicals by antioxidants has a beneficial effect is wishful thinking. We propose, instead, that continuous feedback preserves nucleophilic tone and that this is supported by redox active nutritional phytochemicals. These nonessential compounds, by activating Nrf2, mimic the effect of endogenously produced electrophiles

  4. Alteration by irradiation and storage at amount of heme iron in poultry meat; Alteracoes provocadas pela irradiacao e armazenamento nos teores de ferro heme em carne de frango

    Energy Technology Data Exchange (ETDEWEB)

    Souza, Adriana Regia Marques de; Arthur, Valter Arthur [Centro de Energia Nuclear na Agricultura (CENA), Piracicaba, SP (Brazil). Lab. de Irradiacao de Alimentos e Radioentomologia; Canniatti-Brazaca, Solange Guidolin [Escola Superior de Agricultura Luiz de Queiroz (ESALQ/USP), Piracicaba, SP (Brazil). Dept. de Agroindustria, Alimentos e Nutricao]. E-mail: sgcbraza@esalq.usp.br

    2007-04-15

    Studies of irradiation and storage effects in chicken were carried out to discover the influence in iron heme, non-heme amount, color and total pigments. Chicken thighs and chicken breast were studied. These were irradiated to 0, 1 and 2 kGy stored by 14 days to 4 deg C in refrigerator. Determining the heme content and non-heme of meat was done using the colorimeter method and the Ferrozine reagent. The values of iron heme were influenced both by the irradiation and the storage, reducing the amount throughout the course of time. The iron non-heme was also influenced by the doses and the storage time, however the values increased throughout the course of time, because of the conversion of iron heme in non-heme. The color did not show that it was influenced by the studied doses, except for the storage, and the total number of pigments was affected by the irradiation and the time, reducing the values with the increase of storage. Irradiation was shown to be a good method to conserve iron. (author)

  5. Iron and iron derived radicals

    Energy Technology Data Exchange (ETDEWEB)

    Borg, D.C.; Schaich, K.M.

    1987-04-01

    We have discussed some reactions of iron and iron-derived oxygen radicals that may be important in the production or treatment of tissue injury. Our conclusions challenge, to some extent, the usual lines of thought in this field of research. Insofar as they are born out by subsequent developments, the lessons they teach are two: Think fastexclamation Think smallexclamation In other words, think of the many fast reactions that can rapidly alter the production and fate of highly reactive intermediates, and when considering the impact of competitive reactions on such species, think how they affect the microenvironment (on the molecular scale) ''seen'' by each reactive molecule. 21 refs., 3 figs., 1 tab.

  6. Blockage of mitochondrial calcium uniporter prevents iron accumulation in a model of experimental subarachnoid hemorrhage

    International Nuclear Information System (INIS)

    Highlights: • Iron accumulation was involved in the acute phase following SAH. • Blockage of MCU could attenuate cellular iron accumulation following SAH. • Blockage of MCU could decrease ROS generation and improve cell energy supply following SAH. • Blockage of MCU could alleviate apoptosis and brain injury following SAH. - Abstract: Previous studies have shown that iron accumulation is involved in the pathogenesis of brain injury following subarachnoid hemorrhage (SAH) and chelation of iron reduced mortality and oxidative DNA damage. We previously reported that blockage of mitochondrial calcium uniporter (MCU) provided benefit in the early brain injury after experimental SAH. This study was undertaken to identify whether blockage of MCU could ameliorate iron accumulation-associated brain injury following SAH. Therefore, we used two reagents ruthenium red (RR) and spermine (Sper) to inhibit MCU. Sprague–Dawley (SD) rats were randomly divided into four groups including sham, SAH, SAH + RR, and SAH + Sper. Biochemical analysis and histological assays were performed. The results confirmed the iron accumulation in temporal lobe after SAH. Interestingly, blockage of MCU dramatically reduced the iron accumulation in this area. The mechanism was revealed that inhibition of MCU reversed the down-regulation of iron regulatory protein (IRP) 1/2 and increase of ferritin. Iron–sulfur cluster dependent-aconitase activity was partially conserved when MCU was blocked. In consistence with this and previous report, ROS levels were notably reduced and ATP supply was rescued; levels of cleaved caspase-3 dropped; and integrity of neurons in temporal lobe was protected. Taken together, our results indicated that blockage of MCU could alleviate iron accumulation and the associated injury following SAH. These findings suggest that the alteration of calcium and iron homeostasis be coupled and MCU be considered to be a therapeutic target for patients suffering from SAH

  7. Blockage of mitochondrial calcium uniporter prevents iron accumulation in a model of experimental subarachnoid hemorrhage

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Huiying [Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province (China); Hao, Shuangying; Sun, Xiaoyan [Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu Province (China); Zhang, Dingding; Gao, Xin; Yu, Zhuang [Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province (China); Li, Kuanyu, E-mail: likuanyu@nju.edu.cn [Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu Province (China); Hang, Chun-Hua, E-mail: hang_neurosurgery@163.com [Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province (China)

    2015-01-24

    Highlights: • Iron accumulation was involved in the acute phase following SAH. • Blockage of MCU could attenuate cellular iron accumulation following SAH. • Blockage of MCU could decrease ROS generation and improve cell energy supply following SAH. • Blockage of MCU could alleviate apoptosis and brain injury following SAH. - Abstract: Previous studies have shown that iron accumulation is involved in the pathogenesis of brain injury following subarachnoid hemorrhage (SAH) and chelation of iron reduced mortality and oxidative DNA damage. We previously reported that blockage of mitochondrial calcium uniporter (MCU) provided benefit in the early brain injury after experimental SAH. This study was undertaken to identify whether blockage of MCU could ameliorate iron accumulation-associated brain injury following SAH. Therefore, we used two reagents ruthenium red (RR) and spermine (Sper) to inhibit MCU. Sprague–Dawley (SD) rats were randomly divided into four groups including sham, SAH, SAH + RR, and SAH + Sper. Biochemical analysis and histological assays were performed. The results confirmed the iron accumulation in temporal lobe after SAH. Interestingly, blockage of MCU dramatically reduced the iron accumulation in this area. The mechanism was revealed that inhibition of MCU reversed the down-regulation of iron regulatory protein (IRP) 1/2 and increase of ferritin. Iron–sulfur cluster dependent-aconitase activity was partially conserved when MCU was blocked. In consistence with this and previous report, ROS levels were notably reduced and ATP supply was rescued; levels of cleaved caspase-3 dropped; and integrity of neurons in temporal lobe was protected. Taken together, our results indicated that blockage of MCU could alleviate iron accumulation and the associated injury following SAH. These findings suggest that the alteration of calcium and iron homeostasis be coupled and MCU be considered to be a therapeutic target for patients suffering from SAH.

  8. Deciphering Mineral Homeostasis in Barley Seed Transfer Cells at Transcriptional Level.

    Directory of Open Access Journals (Sweden)

    Behrooz Darbani

    Full Text Available In addition to the micronutrient inadequacy of staple crops for optimal human nutrition, a global downtrend in crop-quality has emerged from intensive breeding for yield. This trend will be aggravated by elevated levels of the greenhouse gas carbon dioxide. Therefore, crop biofortification is inevitable to ensure a sustainable supply of minerals to the large part of human population who is dietary dependent on staple crops. This requires a thorough understanding of plant-mineral interactions due to the complexity of mineral homeostasis. Employing RNA sequencing, we here communicate transfer cell specific effects of excess iron and zinc during grain filling in our model crop plant barley. Responding to alterations in mineral contents, we found a long range of different genes and transcripts. Among them, it is worth to highlight the auxin and ethylene signaling factors Arfs, Abcbs, Cand1, Hps4, Hac1, Ecr1, and Ctr1, diurnal fluctuation components Sdg2, Imb1, Lip1, and PhyC, retroelements, sulfur homeostasis components Amp1, Hmt3, Eil3, and Vip1, mineral trafficking components Med16, Cnnm4, Aha2, Clpc1, and Pcbps, and vacuole organization factors Ymr155W, RabG3F, Vps4, and Cbl3. Our analysis introduces new interactors and signifies a broad spectrum of regulatory levels from chromatin remodeling to intracellular protein sorting mechanisms active in the plant mineral homeostasis. The results highlight the importance of storage proteins in metal ion toxicity-resistance and chelation. Interestingly, the protein sorting and recycling factors Exoc7, Cdc1, Sec23A, and Rab11A contributed to the response as well as the polar distributors of metal-transporters ensuring the directional flow of minerals. Alternative isoform switching was found important for plant adaptation and occurred among transcripts coding for identical proteins as well as transcripts coding for protein isoforms. We also identified differences in the alternative-isoform preference between

  9. Iron excretion in iron dextran-overloaded mice

    Science.gov (United States)

    Musumeci, Marco; Maccari, Sonia; Massimi, Alessia; Stati, Tonino; Sestili, Paola; Corritore, Elisa; Pastorelli, Augusto; Stacchini, Paolo; Marano, Giuseppe; Catalano, Liviana

    2014-01-01

    Background Iron homeostasis in humans is tightly regulated by mechanisms aimed to conserve iron for reutilisation, with a negligible role played by excretory mechanisms. In a previous study we found that mice have an astonishing ability to tolerate very high doses of parenterally administered iron dextran. Whether this ability is linked to the existence of an excretory pathway remains to be ascertained. Materials and methods Iron overload was generated by intraperitoneal injections of iron dextran (1 g/kg) administered once a week for 8 weeks in two different mouse strains (C57bl/6 and B6D2F1). Urinary and faecal iron excretion was assessed by inductively coupling plasma-mass spectrometry, whereas cardiac and liver architecture was evaluated by echocardiography and histological methods. For both strains, 24-hour faeces and urine samples were collected and iron concentration was determined on days 0, 1 and 2 after iron administration. Results In iron-overloaded C57bl/6 mice, the faecal iron concentration increased by 218% and 157% on days 1 and 2, respectively (p<0.01). The iron excreted represented a loss of 14% of total iron administered. Similar but smaller changes was also found in B6D2F1 mice. Conversely, we found no significant changes in the concentration of iron in the urine in either of the strains of mice. In both strains, histological examination showed accumulation of iron in the liver and heart which tended to decrease over time. Conclusions This study indicates that mice have a mechanism for removal of excess body iron and provides insights into the possible mechanisms of excretion. PMID:24960657

  10. Perturbed cholesterol homeostasis in aging spinal cord.

    Science.gov (United States)

    Parkinson, Gemma M; Dayas, Christopher V; Smith, Doug W

    2016-09-01

    The spinal cord is vital for the processing of sensorimotor information and for its propagation to and from both the brain and the periphery. Spinal cord function is affected by aging, however, the mechanisms involved are not well-understood. To characterize molecular mechanisms of spinal cord aging, microarray analyses of gene expression were performed on cervical spinal cords of aging rats. Of the metabolic and signaling pathways affected, cholesterol-associated pathways were the most comprehensively altered, including significant downregulation of cholesterol synthesis-related genes and upregulation of cholesterol transport and metabolism genes. Paradoxically, a significant increase in total cholesterol content was observed-likely associated with cholesterol ester accumulation. To investigate potential mechanisms for the perturbed cholesterol homeostasis, we quantified the expression of myelin and neuroinflammation-associated genes and proteins. Although there was minimal change in myelin-related expression, there was an increase in phagocytic microglial and astrogliosis markers, particularly in the white matter. Together, these results suggest that perturbed cholesterol homeostasis, possibly as a result of increased inflammatory activation in spinal cord white matter, may contribute to impaired spinal cord function with aging. PMID:27459933

  11. Homeostasis of T Cell Diversity

    Institute of Scientific and Technical Information of China (English)

    Vinay S. Mahajan; Ilya B. Leskov; Jianzhu Chen

    2005-01-01

    T cell homeostasis commonly refers to the maintenance of relatively stable T cell numbers in the peripheral lymphoid organs. Among the large numbers of T cells in the periphery, T cells exhibit structural diversity, I.e., the expression of a diverse repertoire of T cell receptors (TCRs), and functional diversity, I.e., the presence of T cells at na(I)ve, effector, and memory developmental stages. Although the homeostasis of T cell numbers has been extensively studied, investigation of the mechanisms underlying the maintenance of structural and functional diversity of T cells is still at an early stage. The fundamental feature throughout T cell development is the interaction between the TCR and either self or foreign peptides in association with MHC molecules. In this review, we present evidence showing that homeostasis of T cell number and diversity is mediated through competition for limiting resources.The number of T cells is maintained through competition for limiting cytokines, whereas the diversity of T cells is maintained by competition for self-peptide-MHC complexes. In other words, diversity of the self-peptide repertoire limits the structural (TCR) diversity of a T cell population. We speculate that cognate low affinity self-peptides,acting as weak agonists and antagonists, regulate the homeostasis of T cell diversity whereas non-cognate or null peptides which are extremely abundant for any given TCR, may contribute to the homeostasis of T cell number by providing survival signals. Moreover, self-peptides and cytokines may form specialized niches for the regulation of T cell homeostasis.

  12. Homeostasis of T Cell Diversity

    Institute of Scientific and Technical Information of China (English)

    VinayS.Mahajan; IlyaB.Leskov; JianzhuChen

    2005-01-01

    T cell homeostasis commonly refers to the maintenance of relatively stable T cell numbers in the peripheral lymphoid organs. Among the large numbers of T cells in the periphery, T cells exhibit structural diversity, i.e., the expression of a diverse repertoire of T cell receptors (TCRs), and functional diversity, i.e., the presence of T cells at naive, effector, and memory developmental stages. Although the homeostasis of T cell numbers has been extensively studied, investigation of the mechanisms underlying the maintenance of structural and functional diversity of T cells is still at an early stage. The fundamental feature throughout T cell development is the interaction between the TCR and either self or foreign peptides in association with MHC molecules. In this review, we present evidence showing that homeostasis of T cell number and diversity is mediated through competition for limiting resources. The number of T cells is maintained through competition for limiting cytokines, whereas the diversity of T cells is maintained by competition for self-peptide-MHC complexes. In other words, diversity of the self-peptide repertoire limits the structural (TCR) diversity of a T cell population. We speculate that cognate low affinity self-peptides, acting as weak agonists and antagonists, regulate the homeostasis of T cell diversity whereas non-cognate or null peptides which are extremely abundant for any given TCR, may contribute to the homeostasis of T cell number by providing survival signals. Moreover, self-peptides and cytokines may form specialized niches for the regulation of T cell homeostasis. Cellular & Molecular Immunology. 2005;2(1): 1-10.

  13. Lipocalin 2 alleviates iron toxicity by facilitating hypoferremia of inflammation and limiting catalytic iron generation.

    Science.gov (United States)

    Xiao, Xia; Yeoh, Beng San; Saha, Piu; Olvera, Rodrigo Aguilera; Singh, Vishal; Vijay-Kumar, Matam

    2016-06-01

    Iron is an essential transition metal ion for virtually all aerobic organisms, yet its dysregulation (iron overload or anemia) is a harbinger of many pathologic conditions. Hence, iron homeostasis is tightly regulated to prevent the generation of catalytic iron (CI) which can damage cellular biomolecules. In this study, we investigated the role of iron-binding/trafficking innate immune protein, lipocalin 2 (Lcn2, aka siderocalin) on iron and CI homeostasis using Lcn2 knockout (KO) mice and their WT littermates. Administration of iron either systemically or via dietary intake strikingly upregulated Lcn2 in the serum, urine, feces, and liver of WT mice. However, similarly-treated Lcn2KO mice displayed elevated CI, augmented lipid peroxidation and other indices of organ damage markers, implicating that Lcn2 responses may be protective against iron-induced toxicity. Herein, we also show a negative association between serum Lcn2 and CI in the murine model of dextran sodium sulfate (DSS)-induced colitis. The inability of DSS-treated Lcn2KO mice to elicit hypoferremic response to acute colitis, implicates the involvement of Lcn2 in iron homeostasis during inflammation. Using bone marrow chimeras, we further show that Lcn2 derived from both immune and non-immune cells participates in CI regulation. Remarkably, exogenous rec-Lcn2 supplementation suppressed CI levels in Lcn2KO serum and urine. Collectively, our results suggest that Lcn2 may facilitate hypoferremia, suppress CI generation and prevent iron-mediated adverse effects. PMID:27007712

  14. Leptin and Hormones: Energy Homeostasis.

    Science.gov (United States)

    Triantafyllou, Georgios A; Paschou, Stavroula A; Mantzoros, Christos S

    2016-09-01

    Leptin, a 167 amino acid adipokine, plays a major role in human energy homeostasis. Its actions are mediated through binding to leptin receptor and activating JAK-STAT3 signal transduction pathway. It is expressed mainly in adipocytes, and its circulating levels reflect the body's energy stores in adipose tissue. Recombinant methionyl human leptin has been FDA approved for patients with generalized non-HIV lipodystrophy and for compassionate use in subjects with congenital leptin deficiency. The purpose of this review is to outline the role of leptin in energy homeostasis, as well as its interaction with other hormones. PMID:27519135

  15. Ethylmalonic encephalopathy ETHE1 R163W/R163Q mutations alter protein stability and redox properties of the iron centre.

    Science.gov (United States)

    Henriques, Bárbara J; Lucas, Tânia G; Rodrigues, João V; Frederiksen, Jane H; Teixeira, Miguel S; Tiranti, Valeria; Bross, Peter; Gomes, Cláudio M

    2014-01-01

    ETHE1 is an iron-containing protein from the metallo β-lactamase family involved in the mitochondrial sulfide oxidation pathway. Mutations in ETHE1 causing loss of function result in sulfide toxicity and in the rare fatal disease Ethylmalonic Encephalopathy (EE). Frequently mutations resulting in depletion of ETHE1 in patient cells are due to severe structural and folding defects. However, some ETHE1 mutations yield nearly normal protein levels and in these cases disease mechanism was suspected to lie in compromised catalytic activity. To address this issue and to elicit how ETHE1 dysfunction results in EE, we have investigated two such pathological mutations, ETHE1-p.Arg163Gln and p.Arg163Trp. In addition, we report a number of benchmark properties of wild type human ETHE1, including for the first time the redox properties of the mononuclear iron centre. We show that loss of function in these variants results from a combination of decreased protein stability and activity. Although structural assessment revealed that the protein fold is not perturbed by mutations, both variants have decreased thermal stabilities and higher proteolytic susceptibilities. ETHE1 wild type and variants bind 1 ± 0.2 mol iron/protein and no zinc; however, the variants exhibited only ≈ 10% of wild-type catalytically activity. Analysis of the redox properties of ETHE1 mononuclear iron centre revealed that the variants have lowered reduction potentials with respect to that of the wild type. This illustrates how point mutation-induced loss of function may arise via very discrete subtle conformational effects on the protein fold and active site chemistry, without extensive disruption of the protein structure or protein-cofactor association. PMID:25198162

  16. Ethylmalonic encephalopathy ETHE1 R163W/R163Q mutations alter protein stability and redox properties of the iron centre.

    Directory of Open Access Journals (Sweden)

    Bárbara J Henriques

    Full Text Available ETHE1 is an iron-containing protein from the metallo β-lactamase family involved in the mitochondrial sulfide oxidation pathway. Mutations in ETHE1 causing loss of function result in sulfide toxicity and in the rare fatal disease Ethylmalonic Encephalopathy (EE. Frequently mutations resulting in depletion of ETHE1 in patient cells are due to severe structural and folding defects. However, some ETHE1 mutations yield nearly normal protein levels and in these cases disease mechanism was suspected to lie in compromised catalytic activity. To address this issue and to elicit how ETHE1 dysfunction results in EE, we have investigated two such pathological mutations, ETHE1-p.Arg163Gln and p.Arg163Trp. In addition, we report a number of benchmark properties of wild type human ETHE1, including for the first time the redox properties of the mononuclear iron centre. We show that loss of function in these variants results from a combination of decreased protein stability and activity. Although structural assessment revealed that the protein fold is not perturbed by mutations, both variants have decreased thermal stabilities and higher proteolytic susceptibilities. ETHE1 wild type and variants bind 1 ± 0.2 mol iron/protein and no zinc; however, the variants exhibited only ≈ 10% of wild-type catalytically activity. Analysis of the redox properties of ETHE1 mononuclear iron centre revealed that the variants have lowered reduction potentials with respect to that of the wild type. This illustrates how point mutation-induced loss of function may arise via very discrete subtle conformational effects on the protein fold and active site chemistry, without extensive disruption of the protein structure or protein-cofactor association.

  17. Icariin regulates systemic iron metabolism by increasing hepatic hepcidin expression through Stat3 and Smad1/5/8 signaling.

    Science.gov (United States)

    Zhang, Miao; Liu, Jing; Guo, Wenli; Liu, Xin; Liu, Sijin; Yin, Huijun

    2016-05-01

    Systemic iron homeostasis is strictly controlled under normal conditions to ensure a balance between the absorption, utilization, storage and recycling of iron. The hepcidin-ferroportin (FPN) axis is of critical importance in the maintenance of iron homeostasis. Hepcidin deficiency gives rise to enhanced dietary iron absorption, as well as to increased iron release from macrophages, and this in turn results in iron accumulation in the plasma and organs, and is associated with a range of tissue pathologies. Low hepcidin levels have been demonstrated in most forms of hereditary hemochromatosis (HH), as well as in β-thalassemia. Therapies that increase hepcidin concentrations may potentially play a role in the treatment of these iron overload-related diseases. To date, natural compounds have not been extensively investigated for this purpose, to the best of our knowledge. Thus, in the present study, we screened natural compounds that have the potential to regulate hepcidin expression. By performing hepcidin promoter-luciferase assay, RT-qPCR and animal experiments, we demonstrated that icariin and berberine were potent stimulators of hepcidin transcription. Mechanistic experiments indicated that icariin and berberine increased hepcidin expression by activating the signal transducer and activator of transcription 3 (Stat3) and Smad1/5/8 signaling pathways. The induction of hepcidin was confirmed in mice following icariin administration, coupled with associated changes in serum and tissue iron concentrations. In support of these findings, the icariin analogues, epimedin A, B and C, also increased hepatic hepcidin expression. However, these changes were not observed in hepcidin-deficient [Hamp1-/- or Hamp1‑knockout (KO)] mice following icariin administration, thereby verifying hepatic hepcidin as the target of icariin. Although berberine exhibited a robust capacity to promote hepcidin expression in vitro, it failed to alter hepcidin expression in mice. Taken together

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

  20. Supplemental dietary inulin of variable chain lengths alters intestinal bacterial populations in young pigs.

    Science.gov (United States)

    Patterson, Jannine K; Yasuda, Koji; Welch, Ross M; Miller, Dennis D; Lei, Xin Gen

    2010-12-01

    Previously, we showed that supplementation of diets with short-chain inulin (P95), long-chain inulin (HP), and a 50:50 mixture of both (Synergy 1) improved body iron status and altered expression of the genes involved in iron homeostasis and inflammation in young pigs. However, the effects of these 3 types of inulin on intestinal bacteria remain unknown. Applying terminal restriction fragment length polymorphism analysis, we determined the abundances of luminal and adherent bacterial populations from 6 segments of the small and large intestines of pigs (n = 4 for each group) fed an iron-deficient basal diet (BD) or the BD supplemented with 4% of P95, Synergy 1, or HP for 5 wk. Compared with BD, all 3 types of inulin enhanced (P inulin on bacterial populations in the lumen contents were found. Meanwhile, all 3 types of inulin suppressed the less desirable bacteria Clostridium spp. and members of the Enterobacteriaceae in the lumen and mucosa of various gut segments. Our findings suggest that the ability of dietary inulin to alter intestinal bacterial populations may partially account for its iron bioavailability-promoting effect and possibly other health benefits.

  1. Altered sleep homeostasis in rev-erbα knockout mice

    OpenAIRE

    Mang, Géraldine M.; La Spada, Francesco; Emmenegger, Yann; Chappuis, Sylvie; Ripperger, Jürgen A; Albrecht, Urs; Franken, Paul

    2016-01-01

    Study Objectives: The nuclear receptor REV-ERBα is a potent, constitutive transcriptional repressor critical for the regulation of key circadian and metabolic genes. Recently, REV-ERBα's involvement in learning, neurogenesis, mood, and dopamine turnover was demonstrated suggesting a specific role in central nervous system functioning. We have previously shown that the brain expression of several core clock genes, including Rev-erbα, is modulated by sleep loss. We here test the consequen...

  2. Transfected parvalbumin alters calcium homeostasis in teratocarcinoma PCC7 cells

    DEFF Research Database (Denmark)

    Müller, B K; Kabos, P; Belhage, B;

    1996-01-01

    Indirect evidence supports a protective role of some EF-hand calcium-binding proteins against calcium-induced neurotoxicity. Little is known about how these proteins influence cytosolic calcium levels. After cloning the parvalbumin cDNA into an expression vector, teratocarcinoma cells (PCC7) were...

  3. Transfected parvalbumin alters calcium homeostasis in teratocarcinoma PCC7 cells

    DEFF Research Database (Denmark)

    Müller, B K; Kabos, P; Belhage, B;

    1996-01-01

    transfected. Parvalbumin-transfected and mock-transfected cells were loaded with the calcium indicator fura-2 and were exposed, in the same dish, to different concentrations of the calcium ionophore A23187 or to KCI. The results show that parvalbumin-transfected PCC7 cells had much better calcium buffering...

  4. Hepcidin Regulation of Iron Transport1–3

    OpenAIRE

    Collins, James F.; Wessling-Resnick, Marianne; Knutson, Mitchell D.

    2008-01-01

    The discovery of hepcidin as a key regulator of iron homeostasis has advanced our current knowledge of this field. Liver-derived hepcidin peptide is secreted in response to iron and inflammation and interacts with the iron export protein ferroportin. This review summarizes recent advances discussed at the Symposium. A particular focus is on molecular interactions between hepcidin and ferroportin, the regulation of hepcidin expression by iron and inflammation, and emerging methods to measure s...

  5. The role of gut microbiota in immune homeostasis and autoimmunity

    OpenAIRE

    Wu, Hsin-Jung; Wu, Eric

    2012-01-01

    Keeping a delicate balance in the immune system by eliminating invading pathogens, while still maintaining self-tolerance to avoid autoimmunity, is critical for the body’s health. The gut microbiota that resides in the gastrointestinal tract provides essential health benefits to its host, particularly by regulating immune homeostasis. Moreover, it has recently become obvious that alterations of these gut microbial communities can cause immune dysregulation, leading to autoimmune disorders. He...

  6. Iron-Responsive Regulation of the Helicobacter pylori Iron-Cofactored Superoxide Dismutase SodB Is Mediated by Fur

    OpenAIRE

    Ernst, Florian D.; Homuth, Georg; Stoof, Jeroen; Mäder, Ulrike; Waidner, Barbara; Kuipers, Ernst J; Kist, Manfred; Kusters, Johannes G.; Bereswill, Stefan; van Vliet, Arnoud H. M.

    2005-01-01

    Maintaining iron homeostasis is a necessity for all living organisms, as free iron augments the generation of reactive oxygen species like superoxide anions, at the risk of subsequent lethal cellular damage. The iron-responsive regulator Fur controls iron metabolism in many bacteria, including the important human pathogen Helicobacter pylori, and thus is directly or indirectly involved in regulation of oxidative stress defense. Here we demonstrate that Fur is a direct regulator of the H. pylo...

  7. Quantitative analysis of dietary iron utilization for erythropoiesis in response to body iron status.

    Science.gov (United States)

    Matsuo-Tezuka, Yukari; Noguchi-Sasaki, Mariko; Kurasawa, Mitsue; Yorozu, Keigo; Shimonaka, Yasushi

    2016-06-01

    Erythropoiesis requires large amounts of iron for hemoglobin synthesis. There are two sources of iron for erythropoiesis, dietary and stored iron; however, their relative contributions to erythropoiesis remain unknown. In this study, we used the stable iron isotope (57)Fe to quantify synthesis of hemoglobin derived from dietary iron. Using this method, we investigated the activities of dietary iron absorption and the utilization of dietary iron for erythropoiesis in responses to stimulated erythropoiesis and to interventions to alter body iron status. Under iron-loaded conditions, the activity of dietary iron absorption was clearly lowered in response to up-regulation of hepcidin, although the estimated activity of iron release from stored iron was not compared with that under control conditions. This result was supported by the observation that two duodenal iron transporters, divalent metal transporter 1 (DMT1) and ferroportin, were downregulated by iron loading, although the levels of expression of ferroportin in iron storage tissues were not changed by iron loading under erythropoietic stimulation by epoetin-β pegol (C.E.R.A., a long-acting erythropoiesis-stimulating agent). These results indicate that the dietary iron absorption system is more sensitive to body iron status than are reticuloendothelial iron- release mechanisms. Our data indicated that there could be a regulatory mechanism favoring use of stored iron over dietary iron under iron-loaded conditions. PMID:26911670

  8. The iron/heme regulated genes of Haemophilus influenzae: comparative transcriptional profiling as a tool to define the species core modulon

    Directory of Open Access Journals (Sweden)

    Morton Daniel J

    2009-01-01

    Full Text Available Abstract Background Haemophilus influenzae requires heme for aerobic growth and possesses multiple mechanisms to obtain this essential nutrient. Although an understanding of the heme acquisition mechanisms of H. influenzae is emerging, significant gaps in our knowledge remain. Unresolved issues include the identities of all genes exhibiting altered transcription in response to iron and heme availability, the fraction of such genes functioning in iron/heme acquisition, and the heterogeneity of this gene set among clinical isolates. Previously we utilized H. influenzae strain Rd KW20 to demonstrate the utility of transcriptional profiling in defining the genes exhibiting altered transcription in response to environmental iron and heme levels. The current study expands upon those observations by determining the iron/heme modulons of two clinical isolates, the type b isolate 10810 and the nontypeable isolate R2866. These data are used to begin to define the core iron/heme modulon of the species. Results Microarray studies were performed to compare gene expression on transition from iron/heme-restricted to iron/heme-replete conditions for each isolate. Of 1820 ORFs on the array corresponding to R2866 genes, 363 were significantly differentially expressed: 233 were maximally transcribed under iron/heme-replete conditions and 130 under iron/heme-restricted conditions. Of the 1883 ORFs representing genes of strain 10810, 353 were significantly differentially transcribed: 150 were preferentially transcribed under iron/heme-replete conditions and 203 under iron/heme-restricted conditions. Comparison of the data sets indicated that 163 genes exhibited similar regulation in both isolates and that 74 of these exhibited similar patterns of regulation in Rd KW20. These comprise the putative core iron/heme modulon. Conclusion This study provides evidence for a conserved core of H. influenzae genes the transcription of which is altered by the availability of

  9. Zinc bioavailability and homeostasis1234

    OpenAIRE

    Hambidge, K Michael; Miller, Leland V; Westcott, Jamie E; Sheng, Xiaoyang; Krebs, Nancy F.

    2010-01-01

    Zinc has earned recognition recently as a micronutrient of outstanding and diverse biological, clinical, and global public health importance. Regulation of absorption by zinc transporters in the enterocyte, together with saturation kinetics of the absorption process into and across the enterocyte, are the principal means by which whole-body zinc homeostasis is maintained. Several physiologic factors, most notably the quantity of zinc ingested, determine the quantity of zinc absorbed and the e...

  10. Influence of Various Levels of Iron and Other Abiotic Factors on Siderophorogenesis in Paddy Field Cyanobacterium Anabaena oryzae.

    Science.gov (United States)

    Singh, Anumeha; Mishra, Arun Kumar

    2015-05-01

    Siderophore production in Anabaena oryzae was investigated under the influence of various levels of iron and other abiotic factors such as pH, temperature, light and different nitrogen sources. Optimization of culture conditions under controlled mechanisms of these abiotic factors lead to the siderophore production in significant amount. Under iron-starved condition, A. oryzae extracellularly releases 89.17% hydroxymate-type siderophore. Slightly alkaline pH and 30 °C temperature was found stimulatory for the cyanobacterial growth and siderophorogenesis (88.52% SU and 83.87% SU, respectively). Excess iron loading had a negative impact on siderophore production along with the alterations in the morphology and growth. Further, scanning electron microphotographs signified that higher concentrations of iron lead to complete damage of the cells and alterations in membrane proteins possibly transporters responsible for exchange of siderophore complex from environment to the cell. SDS-PAGE analysis of whole cell proteins showed overexpression of low molecular weight proteins ranges between 20.1 to 29.0 kDa up to 100-μM iron concentrations. These polypeptides/proteins might be involved in maintaining iron homeostasis by regulating siderophore production. Results suggest that lower concentrations of iron ≤ 50 μM along with other abiotic factors are stimulatory, whereas higher concentrations (>50 μM) are toxic. Data further suggested that cyanobacterium A. oryzae can serve as a potential biofertilizer especially in iron-rich soil through sequestration by the power of natural Fe(III)-siderophore complex formation.

  11. Iron deficiency and cognitive functions

    Directory of Open Access Journals (Sweden)

    Jáuregui-Lobera I

    2014-11-01

    Full Text Available Ignacio Jáuregui-Lobera Department of Nutrition and Bromatology, Pablo de Olavide University, Seville, Spain Abstract: Micronutrient deficiencies, especially those related to iodine and iron, are linked to different cognitive impairments, as well as to potential long-term behavioral changes. Among the cognitive impairments caused by iron deficiency, those referring to attention span, intelligence, and sensory perception functions are mainly cited, as well as those associated with emotions and behavior, often directly related to the presence of iron deficiency anemia. In addition, iron deficiency without anemia may cause cognitive disturbances. At present, the prevalence of iron deficiency and iron deficiency anemia is 2%–6% among European children. Given the importance of iron deficiency relative to proper cognitive development and the alterations that can persist through adulthood as a result of this deficiency, the objective of this study was to review the current state of knowledge about this health problem. The relevance of iron deficiency and iron deficiency anemia, the distinction between the cognitive consequences of iron deficiency and those affecting specifically cognitive development, and the debate about the utility of iron supplements are the most relevant and controversial topics. Despite there being methodological differences among studies, there is some evidence that iron supplementation improves cognitive functions. Nevertheless, this must be confirmed by means of adequate follow-up studies among different groups. Keywords: iron deficiency, anemia, cognitive functions, supplementation

  12. Superparamagnetic iron oxide nanoparticles: magnetic nanoplatforms as drug carriers

    Directory of Open Access Journals (Sweden)

    Wahajuddin

    2012-07-01

    Full Text Available Wahajuddin,1,2 Sumit Arora21Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, 2Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Rae Bareli, IndiaAbstract: A targeted drug delivery system is the need of the hour. Guiding magnetic iron oxide nanoparticles with the help of an external magnetic field to its target is the principle behind the development of superparamagnetic iron oxide nanoparticles (SPIONs as novel drug delivery vehicles. SPIONs are small synthetic γ-Fe2O3 (maghemite or Fe3O4 (magnetite particles with a core ranging between 10 nm and 100 nm in diameter. These magnetic particles are coated with certain biocompatible polymers, such as dextran or polyethylene glycol, which provide chemical handles for the conjugation of therapeutic agents and also improve their blood distribution profile. The current research on SPIONs is opening up wide horizons for their use as diagnostic agents in magnetic resonance imaging as well as for drug delivery vehicles. Delivery of anticancer drugs by coupling with functionalized SPIONs to their targeted site is one of the most pursued areas of research in the development of cancer treatment strategies. SPIONs have also demonstrated their efficiency as nonviral gene vectors that facilitate the introduction of plasmids into the nucleus at rates multifold those of routinely available standard technologies. SPION-induced hyperthermia has also been utilized for localized killing of cancerous cells. Despite their potential biomedical application, alteration in gene expression profiles, disturbance in iron homeostasis, oxidative stress, and altered cellular responses are some SPION-related toxicological aspects which require due consideration. This review provides a comprehensive understanding of SPIONs with regard to their method of preparation, their utility as drug delivery vehicles, and some concerns which need to

  13. Oxygen isotope exchange kinetics of mineral pairs in closed and open systems: Applications to problems of hydrothermal alteration of igneous rocks and Precambrian iron formations

    Science.gov (United States)

    Gregory, R.T.; Criss, R.E.; Taylor, H.P.

    1989-01-01

    heat-balance constraints, we can utilize the 18O 16O data on natural mineral assemblages to calculate the kinetic rate constants (k's) and the effective diffusion constants (D's) for mineral-H2O exchange: these calculated values (kqtz ??? 10-14, kfeld ??? 10-13-10-12) agree with experimental determinations of such constants. In nature, once the driving force or energy source for the external infiltrating fluid phase is removed, the disequilibrium mineral-pair arrays will either: (1) remain "frozen" in their existing state, if the temperatures are low enough, or (2) re-equilibrate along specific closed-system exchange vectors determined solely by the temperature path and the mineral modal proportions. Thus, modal mineralogical information is a particularly important parameter in both the open- and closed-system scenarios, and should in general always be reported in stable-isotopic studies of mineral assemblages. These concepts are applied to an analysis of 18O 16O systematics of gabbros (Plagioclase-clinopyroxene and plagioclase-amphibole pairs), granitic plutons (quartz-feldspar pairs), and Precambrian siliceous iron formations (quartz-magnetite pairs). In all these examples, striking regularities are observed on ??-?? and ??-?? plots, but we point out that ??-?? plots have many advantages over their equivalent ??-?? diagrams, as the latter are more susceptible to misinterpretation. Using the equations developed in this study, these regularities can be interpreted to give semiquantitative information on the exchange histories of these rocks subsequent to their formation. In particular, we present a new interpretation indicating that Precambrian cherty iron formations have in general undergone a complex fluid exchange history in which the iron oxide (magnetite precursor?) has exchanged much faster with low-temperature (< 400??C) fluids than has the relatively inert quartz. ?? 1989.

  14. [Iron deficiency in elderly patients: use of biomarkers].

    Science.gov (United States)

    Le Petitcorps, Hélène; Monti, Alexandra; Pautas, Éric

    2015-01-01

    Iron deficiency, due to blood loss or malabsorption, is commonly observed in geriatric practice. In elderly people, association of inflammatory diseases to iron loss makes diagnosis of absolute iron deficiency sometimes difficult. In case of inflammation, the interpretation of usual biomarkers of iron deficiency (serum ferritin, transferrin saturation, serum iron) may be difficult. The recent discovery of the role of hepcidine in the iron homeostasis, in physiological and pathological situation, contributes to better understanding of the iron regulation. The aim of this short paper is to underline some specificities of elderly iron physiology, to explain hepcidine's role in physiological and pathological situations and to propose a diagnostic approach for a better interpretation of usual biomarkers, in order to differentiate absolute iron deficiency and functional iron deficiency.

  15. Haemolysis and perturbations in the systemic iron metabolism of suckling, copper-deficient mosaic mutant mice - an animal model of Menkes disease.

    Directory of Open Access Journals (Sweden)

    Małgorzata Lenartowicz

    Full Text Available The biological interaction between copper and iron is best exemplified by the decreased activity of multicopper ferroxidases under conditions of copper deficiency that limits the availability of iron for erythropoiesis. However, little is known about how copper deficiency affects iron homeostasis through alteration of the activity of other copper-containing proteins, not directly connected with iron metabolism, such as superoxide dismutase 1 (SOD1. This antioxidant enzyme scavenges the superoxide anion, a reactive oxygen species contributing to the toxicity of iron via the Fenton reaction. Here, we analyzed changes in the systemic iron metabolism using an animal model of Menkes disease: copper-deficient mosaic mutant mice with dysfunction of the ATP7A copper transporter. We found that the erythrocytes of these mutants are copper-deficient, display decreased SOD1 activity/expression and have cell membrane abnormalities. In consequence, the mosaic mice show evidence of haemolysis accompanied by haptoglobin-dependent elimination of haemoglobin (Hb from the circulation, as well as the induction of haem oxygenase 1 (HO1 in the liver and kidney. Moreover, the hepcidin-ferroportin regulatory axis is strongly affected in mosaic mice. These findings indicate that haemolysis is an additional pathogenic factor in a mouse model of Menkes diseases and provides evidence of a new indirect connection between copper deficiency and iron metabolism.

  16. Global Transcriptional Response to Hfe Deficiency and Dietary Iron Overload in Mouse Liver and Duodenum

    OpenAIRE

    Alejandra Rodriguez; Tiina Luukkaala; Fleming, Robert E.; Britton, Robert S.; Bacon, Bruce R.; Seppo Parkkila

    2009-01-01

    Iron is an essential trace element whose absorption is usually tightly regulated in the duodenum. HFE-related hereditary hemochromatosis (HH) is characterized by abnormally low expression of the iron-regulatory hormone, hepcidin, which results in increased iron absorption. The liver is crucial for iron homeostasis as it is the main production site of hepcidin. The aim of this study was to explore and compare the genome-wide transcriptome response to Hfe deficiency and dietary iron overload in...

  17. Alpha Klotho and phosphate homeostasis

    OpenAIRE

    Bian, Ao; Xing, Changying; Hu, Ming Chang

    2014-01-01

    The Klotho family consists of three single-pass transmembrane proteins—αKlotho, βKlotho and γKlotho. Each of them combines with fibroblast growth factor (FGF) receptors (FGFRs) to form receptor complexes for various FGF’s. αKlotho is a co-receptor for physiological FGF23 signaling and appears essential for FGF23-mediated regulation of mineral metabolism. αKlotho protein also plays a FGF23-independent role in phosphate homeostasis. Animal experimental studies and clinical observations have dem...

  18. A physiologist's view of homeostasis.

    Science.gov (United States)

    Modell, Harold; Cliff, William; Michael, Joel; McFarland, Jenny; Wenderoth, Mary Pat; Wright, Ann

    2015-12-01

    Homeostasis is a core concept necessary for understanding the many regulatory mechanisms in physiology. Claude Bernard originally proposed the concept of the constancy of the "milieu interieur," but his discussion was rather abstract. Walter Cannon introduced the term "homeostasis" and expanded Bernard's notion of "constancy" of the internal environment in an explicit and concrete way. In the 1960s, homeostatic regulatory mechanisms in physiology began to be described as discrete processes following the application of engineering control system analysis to physiological systems. Unfortunately, many undergraduate texts continue to highlight abstract aspects of the concept rather than emphasizing a general model that can be specifically and comprehensively applied to all homeostatic mechanisms. As a result, students and instructors alike often fail to develop a clear, concise model with which to think about such systems. In this article, we present a standard model for homeostatic mechanisms to be used at the undergraduate level. We discuss common sources of confusion ("sticky points") that arise from inconsistencies in vocabulary and illustrations found in popular undergraduate texts. Finally, we propose a simplified model and vocabulary set for helping undergraduate students build effective mental models of homeostatic regulation in physiological systems.

  19. Iron deficiency.

    Science.gov (United States)

    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.

  20. Increased duodenal DMT-1 expression and unchanged HFE mRNA levels in HFE-associated hereditary hemochromatosis and iron deficiency.

    Science.gov (United States)

    Byrnes, V; Barrett, S; Ryan, E; Kelleher, T; O'Keane, C; Coughlan, B; Crowe, J

    2002-01-01

    HFE-associated hereditary hemochromatosis is characterized by imbalances of iron homeostasis and alterations in intestinal iron absorption. The identification of the HFE gene and the apical iron transporter divalent metal transporter-1, DMT-1, provide a direct method to address the mechanisms of iron overload in this disease. The aim of this study was to evaluate the regulation of duodenal HFE and DMT-1 gene expression in HFE-associated hereditary hemochromatosis. Small bowel biopsies and serum iron indices were obtained from a total of 33 patients. The study population comprised 13 patients with hereditary hemochromatosis (C282Y homozygous), 10 patients with iron deficiency anemia, and 10 apparently healthy controls, all of whom were genotyped for the two common mutations in the HFE gene (C282Y and H63D). Total RNA was isolated from tissue and amplified via RT-PCR for HFE, DMT-1, and the internal control GAPDH. DMT-1 protein expression was additionally assessed by immunohistochemistry. Levels of HFE mRNA did not differ significantly between patient groups (P = 0.09), specifically between C282Y homozygotes and iron deficiency anemic patients, when compared to controls (P = 0.09, P = 0.9, respectively). In contrast, DMT-1 mRNA levels were at least twofold greater in patients with hereditary hemochromatosis and iron deficiency anemia when compared to controls (P = 0.02, P = 0.01, respectively). Heightened DMT-1 protein expression correlated with mRNA levels in all patients. Loss of HFE function in hereditary hemochromatosis is not derived from inhibition of its gene expression. DMT-1 expression in C282Y homozygote subjects is consistent with the hypothesis of a "paradoxical" duodenal iron deficiency in hereditary hemochromatosis. The observed twofold upregulation of the DMT-1 is consistent with the slow but steady increase in body iron stores observed in those presenting with clinical features of hereditary hemochromatosis.

  1. ER Stress Controls Iron Metabolism Through Induction of Hepcidin

    OpenAIRE

    Vecchi, Chiara; Montosi, Giuliana; Zhang, Kezhong; Lamberti, Igor; Duncan, Stephen A.; Kaufman, Randal J.; Pietrangelo, Antonello

    2009-01-01

    Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin overproduction causes anemia of inflammation, whereas its deficiency leads to hemochromatosis. Inflammation and iron are known extracellular stimuli for hepcidin expression. We found that endoplasmic reticulum (ER) stress also induces hepcidin expression and causes hypoferremia and spleen iron sequestration in mice. CREBH (cyclic AMP response element–binding protein H), an ER stress–activa...

  2. Epigenetic Regulation of Cholesterol Homeostasis

    Directory of Open Access Journals (Sweden)

    Steve eMeaney

    2014-09-01

    Full Text Available Although best known as a risk factor for cardiovascular disease, cholesterol is a vital component of all mammalian cells. In addition to key structural roles, cholesterol is a vital biochemical precursor for numerous biologically important compounds including oxysterols and bile acids, as well as acting as an activator of critical morphogenic systems (e.g. the Hedgehog system. A variety of sophisticated regulatory mechanisms interact to coordinate the overall level of cholesterol in cells, tissues and the entire organism. Accumulating evidence indicates that in additional to the more ‘traditional’ regulatory schemes, cholesterol homeostasis is also under the control of epigenetic mechanisms such as histone acetylation and DNA methylation. The available evidence supporting a role for these mechanisms in the control of cholesterol synthesis, elimination, transport and storage are the focus of this review.

  3. Copper Homeostasis in Mycobacterium tuberculosis

    Science.gov (United States)

    Shi, Xiaoshan; Darwin, K. Heran

    2015-01-01

    Copper (Cu) is a trace element essential for the growth and development of almost all organisms, including bacteria. However, Cu overload in most systems is toxic. Studies show Cu accumulates in macrophage phagosomes infected with bacteria, suggesting Cu provides an innate immune mechanism to combat invading pathogens. To counteract the host-supplied Cu, increasing evidence suggests that bacteria have evolved Cu resistance mechanisms to facilitate their pathogenesis. In particular, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, has evolved multiple pathways to respond to Cu. Here, we summarize what is currently known about Cu homeostasis in Mtb and discuss potential sources of Cu encountered by this and other pathogens in a mammalian host. PMID:25614981

  4. Parkinson's Disease: The Mitochondria-Iron Link.

    Science.gov (United States)

    Muñoz, Yorka; Carrasco, Carlos M; Campos, Joaquín D; Aguirre, Pabla; Núñez, Marco T

    2016-01-01

    Mitochondrial dysfunction, iron accumulation, and oxidative damage are conditions often found in damaged brain areas of Parkinson's disease. We propose that a causal link exists between these three events. Mitochondrial dysfunction results not only in increased reactive oxygen species production but also in decreased iron-sulfur cluster synthesis and unorthodox activation of Iron Regulatory Protein 1 (IRP1), a key regulator of cell iron homeostasis. In turn, IRP1 activation results in iron accumulation and hydroxyl radical-mediated damage. These three occurrences-mitochondrial dysfunction, iron accumulation, and oxidative damage-generate a positive feedback loop of increased iron accumulation and oxidative stress. Here, we review the evidence that points to a link between mitochondrial dysfunction and iron accumulation as early events in the development of sporadic and genetic cases of Parkinson's disease. Finally, an attempt is done to contextualize the possible relationship between mitochondria dysfunction and iron dyshomeostasis. Based on published evidence, we propose that iron chelation-by decreasing iron-associated oxidative damage and by inducing cell survival and cell-rescue pathways-is a viable therapy for retarding this cycle.

  5. Parkinson's Disease: The Mitochondria-Iron Link.

    Science.gov (United States)

    Muñoz, Yorka; Carrasco, Carlos M; Campos, Joaquín D; Aguirre, Pabla; Núñez, Marco T

    2016-01-01

    Mitochondrial dysfunction, iron accumulation, and oxidative damage are conditions often found in damaged brain areas of Parkinson's disease. We propose that a causal link exists between these three events. Mitochondrial dysfunction results not only in increased reactive oxygen species production but also in decreased iron-sulfur cluster synthesis and unorthodox activation of Iron Regulatory Protein 1 (IRP1), a key regulator of cell iron homeostasis. In turn, IRP1 activation results in iron accumulation and hydroxyl radical-mediated damage. These three occurrences-mitochondrial dysfunction, iron accumulation, and oxidative damage-generate a positive feedback loop of increased iron accumulation and oxidative stress. Here, we review the evidence that points to a link between mitochondrial dysfunction and iron accumulation as early events in the development of sporadic and genetic cases of Parkinson's disease. Finally, an attempt is done to contextualize the possible relationship between mitochondria dysfunction and iron dyshomeostasis. Based on published evidence, we propose that iron chelation-by decreasing iron-associated oxidative damage and by inducing cell survival and cell-rescue pathways-is a viable therapy for retarding this cycle. PMID:27293957

  6. Molecular Determinants of Magnesium Homeostasis: Insights from Human Disease

    Science.gov (United States)

    Alexander, R. Todd; Hoenderop, Joost G.; Bindels, René J.

    2016-01-01

    The past decade has witnessed multiple advances in our understanding of magnesium (Mg2+) homeostasis. The discovery that mutations in claudin-16/paracellin-1 or claudin-19 are responsible for familial hypomagnesemia with hypercalciuria and nephrocalcinosis provided insight into the molecular mechanisms governing paracellular transport of Mg2+. Our understanding of the transcellular movement of Mg2+ was similarly enhanced by the realization that defects in transient receptor potential melastatin 6 (TRPM6) cause hypomagnesemia with secondary hypocalcemia. This channel regulates the apical entry of Mg2+ into epithelia. In so doing, TRPM6 alters whole-body Mg2+ homeostasis by controlling urinary excretion. Consequently, investigation into the regulation of TRPM6 has increased. Acid-base status, 17β estradiol, and the immunosuppressive agents FK506 and cyclosporine affect plasma Mg2+ levels by altering TRPM6 expression. A mutation in epithelial growth factor is responsible for isolated autosomal recessive hypomagnesemia, and epithelial growth factor activates TRPM6. A defect in the γ-subunit of the Na,K-ATPase causes isolated dominant hypomagnesemia by altering TRPM6 activity through a decrease in the driving force for apical Mg2+ influx. We anticipate that the next decade will provide further detail into the control of the gatekeeper TRPM6 and, therefore, overall whole-body Mg2+ balance. PMID:18562569

  7. MicroRNAs and liver cancer associated with iron overload: therapeutic targets unravelled.

    Science.gov (United States)

    Greene, Catherine M; Varley, Robert B; Lawless, Matthew W

    2013-08-28

    Primary liver cancer is a global disease that is on the increase. Hepatocellular carcinoma (HCC) accounts for most primary liver cancers and has a notably low survival rate, largely attributable to late diagnosis, resistance to treatment, tumour recurrence and metastasis. MicroRNAs (miRNAs/miRs) are regulatory RNAs that modulate protein synthesis. miRNAs are involved in several biological and pathological processes including the development and progression of HCC. Given the poor outcomes with current HCC treatments, miRNAs represent an important new target for therapeutic intervention. Several studies have demonstrated their role in HCC development and progression. While many risk factors underlie the development of HCC, one process commonly altered is iron homeostasis. Iron overload occurs in several liver diseases associated with the development of HCC including Hepatitis C infection and the importance of miRNAs in iron homeostasis and hepatic iron overload is well characterised. Aberrant miRNA expression in hepatic fibrosis and injury response have been reported, as have dysregulated miRNA expression patterns affecting cell cycle progression, evasion of apoptosis, invasion and metastasis. In 2009, miR-26a delivery was shown to prevent HCC progression, highlighting its therapeutic potential. Several studies have since investigated the clinical potential of other miRNAs with one drug, Miravirsen, currently in phase II clinical trials. miRNAs also have potential as biomarkers for the diagnosis of HCC and to evaluate treatment efficacy. Ongoing studies and clinical trials suggest miRNA-based treatments and diagnostic methods will have novel clinical applications for HCC in the coming years, yielding improved HCC survival rates and patient outcomes.

  8. Obesity as an Emerging Risk Factor for Iron Deficiency

    Directory of Open Access Journals (Sweden)

    Elmar Aigner

    2014-09-01

    Full Text Available Iron homeostasis is affected by obesity and obesity-related insulin resistance in a many-facetted fashion. On one hand, iron deficiency and anemia are frequent findings in subjects with progressed stages of obesity. This phenomenon has been well studied in obese adolescents, women and subjects undergoing bariatric surgery. On the other hand, hyperferritinemia with normal or mildly elevated transferrin saturation is observed in approximately one-third of patients with metabolic syndrome (MetS or nonalcoholic fatty liver disease (NAFLD. This constellation has been named the “dysmetabolic iron overload syndrome (DIOS”. Both elevated body iron stores and iron deficiency are detrimental to health and to the course of obesity-related conditions. Iron deficiency and anemia may impair mitochondrial and cellular energy homeostasis and further increase inactivity and fatigue of obese subjects. Obesity-associated inflammation is tightly linked to iron deficiency and involves impaired duodenal iron absorption associated with low expression of duodenal ferroportin (FPN along with elevated hepcidin concentrations. This review summarizes the current understanding of the dysregulation of iron homeostasis in obesity.

  9. Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans.

    Directory of Open Access Journals (Sweden)

    Thomas C Darton

    2015-09-01

    Full Text Available Iron is a key pathogenic determinant of many infectious diseases. Hepcidin, the hormone responsible for governing systemic iron homeostasis, is widely hypothesized to represent a key component of nutritional immunity through regulating the accessibility of iron to invading microorganisms during infection. However, the deployment of hepcidin in human bacterial infections remains poorly characterized. Typhoid fever is a globally significant, human-restricted bacterial infection, but understanding of its pathogenesis, especially during the critical early phases, likewise is poorly understood. Here, we investigate alterations in hepcidin and iron/inflammatory indices following experimental human typhoid challenge.Fifty study participants were challenged with Salmonella enterica serovar Typhi and monitored for evidence of typhoid fever. Serum hepcidin, ferritin, serum iron parameters, C-reactive protein (CRP, and plasma IL-6 and TNF-alpha concentrations were measured during the 14 days following challenge. We found that hepcidin concentrations were markedly higher during acute typhoid infection than at baseline. Hepcidin elevations mirrored the kinetics of fever, and were accompanied by profound hypoferremia, increased CRP and ferritin, despite only modest elevations in IL-6 and TNF-alpha in some individuals. During inflammation, the extent of hepcidin upregulation associated with the degree of hypoferremia.We demonstrate that strong hepcidin upregulation and hypoferremia, coincident with fever and systemic inflammation, are hallmarks of the early innate response to acute typhoid infection. We hypothesize that hepcidin-mediated iron redistribution into macrophages may contribute to S. Typhi pathogenesis by increasing iron availability for macrophage-tropic bacteria, and that targeting macrophage iron retention may represent a strategy for limiting infections with macrophage-tropic pathogens such as S. Typhi.

  10. Native iron

    DEFF Research Database (Denmark)

    Brooks, Charles Kent

    2015-01-01

    , a situation unique in the Solar System. In such a world, iron metal is unstable and, as we all know, oxidizes to the ferric iron compounds we call 'rust'. If we require iron metal it must be produced at high temperatures by reacting iron ore, usually a mixture of ferrous (Fe2+) and ferric (Fe3+) oxides (Fe2O3......, hematite, or FeO.Fe2O3, magnetite), with carbon in the form of coke. This is carried out in a blast furnace. Although the Earth's core consists of metallic iron, which may also be present in parts of the mantle, this is inaccessible to us, so we must make our own. In West Greenland, however, some almost...... unique examples of iron metal, otherwise called 'native iron' or 'telluric iron', occur naturally....

  11. Cholesterol homeostasis: How do cells sense sterol excess?

    Science.gov (United States)

    Howe, Vicky; Sharpe, Laura J; Alexopoulos, Stephanie J; Kunze, Sarah V; Chua, Ngee Kiat; Li, Dianfan; Brown, Andrew J

    2016-09-01

    Cholesterol is vital in mammals, but toxic in excess. Consequently, elaborate molecular mechanisms have evolved to maintain this sterol within narrow limits. How cells sense excess cholesterol is an intriguing area of research. Cells sense cholesterol, and other related sterols such as oxysterols or cholesterol synthesis intermediates, and respond to changing levels through several elegant mechanisms of feedback regulation. Cholesterol sensing involves both direct binding of sterols to the homeostatic machinery located in the endoplasmic reticulum (ER), and indirect effects elicited by sterol-dependent alteration of the physical properties of membranes. Here, we examine the mechanisms employed by cells to maintain cholesterol homeostasis. PMID:26993747

  12. Iron and genome stability: An update

    International Nuclear Information System (INIS)

    Iron is an essential micronutrient which is required in a relatively narrow range for maintaining metabolic homeostasis and genome stability. Iron participates in oxygen transport and mitochondrial respiration as well as in antioxidant and nucleic acid metabolism. Iron deficiency impairs these biological pathways, leading to oxidative stress and possibly carcinogenesis. Iron overload has been linked to genome instability as well as to cancer risk increase, as seen in hereditary hemochromatosis. Iron is an extremely reactive transition metal that can interact with hydrogen peroxide to generate hydroxyl radicals that form the 8-hydroxy-guanine adduct, cause point mutations as well as DNA single and double strand breaks. Iron overload also induces DNA hypermethylation and can reduce telomere length. The current Recommended Dietary Allowances (RDA) for iron, according with Institute of Medicine Dietary Reference Intake (DRI), is based in the concept of preventing anemia, and ranges from 7 mg/day to 18 mg/day depending on life stage and gender. Pregnant women need 27 mg/day. The maximum safety level for iron intake, the Upper Level (UL), is 40–45 mg/day, based on the prevention of gastrointestinal distress associated to high iron intakes. Preliminary evidence indicates that 20 mg/day iron, an intake slightly higher than the RDA, may reduce the risk of gastrointestinal cancer in the elderly as well as increasing genome stability in lymphocytes of children and adolescents. Current dietary recommendations do not consider the concept of genome stability which is of concern because damage to the genome has been linked to the origin and progression of many diseases and is the most fundamental pathology. Given the importance of iron for homeostasis and its potential influence over genome stability and cancer it is recommended to conduct further studies that conclusively define these relationships.

  13. Iron and genome stability: An update

    Energy Technology Data Exchange (ETDEWEB)

    Pra, Daniel, E-mail: daniel_pra@yahoo.com [PPG em Promocao da Saude, Universidade de Santa Cruz do Sul (UNISC), Santa Cruz do Sul, RS (Brazil); PPG em Saude e Comportamento, Universidade Catolica de Pelotas, Pelotas, RS (Brazil); Franke, Silvia Isabel Rech [PPG em Promocao da Saude, Universidade de Santa Cruz do Sul (UNISC), Santa Cruz do Sul, RS (Brazil); Henriques, Joao Antonio Pegas [Instituto de Biotecnologia, Universidade de Caxias do Sul, Caxias do Sul, RS (Brazil); Fenech, Michael [CSIRO Food and Nutritional Sciences, Adelaide, SA (Australia)

    2012-05-01

    Iron is an essential micronutrient which is required in a relatively narrow range for maintaining metabolic homeostasis and genome stability. Iron participates in oxygen transport and mitochondrial respiration as well as in antioxidant and nucleic acid metabolism. Iron deficiency impairs these biological pathways, leading to oxidative stress and possibly carcinogenesis. Iron overload has been linked to genome instability as well as to cancer risk increase, as seen in hereditary hemochromatosis. Iron is an extremely reactive transition metal that can interact with hydrogen peroxide to generate hydroxyl radicals that form the 8-hydroxy-guanine adduct, cause point mutations as well as DNA single and double strand breaks. Iron overload also induces DNA hypermethylation and can reduce telomere length. The current Recommended Dietary Allowances (RDA) for iron, according with Institute of Medicine Dietary Reference Intake (DRI), is based in the concept of preventing anemia, and ranges from 7 mg/day to 18 mg/day depending on life stage and gender. Pregnant women need 27 mg/day. The maximum safety level for iron intake, the Upper Level (UL), is 40-45 mg/day, based on the prevention of gastrointestinal distress associated to high iron intakes. Preliminary evidence indicates that 20 mg/day iron, an intake slightly higher than the RDA, may reduce the risk of gastrointestinal cancer in the elderly as well as increasing genome stability in lymphocytes of children and adolescents. Current dietary recommendations do not consider the concept of genome stability which is of concern because damage to the genome has been linked to the origin and progression of many diseases and is the most fundamental pathology. Given the importance of iron for homeostasis and its potential influence over genome stability and cancer it is recommended to conduct further studies that conclusively define these relationships.

  14. Homeostasis and its disruption in the lung microbiome.

    Science.gov (United States)

    Dickson, Robert P; Erb-Downward, John R; Huffnagle, Gary B

    2015-11-15

    The disciplines of physiology and ecology are united by the shared centrality of the concept of homeostasis: the stability of a complex system via internal mechanisms of self-regulation, resilient to external perturbation. In the past decade, these fields of study have been bridged by the discovery of the lung microbiome. The respiratory tract, long considered sterile, is in fact a dynamic ecosystem of microbiota, intimately associated with the host inflammatory response, altered in disease states. If the microbiome is a "newly discovered organ," ecology is the language we use to explain how it establishes, maintains, and loses homeostasis. In this essay, we review recent insights into the feedback mechanisms by which the lung microbiome and the host response are regulated in health and dysregulated in acute and chronic lung disease. We propose three explanatory models supported by recent studies: the adapted island model of lung biogeography, nutritional homeostasis at the host-microbiome interface, and interkingdom signaling and the community stress response.

  15. Taste bud homeostasis in health, disease, and aging.

    Science.gov (United States)

    Feng, Pu; Huang, Liquan; Wang, Hong

    2014-01-01

    The mammalian taste bud is an onion-shaped epithelial structure with 50-100 tightly packed cells, including taste receptor cells, supporting cells, and basal cells. Taste receptor cells detect nutrients and toxins in the oral cavity and transmit the sensory information to gustatory nerve endings in the buds. Supporting cells may play a role in the clearance of excess neurotransmitters after their release from taste receptor cells. Basal cells are precursor cells that differentiate into mature taste cells. Similar to other epithelial cells, taste cells turn over continuously, with an average life span of about 8-12 days. To maintain structural homeostasis in taste buds, new cells are generated to replace dying cells. Several recent studies using genetic lineage tracing methods have identified populations of progenitor/stem cells for taste buds, although contributions of these progenitor/stem cell populations to taste bud homeostasis have yet to be fully determined. Some regulatory factors of taste cell differentiation and degeneration have been identified, but our understanding of these aspects of taste bud homoeostasis remains limited. Many patients with various diseases develop taste disorders, including taste loss and taste distortion. Decline in taste function also occurs during aging. Recent studies suggest that disruption or alteration of taste bud homeostasis may contribute to taste dysfunction associated with disease and aging. PMID:24287552

  16. Metal Homeostasis Regulators Suppress FRDA Phenotypes in a Drosophila Model of the Disease

    Science.gov (United States)

    Soriano, Sirena; Calap-Quintana, Pablo; Llorens, José Vicente; Al-Ramahi, Ismael; Gutiérrez, Lucía; Martínez-Sebastián, María José; Botas, Juan; Moltó, María Dolores

    2016-01-01

    Friedreich’s ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets. PMID:27433942

  17. Metal Homeostasis Regulators Suppress FRDA Phenotypes in a Drosophila Model of the Disease.

    Directory of Open Access Journals (Sweden)

    Sirena Soriano

    Full Text Available Friedreich's ataxia (FRDA, the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets.

  18. Duodenal Cytochrome b (DCYTB in Iron Metabolism: An Update on Function and Regulation

    Directory of Open Access Journals (Sweden)

    Darius J. R. Lane

    2015-03-01

    Full Text Available Iron and ascorbate are vital cellular constituents in mammalian systems. The bulk-requirement for iron is during erythropoiesis leading to the generation of hemoglobin-containing erythrocytes. Additionally; both iron and ascorbate are required as co-factors in numerous metabolic reactions. Iron homeostasis is controlled at the level of uptake; rather than excretion. Accumulating evidence strongly suggests that in addition to the known ability of dietary ascorbate to enhance non-heme iron absorption in the gut; ascorbate regulates iron homeostasis. The involvement of ascorbate in dietary iron absorption extends beyond the direct chemical reduction of non-heme iron by dietary ascorbate. Among other activities; intra-enterocyte ascorbate appears to be involved in the provision of electrons to a family of trans-membrane redox enzymes; namely those of the cytochrome b561 class. These hemoproteins oxidize a pool of ascorbate on one side of the membrane in order to reduce an electron acceptor (e.g., non-heme iron on the opposite side of the membrane. One member of this family; duodenal cytochrome b (DCYTB; may play an important role in ascorbate-dependent reduction of non-heme iron in the gut prior to uptake by ferrous-iron transporters. This review discusses the emerging relationship between cellular iron homeostasis; the emergent “IRP1-HIF2α axis”; DCYTB and ascorbate in relation to iron metabolism.

  19. Activation of the NLRP3 inflammasome by cellular labile iron.

    Science.gov (United States)

    Nakamura, Kyohei; Kawakami, Toru; Yamamoto, Naoki; Tomizawa, Miyu; Fujiwara, Tohru; Ishii, Tomonori; Harigae, Hideo; Ogasawara, Kouetsu

    2016-02-01

    Cellular labile iron, which contains chelatable redox-active Fe(2+), has been implicated in iron-mediated cellular toxicity leading to multiple organ dysfunction. Iron homeostasis is controlled by monocytes/macrophages through their iron recycling and storage capacities. Furthermore, iron sequestration by monocytes/macrophages is regulated by pro-inflammatory cytokines including interleukin-1, highlighting the importance of these cells in the crosstalk between inflammation and iron homeostasis. However, a role for cellular labile iron in monocyte/macrophage-mediated inflammatory responses has not been defined. Here we describe how cellular labile iron activates the NLRP3 inflammasome in human monocytes. Stimulation of lipopolysaccharide-primed peripheral blood mononuclear cells with ferric ammonium citrate increases the level of cellular Fe(2+) levels in monocytes and induces production of interleukin-1β in a dose-dependent manner. This ferric ammonium citrate-induced interleukin-1β production is dependent on caspase-1 and is significantly inhibited by an Fe(2+)-specific chelator. Ferric ammonium citrate consistently induced interleukin-1β secretion in THP1 cells, but not in NLRP3-deficient THP1 cells, indicating a requirement for the NLRP3 inflammasome. Additionally, activation of the inflammasome is mediated by potassium efflux, reactive oxygen species-mediated mitochondrial dysfunction, and lysosomal membrane permeabilization. Thus, these results suggest that monocytes/macrophages not only sequestrate iron during inflammation, but also mediate inflammation in response to cellular labile iron, which provides novel insights into the role of iron in chronic inflammation. PMID:26577567

  20. [Iron and sulfur in proteins. How does the cell build Fe-S clusters, cofactors essential for life?].

    Science.gov (United States)

    Py, Béatrice; Barras, Frédéric

    2014-12-01

    Iron-sulfur clusters (Fe-S) are ubiquitous cofactors present in numerous proteins of most living organisms. By way of an example, the E. coli bacterium synthesizes more that 130 different types of Fe-S proteins. Fe-S proteins are involved in a great diversity of biological processes, ranging from respiration, photosynthesis, central metabolism, to genetic expression and genomic stability. Proteins can acquire spontaneously Fe-S clusters in vitro, but in vivo, dedicated molecular machineries are necessary. Dysfunction of these machineries alters cellular capacities leading to lethality in bacteria and severe pathologies in humans. In this review we will describe how cells make Fe-S clusters and deliver them to clients proteins. The importance of Fe-S clusters homeostasis will be illustrated by reporting a list of cellular dysfunctions associated with mutations altering either Fe-S proteins or Fe-S biogenesis machineries.

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

    Directory of Open Access Journals (Sweden)

    Guofen Gao

    2015-01-01

    Full Text Available 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.

  2. Role of alcohol in the regulation of iron metabolism

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate alcohol consumption has been shown to increase the prevalence of iron overload. Moreover, increased hepatic iron content is associated with greater mortality from alcoholic cirrhosis, suggesting a pathogenic role for iron in alcoholic liver disease. Alcohol increases the severity of disease in patients with genetic hemochromatosis,an iron overload disorder common in the Caucasian population. Both iron and alcohol individually cause oxidative stress and lipid peroxidation, which culminates in liver injury. Despite these observations, the underlying mechanisms of iron accumulation and the source of the excess iron observed in alcoholic liver disease remain unclear. Over the last decade, several novel iron-regulatory proteins have been identified and these have greatly enhanced our understanding of iron metabolism. For example, hepcidin, a circulatory antimicrobial peptide synthesized by the hepatocytes of the liver is now known to play a central role in the regulation of iron homeostasis. This review attempts to describe the interaction of alcohol and iron-regulatory molecules. Understanding these molecular mechanisms is of considerable clinical importance because both alcoholic liver disease and genetic hemochromatosis are common diseases, in which alcohol and iron appear to act synergistically to cause liver injury.

  3. Pancreatic regulation of glucose homeostasis.

    Science.gov (United States)

    Röder, Pia V; Wu, Bingbing; Liu, Yixian; Han, Weiping

    2016-01-01

    In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed. PMID:26964835

  4. Redox Homeostasis in Pancreatic Cells

    Directory of Open Access Journals (Sweden)

    Petr Ježek

    2012-01-01

    Full Text Available We reviewed mechanisms that determine reactive oxygen species (redox homeostasis, redox information signaling and metabolic/regulatory function of autocrine insulin signaling in pancreatic β cells, and consequences of oxidative stress and dysregulation of redox/information signaling for their dysfunction. We emphasize the role of mitochondrion in β cell molecular physiology and pathology, including the antioxidant role of mitochondrial uncoupling protein UCP2. Since in pancreatic β cells pyruvate cannot be easily diverted towards lactate dehydrogenase for lactate formation, the respiration and oxidative phosphorylation intensity are governed by the availability of glucose, leading to a certain ATP/ADP ratio, whereas in other cell types, cell demand dictates respiration/metabolism rates. Moreover, we examine the possibility that type 2 diabetes mellitus might be considered as an inevitable result of progressive self-accelerating oxidative stress and concomitantly dysregulated information signaling in peripheral tissues as well as in pancreatic β cells. It is because the redox signaling is inherent to the insulin receptor signaling mechanism and its impairment leads to the oxidative and nitrosative stress. Also emerging concepts, admiting participation of redox signaling even in glucose sensing and insulin release in pancreatic β cells, fit in this view. For example, NADPH has been firmly established to be a modulator of glucose-stimulated insulin release.

  5. A structural and functional homolog supports a general role for frataxin in cellular iron chemistry.

    Science.gov (United States)

    Qi, Wenbin; Cowan, J A

    2010-02-01

    Bacillus subtilis YdhG lacks sequence homology, but demonstrates structural and functional similarity to the frataxin family, supporting a general cellular role for frataxin-type proteins in cellular iron homeostasis.

  6. Pathophysiology in Medicine: Hepcidin and iron regulation in health and disease

    OpenAIRE

    Means, Robert T.

    2013-01-01

    A decade ago hepcidin, an antimicrobial peptide with iron-regulatory properties, was discovered and proposed as playing a significant role in the pathogenesis of the anemia of chronic disease. Subsequent studies have demonstrated that hepcidin is the keystone of the linked systems of iron balance and iron transport in health and in disease. The definition of the role of hepcidin and of its regulation has permitted the mechanisms of disorders of iron homeostasis to be understood at a molecular...

  7. Sustained sleep fragmentation induces sleep homeostasis in mice

    KAUST Repository

    Baud, Maxime O.

    2015-04-01

    Study Objectives: Sleep fragmentation (SF) is an integral feature of sleep apnea and other prevalent sleep disorders. Although the effect of repetitive arousals on cognitive performance is well documented, the effects of long-term SF on electroencephalography (EEG) and molecular markers of sleep homeostasis remain poorly investigated. To address this question, we developed a mouse model of chronic SF and characterized its effect on EEG spectral frequencies and the expression of genes previously linked to sleep homeostasis including clock genes, heat shock proteins, and plasticity-related genes. Design: N/A. Setting: Animal sleep research laboratory. Participants : Sixty-six C57BL6/J adult mice. Interventions: Instrumental sleep disruption at a rate of 60/h during 14 days Measurements and Results: Locomotor activity and EEG were recorded during 14 days of SF followed by recovery for 2 days. Despite a dramatic number of arousals and decreased sleep bout duration, SF minimally reduced total quantity of sleep and did not significantly alter its circadian distribution. Spectral analysis during SF revealed a homeostatic drive for slow wave activity (SWA; 1-4 Hz) and other frequencies as well (4-40 Hz). Recordings during recovery revealed slow wave sleep consolidation and a transient rebound in SWA, and paradoxical sleep duration. The expression of selected genes was not induced following chronic SF. Conclusions: Chronic sleep fragmentation (SF) increased sleep pressure confirming that altered quality with preserved quantity triggers core sleep homeostasis mechanisms. However, it did not induce the expression of genes induced by sleep loss, suggesting that these molecular pathways are not sustainably activated in chronic diseases involving SF.

  8. Bloodletting therapy in hemochromatosis: Does it affect trace element homeostasis?

    Science.gov (United States)

    Bolann, Bjørn J; Distante, Sonia; Mørkrid, Lars; Ulvik, Rune J

    2015-01-01

    Hemochromatosis is the most common hereditary disorder in the Nordic population, if left untreated it can result in severe parenchymal iron accumulation. Bloodletting is mainstay treatment. Iron and trace elements partially share cellular uptake and transport mechanisms, and the aim of the present study was to see if bloodletting for hemochromatosis affects trace elements homeostasis. We recruited patients referred for diagnosis and treatment of hemochromatosis, four women and 22 men 23-68 years of age. Thirteen were C282Y homozygote, one was C282Y heterozygote, three were H63D homozygote, seven were compound heterozygote and two had none of the mutations above. Iron and liver function tests were performed; serum levels of trace elements were measured using inductively coupled plasma mass spectrometry. Results before the start of treatment and after normalization of iron parameters were compared. On completion of the bloodlettings the following average serum concentrations increased: Co from 5.6 to 11.5 nmol/L, serum Cu 16.2-17.6 μmol/L, Ni increased from 50.0 to 52.6 nmol/L and Sb from 13.2 to 16.3 nmol/L. Average serum Mn concentration declined from 30.2 to 28.3 nmol/L. All changes were statistically significant (by paired t-test). B, Ba, Cs, Mo, Se, Sr and Zn were not significantly changed. We conclude that bloodlettings in hemochromatosis lead to changes in trace element metabolism, including increased absorption of potentially toxic elements.

  9. Aberrant water homeostasis detected by stable isotope analysis.

    Directory of Open Access Journals (Sweden)

    Shannon P O'Grady

    Full Text Available While isotopes are frequently used as tracers in investigations of disease physiology (i.e., 14C labeled glucose, few studies have examined the impact that disease, and disease-related alterations in metabolism, may have on stable isotope ratios at natural abundance levels. The isotopic composition of body water is heavily influenced by water metabolism and dietary patterns and may provide a platform for disease detection. By utilizing a model of streptozotocin (STZ-induced diabetes as an index case of aberrant water homeostasis, we demonstrate that untreated diabetes mellitus results in distinct combinations, or signatures, of the hydrogen (delta2H and oxygen (delta18O isotope ratios in body water. Additionally, we show that the delta2H and delta18O values of body water are correlated with increased water flux, suggesting altered blood osmolality, due to hyperglycemia, as the mechanism behind this correlation. Further, we present a mathematical model describing the impact of water flux on the isotopic composition of body water and compare model predicted values with actual values. These data highlight the importance of factors such as water flux and energy expenditure on predictive models of body water and additionally provide a framework for using naturally occurring stable isotope ratios to monitor diseases that impact water homeostasis.

  10. Calcium homeostasis in barley aleurone

    Energy Technology Data Exchange (ETDEWEB)

    Jones, R.L.

    1990-02-21

    Under the auspices of the Department of Energy we investigated calcium homeostasis in aleurone cells of barley. This investigation was initiated to explore the role played by extracellular Ca{sup 2+} in gibberellic acid (GA)-induced synthesis and secretion of hydrolases in the aleurone layer. We have focused our attention on four topics that relate to the role of Ca{sup 2+} in regulating the synthesis of {alpha}-amylase. First, we determined the stoichiometry of Ca{sup 2+} binding to the two principal classes of barley {alpha}-amylase and examined some of the biochemical and physical properties of the native and Ca{sup 2+}-depleted forms of the enzyme. Second, since {alpha}-amylase is a Ca{sup 2+} containing metalloenzyme that binds one atom of Ca{sup 2+} per molecule, we developed methods to determine the concentration of Ca{sup 2+} in the cytosol of the aleurone cell. We developed a technique for introducing Ca{sup 2+}-sensitive dyes into aleurone protoplasts that allows the measurement of Ca{sup 2+} in both cytosol and endoplasmic reticulum (ER). Third, because the results of our Ca{sup 2+} measurements showed higher levels of Ca{sup 2+} in the ER than in the cytosol, we examined Ca{sup 2+} transport into the ER of control and GA-treated aleurone tissue. And fourth, we applied the technique of patch-clamping to the barley aleurone protoplast to examine ion transport at the plasma membrane. Our results with the patch-clamp technique established the presence of K{sup +} channels in the plasma membrane of the aleurone protoplast, and they showed that this cell is ideally suited for the application of this methodology for studying ion transport. 34 refs.

  11. microRNA Regulation of Peritoneal Cavity Homeostasis in Peritoneal Dialysis

    Science.gov (United States)

    Lopez-Anton, Melisa; Bowen, Timothy; Jenkins, Robert H.

    2015-01-01

    Preservation of peritoneal cavity homeostasis and peritoneal membrane function is critical for long-term peritoneal dialysis (PD) treatment. Several microRNAs (miRNAs) have been implicated in the regulation of key molecular pathways driving peritoneal membrane alterations leading to PD failure. miRNAs regulate the expression of the majority of protein coding genes in the human genome, thereby affecting most biochemical pathways implicated in cellular homeostasis. In this review, we report published findings on miRNAs and PD therapy, with emphasis on evidence for changes in peritoneal miRNA expression during long-term PD treatment. Recent work indicates that PD effluent- (PDE-) derived cells change their miRNA expression throughout the course of PD therapy, contributing to the loss of peritoneal cavity homeostasis and peritoneal membrane function. Changes in miRNA expression profiles will alter regulation of key molecular pathways, with the potential to cause profound effects on peritoneal cavity homeostasis during PD treatment. However, research to date has mainly adopted a literature-based miRNA-candidate methodology drawing conclusions from modest numbers of patient-derived samples. Therefore, the study of miRNA expression during PD therapy remains a promising field of research to understand the mechanisms involved in basic peritoneal cell homeostasis and PD failure. PMID:26495316

  12. microRNA Regulation of Peritoneal Cavity Homeostasis in Peritoneal Dialysis

    Directory of Open Access Journals (Sweden)

    Melisa Lopez-Anton

    2015-01-01

    Full Text Available Preservation of peritoneal cavity homeostasis and peritoneal membrane function is critical for long-term peritoneal dialysis (PD treatment. Several microRNAs (miRNAs have been implicated in the regulation of key molecular pathways driving peritoneal membrane alterations leading to PD failure. miRNAs regulate the expression of the majority of protein coding genes in the human genome, thereby affecting most biochemical pathways implicated in cellular homeostasis. In this review, we report published findings on miRNAs and PD therapy, with emphasis on evidence for changes in peritoneal miRNA expression during long-term PD treatment. Recent work indicates that PD effluent- (PDE- derived cells change their miRNA expression throughout the course of PD therapy, contributing to the loss of peritoneal cavity homeostasis and peritoneal membrane function. Changes in miRNA expression profiles will alter regulation of key molecular pathways, with the potential to cause profound effects on peritoneal cavity homeostasis during PD treatment. However, research to date has mainly adopted a literature-based miRNA-candidate methodology drawing conclusions from modest numbers of patient-derived samples. Therefore, the study of miRNA expression during PD therapy remains a promising field of research to understand the mechanisms involved in basic peritoneal cell homeostasis and PD failure.

  13. Serum Iron Parameters, HFE C282Y Genotype, and Cognitive Performance in Older Adults: Results From the FACIT Study

    NARCIS (Netherlands)

    Schiepers, O.J.G.; Boxtel, van M.P.J.; Groot, R.H.M.; Jolles, J.; Kort, de W.L.A.M.; Swinkels, D.W.; Kok, F.J.; Verhoef, P.; Durga, J.

    2010-01-01

    Although iron homeostasis is essential for brain functioning, the effects of iron levels on cognitive performance in older individuals have scarcely been investigated. In the present study, serum iron parameters and hemochromatosis (HFE) C282Y genotype were determined in 818 older individuals who pa

  14. Decreased serum hepcidin, inflammation, and improved functional iron status six-months post-restrictive bariatric surgery.

    Science.gov (United States)

    Excess adiposity is associated with low-grade inflammation and decreased iron status. Iron depletion (ID) in obesity is thought to be mediated by an inflammation-induced increase in the body’s main regulator of iron homeostasis, hepcidin. Elevated hepcidin can result in ID as it prevents the release...

  15. Serum hepcidin is significantly associated with iron absorption from food and supplemental sources in healthy young woman

    Science.gov (United States)

    Hepcidin is a key regulator of iron homeostasis, but to date no studies have examined the effect of hepcidin on iron absorption in humans. Our objective was to assess relations between both serum hepcidin and serum prohepcidin with nonheme-iron absorption in the presence and absence of food with the...

  16. The role of malate in plant homeostasis

    OpenAIRE

    Finkemeier, Iris; Sweetlove, Lee J.

    2009-01-01

    Malate is a central metabolite of the plant cell with important roles in plant physiology and metabolism. Here, we summarize the most recent advances in our understanding of malate homeostasis in central metabolism, guard cell functioning, and root exudation.

  17. The role of sirtuins in cellular homeostasis.

    Science.gov (United States)

    Kupis, Wioleta; Pałyga, Jan; Tomal, Ewa; Niewiadomska, Ewa

    2016-09-01

    Sirtuins are evolutionarily conserved nicotinamide adenine dinucleotide (NAD(+))-dependent lysine deacylases or ADP-ribosyltransferases. These cellular enzymes are metabolic sensors sensitive to NAD(+) levels that maintain physiological homeostasis in the animal and plant cells. PMID:27154583

  18. Iron Regulatory Proteins Control a Mucosal Block to Intestinal Iron Absorption

    Directory of Open Access Journals (Sweden)

    Bruno Galy

    2013-03-01

    Full Text Available Mammalian iron metabolism is regulated systemically by the hormone hepcidin and cellularly by iron regulatory proteins (IRPs that orchestrate a posttranscriptional regulatory network. Through ligand-inducible genetic ablation of both IRPs in the gut epithelium of adult mice, we demonstrate that IRP deficiency impairs iron absorption and promotes mucosal iron retention via a ferritin-mediated “mucosal block.” We show that IRP deficiency does not interfere with intestinal sensing of body iron loading and erythropoietic iron need, but rather alters the basal expression of the iron-absorption machinery. IRPs thus secure sufficient iron transport across absorptive enterocytes by restricting the ferritin “mucosal block” and define a basal set point for iron absorption upon which IRP-independent systemic regulatory inputs are overlaid.

  19. Leptin therapy, insulin sensitivity, and glucose homeostasis

    OpenAIRE

    Gilberto Paz-Filho; Claudio Mastronardi; Ma-Li Wong; Julio Licinio

    2012-01-01

    Glucose homeostasis is closely regulated not only by insulin, but also by leptin. Both hormones act centrally, regulating food intake and adiposity in humans. Leptin has several effects on the glucose-insulin homeostasis, some of which are independent of body weight and adiposity. Those effects of leptin are determined centrally in the hypothalamus and peripherally in the pancreas, muscles and liver. Leptin has beneficial effects on the glucose-insulin metabolism, by decreasing glycemia, insu...

  20. Iron load

    Directory of Open Access Journals (Sweden)

    Filippo Cassarà

    2013-03-01

    Full Text Available Recent research addressed the main role of hepcidin in the regulation of iron metabolism. However, while this mechanism could be relevant in causing iron load in Thalassemia Intermedia and Sickle-Cell Anemia, its role in Thalassemia Major (TM is marginal. This is mainly due to the high impact of transfusional requirement into the severe increase of body iron. Moreover, the damage of iron load may be worsened by infections, as HCV hepatitis, or liver and endocrinological damage. One of the most relevant associations was found between splenectomy and increase of risk for mortality due,probably, to more severe iron load. These issues suggest as morbidity and mortality of this group of patients they do not depend only by our ability in controlling heart damage but even in preventing or treating particular infections and complications. This finding is supported by the impairment of survival curves in patients with complications different from heart damage. However, because, during recent years different direct and indirect methods to detect iron overload in patients affected by secondary hemochromatosis have been implemented, our ability to maintain under control iron load is significantly improved. Anyway, the future in iron load management remains to be able to have an iron load map of our body for targeting chelation and other medical treatment according to the single organ damage.

  1. PfeT, a P1B4 -type ATPase, effluxes ferrous iron and protects Bacillus subtilis against iron intoxication.

    Science.gov (United States)

    Guan, Guohua; Pinochet-Barros, Azul; Gaballa, Ahmed; Patel, Sarju J; Argüello, José M; Helmann, John D

    2015-11-01

    Iron is an essential element for nearly all cells and limited iron availability often restricts growth. However, excess iron can also be deleterious, particularly when cells expressing high affinity iron uptake systems transition to iron rich environments. Bacillus subtilis expresses numerous iron importers, but iron efflux has not been reported. Here, we describe the B. subtilis PfeT protein (formerly YkvW/ZosA) as a P1B4 -type ATPase in the PerR regulon that serves as an Fe(II) efflux pump and protects cells against iron intoxication. Iron and manganese homeostasis in B. subtilis are closely intertwined: a pfeT mutant is iron sensitive, and this sensitivity can be suppressed by low levels of Mn(II). Conversely, a pfeT mutant is more resistant to Mn(II) overload. In vitro, the PfeT ATPase is activated by both Fe(II) and Co(II), although only Fe(II) efflux is physiologically relevant in wild-type cells, and null mutants accumulate elevated levels of intracellular iron. Genetic studies indicate that PfeT together with the ferric uptake repressor (Fur) cooperate to prevent iron intoxication, with iron sequestration by the MrgA mini-ferritin playing a secondary role. Protection against iron toxicity may also be a key role for related P1B4 -type ATPases previously implicated in bacterial pathogenesis. PMID:26261021

  2. Iron Availability Affects Phosphate Deficiency-Mediated Responses, and Evidence of Cross-Talk with Auxin and Zinc in Arabidopsis.

    Science.gov (United States)

    Rai, Vandna; Sanagala, Raghavendrarao; Sinilal, Bhaskaran; Yadav, Sandeep; Sarkar, Ananda K; Dantu, Prem Kumar; Jain, Ajay

    2015-06-01

    Phosphate (Pi) is pivotal for plant growth and development. Pi deficiency triggers local and systemically regulated adaptive responses in Arabidopsis thaliana. Inhibition of primary root growth (PRG) and retarded development of lateral roots (LRs) are typical local Pi deficiency-mediated responses of the root system. Expression of Pi starvation-responsive (PSR) genes is regulated systemically. Here, we report the differential influence of iron (Fe) availability on local and systemic sensing of Pi by Arabidopsis. P-Fe- condition disrupted local Pi sensing, resulting in an elongated primary root (PR). Altered Fe homeostasis in the lpsi mutant with aberration in local Pi sensing provided circumstantial evidence towards the role of Fe in the maintenance of Pi homeostasis. Reporter gene assays, expression analysis of auxin-responsive genes (ARGs) and root phenotyping of the arf7arf19 mutant demonstrated the role of Fe availability on local Pi deficiency-mediated LR development. In addition, Fe availability also exerted a significant influence on PSR genes belonging to different functional categories. Together, these results demonstrated a substantial influence of Fe availability on Pi deficiency-mediated responses of ontogenetically distinct traits of the root system and PSR genes. The study also provided evidence of cross-talk between Pi, Fe and Zn, highlighting a complex tripartite interaction amongst them for maintaining Pi homeostasis.

  3. Influence of whole-body irradiation on calcium and phosphate homeostasis in the rat

    International Nuclear Information System (INIS)

    Previous irradiation studies have revealed marked alterations in calcium metabolism. Moreover, the maintenance of calcium homeostasis with parathyroid hormone or calcium salts has been reported to reduce radiation lethality. Therefore, the present study was designed to evaluate the influence of irradiation on calcium homeostasis in the rat. Nine hundred rad of whole-body irradiation produced a significant depression of both plasma calcium and phosphate at 4 days postirradiation. This effect of irradiation was observed to be dose-dependent over a range of 600 to 1200 rad, and possibly related to irradiation-induced anorexia. The physiological significance of these observations is discussed

  4. Prenatal inflammation-induced hypoferremia alters dopamine function in the adult offspring in rat: relevance for schizophrenia.

    Directory of Open Access Journals (Sweden)

    Argel Aguilar-Valles

    Full Text Available Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans.

  5. HFE gene in primary and secondary hepatic iron overload

    Institute of Scientific and Technical Information of China (English)

    Giada Sebastiani; Ann P Walker

    2007-01-01

    Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe (HFE) gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and nonalcoholic fatty liver diseases and porphyria cutanea tarda.We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.

  6. High hepcidin level accounts for the nigral iron accumulation in acute peripheral iron intoxication rats.

    Science.gov (United States)

    Sun, Chao; Song, Ning; Xie, Anmu; Xie, Junxia; Jiang, Hong

    2012-08-01

    Hepcidin is considered to be a circulatory hormone and a major mechanism regulating iron homeostasis. Our previous publication revealed that acute iron intoxication induced iron deposit and dopaminergic neuron degeneration in the substantia nigra (SN) of a rat model. However, whether and how hepcidin functions in this nigral iron accumulation has not been elucidated. In the present study, we observed a decreased of FPN1 protein level in the SN triggered by peripheral iron overload within 4 h, which correlated with a high hepcidin level. To further investigate the role of intracellular hepcidin under iron overload circumstances, we assessed the expression of hepcidin mRNA and FPN1 protein in vitro. We observed that hepcidin mRNA level was up-regulated and FPN1 protein level was down-regulated in MES23.5 dopaminergic cells in a period of 4h incubation with iron. Both in pCMV-XL4-hepcidin transfected and hepcidin-treated cells, decreased FPN1 protein levels were observed. Our data provide direct evidence that the role for intracellular hepcidin generated in the SN is particularly relevant to restrict iron release by down-regulation FPN1 expression in this region, thus an important contributor to the abnormal iron deposit occurred at an early stage in conditions of peripheral iron intoxication. PMID:22659129

  7. Hepcidin in human iron disorders: diagnostic implications

    OpenAIRE

    Kroot, J.J.C.; Tjalsma, H.; Fleming, R E; Swinkels, D. W.

    2011-01-01

    BACKGROUND: The peptide hormone hepcidin plays a central role in regulating dietary iron absorption and body iron distribution. Many human diseases are associated with alterations in hepcidin concentrations. The measurement of hepcidin in biological fluids is therefore a promising tool in the diagnosis and management of medical conditions in which iron metabolism is affected. CONTENT: We describe hepcidin structure, kinetics, function, and regulation. We moreover explore the therapeutic poten...

  8. Iron-dependent regulation of hepcidin in Hjv-/- mice: evidence that hemojuvelin is dispensable for sensing body iron levels.

    Directory of Open Access Journals (Sweden)

    Konstantinos Gkouvatsos

    Full Text Available Hemojuvelin (Hjv is a bone morphogenetic protein (BMP co-receptor involved in the control of systemic iron homeostasis. Functional inactivation of Hjv leads to severe iron overload in humans and mice due to marked suppression of the iron-regulatory hormone hepcidin. To investigate the role of Hjv in body iron sensing, Hjv-/- mice and isogenic wild type controls were placed on a moderately low, a standard or a high iron diet for four weeks. Hjv-/- mice developed systemic iron overload under all regimens. Transferrin (Tf was highly saturated regardless of the dietary iron content, while liver iron deposition was proportional to it. Hepcidin mRNA expression responded to fluctuations in dietary iron intake, despite the absence of Hjv. Nevertheless, iron-dependent upregulation of hepcidin was more than an order of magnitude lower compared to that seen in wild type controls. Likewise, iron signaling via the BMP/Smad pathway was preserved but substantially attenuated. These findings suggest that Hjv is not required for sensing of body iron levels and merely functions as an enhancer for iron signaling to hepcidin.

  9. Chronic Effect of Aspartame on Ionic Homeostasis and Monoamine Neurotransmitters in the Rat Brain.

    Science.gov (United States)

    Abhilash, M; Alex, Manju; Mathews, Varghese V; Nair, R Harikumaran

    2014-05-28

    Aspartame is one of the most widely used artificial sweeteners globally. Data concerning acute neurotoxicity of aspartame is controversial, and knowledge on its chronic effect is limited. In the current study, we investigated the chronic effects of aspartame on ionic homeostasis and regional monoamine neurotransmitter concentrations in the brain. Our results showed that aspartame at high dose caused a disturbance in ionic homeostasis and induced apoptosis in the brain. We also investigated the effects of aspartame on brain regional monoamine synthesis, and the results revealed that there was a significant decrease of dopamine in corpus striatum and cerebral cortex and of serotonin in corpus striatum. Moreover, aspartame treatment significantly alters the tyrosine hydroxylase activity and amino acids levels in the brain. Our data suggest that chronic use of aspartame may affect electrolyte homeostasis and monoamine neurotransmitter synthesis dose dependently, and this might have a possible effect on cognitive functions.

  10. [Iron deficiency in the elderly].

    Science.gov (United States)

    Helsen, Tuur; Joosten, Etienne

    2016-06-01

    Anemia is a common diagnosis in the geriatric population, especially in institutionalized and hospitalized elderly. Most common etiologies for anemia in elderly people admitted to a geriatric ward are iron-deficiency anemia and anemia associated with chronic disease.Determination of serum ferritin is the most used assay in the differential diagnosis, despite low sensitivity and moderate specificity. New insights into iron homeostasis lead to new diagnostic assays such as serum hepcidin, serum transferrin receptor and reticulocyte hemoglobin equivalent.Importance of proper diagnosis and treatment for this population is large since there is a correlation between anemia and morbidity - mortality. Anemia is usually defined as hemoglobin less than 12 g/dl for women and less than 13 g/dl for men. There is no consensus for which hemoglobinvalue an investigation into underlying pathology is obligatory. This needs to be evaluated depending on functional condition of the patient. PMID:27106490

  11. Understanding metal homeostasis in primary cultured neurons. Studies using single neuron subcellular and quantitative metallomics.

    Science.gov (United States)

    Colvin, Robert A; Lai, Barry; Holmes, William R; Lee, Daewoo

    2015-07-01

    The purpose of this study was to demonstrate how single cell quantitative and subcellular metallomics inform us about both the spatial distribution and cellular mechanisms of metal buffering and homeostasis in primary cultured neurons from embryonic rat brain, which are often used as models of human disease involving metal dyshomeostasis. The present studies utilized synchrotron radiation X-ray fluorescence (SRXRF) and focused primarily on zinc and iron, two abundant metals in neurons that have been implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Total single cell contents for calcium, iron, zinc, copper, manganese, and nickel were determined. Resting steady state zinc showed a diffuse distribution in both soma and processes, best defined by the mass profile of the neuron with an enrichment in the nucleus compared with the cytoplasm. Zinc buffering and homeostasis was studied using two modes of cellular zinc loading - transporter and ionophore (pyrithione) mediated. Single neuron zinc contents were shown to statistically significantly increase by either loading method - ionophore: 160 million to 7 billion; transporter 160 million to 280 million atoms per neuronal soma. The newly acquired and buffered zinc still showed a diffuse distribution. Soma and processes have about equal abilities to take up zinc via transporter mediated pathways. Copper levels are distributed diffusely as well, but are relatively higher in the processes relative to zinc levels. Prior studies have observed iron puncta in certain cell types, but others have not. In the present study, iron puncta were characterized in several primary neuronal types. The results show that iron puncta could be found in all neuronal types studied and can account for up to 50% of the total steady state content of iron in neuronal soma. Although other metals can be present in iron puncta, they are predominantly iron containing and do not appear to be

  12. Leptin therapy, insulin sensitivity, and glucose homeostasis

    Directory of Open Access Journals (Sweden)

    Gilberto Paz-Filho

    2012-01-01

    Full Text Available Glucose homeostasis is closely regulated not only by insulin, but also by leptin. Both hormones act centrally, regulating food intake and adiposity in humans. Leptin has several effects on the glucose-insulin homeostasis, some of which are independent of body weight and adiposity. Those effects of leptin are determined centrally in the hypothalamus and peripherally in the pancreas, muscles and liver. Leptin has beneficial effects on the glucose-insulin metabolism, by decreasing glycemia, insulinemia and insulin resistance. The understanding of the effects of leptin on the glucose-insulin homeostasis will lead to the development of leptin-based therapies against diabetes and other insulin resistance syndromes. In these review, we summarize the interactions between leptin and insulin, and their effects on the glucose metabolism.

  13. Iron biology, immunology, aging and obesity: four fields connected by the small peptide hormone, hepcidin

    Science.gov (United States)

    It is well-known that obesity and aging have a negative impact on iron status and immune response, but little is known about the additional impact that obesity may have on iron homeostasis and immunity in the elderly. This question is relevant given the rising numbers of elderly obese individuals a...

  14. Elevated systemic hepcidin and iron depletion in obese pre-menopausal females.

    Science.gov (United States)

    Hepcidin, the body’s main regulator of systemic iron homeostasis, is unregulated in response to inflammation, and is thought to play a role in the manifestation of iron deficiency (ID) observed in obese populations. We determined systemic hepcidin levels and its association with body mass, inflammat...

  15. The effect of iron limitation on the transcriptome and proteome of Pseudomonas fluorescens Pf-5

    Science.gov (United States)

    We investigated the transcriptomic and proteomic effects of iron limitation on Pf-5 by employing microarray and iTRAQ techniques, respectively. Analysis of this data revealed that molecular elements involved in iron homeostasis, including the pyoverdine and enantio-pyochelin biosynthesis clusters a...

  16. Iron overdose

    Science.gov (United States)

    ... PA: Elsevier Saunders; 2014:chap 147. Liebelt EL. Iron. In: Shannon MW, Borron SW, Burns MJ, eds. Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose . 4th ed. Philadelphia, PA: Elsevier ...

  17. [Epithelial cell in intestinal homeostasis and inflammatory bowel diseases].

    Science.gov (United States)

    Zouiten-Mekki, Lilia; Serghini, Meriem; Fekih, Monia; Kallel, Lamia; Matri, Samira; Ben Mustapha, Nadia; Boubaker, Jalel; Filali, Azza

    2013-12-01

    Crohn's disease (CD) and ulcerative colitis (UC) are the principal inflammatory bowel diseases (IBD) which physiopathology is currently poorly elucidated. During these diseases, the participation of the epithelial cell in the installation and the perpetuation of the intestinal inflammation is now clearly implicated. In fact, the intestinal epithelium located at the interface between the internal environment and the intestinal luminal, is key to the homeostatic regulation of the intestinal barrier. This barrier can schematically be regarded as being three barriers in one: a physical, chemical and immune barrier. The barrier function of epithelial cell can be altered by various mechanisms as occurs in IBD. The goal of this article is to review the literature on the role of the epithelial cell in intestinal homeostasis and its implication in the IBD. PMID:24356146

  18. Heterozygous Mutations in BMP6 Pro-peptide Lead to Inappropriate Hepcidin Synthesis and Moderate Iron Overload in Humans

    OpenAIRE

    Daher, Raed; Kannengiesser, Caroline; Houamel, Dounia; Lefebvre, Thibaud; Bardou-Jacquet, Edouard; Ducrot, Nicolas; Kerguenec, Caroline,; Jouanolle, Anne-Marie; Robreau, Anne-Marie; Oudin, Claire; Le Gac, Gerald; Moulouel, Boualem; Loustaud-Ratti, Véronique; Bedossa, Pierre; Valla, Dominique

    2015-01-01

    Background & Aims Hereditary hemochromatosis is a heterogeneous group of genetic disorders characterized by parenchymal iron overload. It is caused by defective expression of liver hepcidin, the main regulator of iron homeostasis. Iron stimulates the gene encoding (HAMP) hepcidin via the BMP6 signaling to SMAD. Although several genetic factors have been found to cause late-onset hemochromatosis, many patients have unexplained signs of iron overload. We investigated BMP6 function in these indi...

  19. Dysregulation of bile acid homeostasis in parenteral nutrition mouse model.

    Science.gov (United States)

    Zhan, Le; Yang, Ill; Kong, Bo; Shen, Jianliang; Gorczyca, Ludwik; Memon, Naureen; Buckley, Brian T; Guo, Grace L

    2016-01-15

    Long-term parenteral nutrition (PN) administration can lead to PN-associated liver diseases (PNALD). Although multiple risk factors have been identified for PNALD, to date, the roles of bile acids (BAs) and the pathways involved in BA homeostasis in the development and progression of PNALD are still unclear. We have established a mouse PN model with IV infusion of PN solution containing soybean oil-based lipid emulsion (SOLE). Our results showed that PN altered the expression of genes involved in a variety of liver functions at the mRNA levels. PN increased liver gene expression of Cyp7a1 and markedly decreased that of Cyp8b1, Cyp7b1, Bsep, and Shp. CYP7A1 and CYP8B1 are important for synthesizing the total amount of BAs and regulating the hydrophobicity of BAs, respectively. Consistently, both the levels and the percentages of primary BAs as well as total non-12α-OH BAs increased significantly in the serum of PN mice compared with saline controls, whereas liver BA profiles were largely similar. The expression of several key liver-X receptor-α (LXRα) target genes involved in lipid synthesis was also increased in PN mouse livers. Retinoid acid-related orphan receptor-α (RORα) has been shown to induce the expression of Cyp8b1 and Cyp7b1, as well as to suppress LXRα function. Western blot showed significantly reduced nuclear migration of RORα protein in PN mouse livers. This study shows that continuous PN infusion with SOLE in mice leads to dysregulation of BA homeostasis. Alterations of liver RORα signaling in PN mice may be one of the mechanisms implicated in the pathogenesis of PNALD. PMID:26564717

  20. Calcium homeostasis in fly photoreceptor cells

    NARCIS (Netherlands)

    Oberwinkler, J

    2002-01-01

    In fly photoreceptor cells, two processes dominate the Ca2+ homeostasis: light-induced Ca2+ influx through members of the TRP family of ion channels, and Ca2+ extrusion by Na+/Ca2+ exchange.Ca2+ release from intracellular stores is quantitatively insignificant. Both, the light-activated channels and

  1. [The role of iron as a deficient element].

    Science.gov (United States)

    Schümann, K

    1989-12-01

    Iron is an essential trace element. In its heme-form as well as in its non heme-form it is a part of enzymes and hemoproteins. For a safe and adequate dietary intake 10-18 mg of iron are recommended daily. Frequently, this quantity is not available: approximately 20% of the world population is iron-deficient. In this state the enteral transfer capacity for toxic metals, e.g., Cd and Pb, is increased and the adaptation to physical strain as well as the immunological responses are depressed. Alterations of body iron-stores are almost exclusively balanced by adequate adaptation of the enteral iron-transfer capacity. The mechanism of this adaptation process can neither be satisfactorily explained by the "mucosal block hypothesis", nor by the "mucosal transferrin hypothesis". When the time-course of iron storage and its relation to intestinal iron transfer was investigated after i.v. iron administration to iron-deficient rats, the results indicated that the process of adaptation is located in the intestinal mucosa. Intestinal iron loading is decreased in iron deficiency, whereas the iron transfer into the organism is increased. Further investigation is necessary to find out by which mechanism the iron manages to bypass existing mucosal storage capacity in this situation. The geographical distribution of iron deficiency is influenced by a variety of local factors. Still, the paramount causes of iron-deficiency are unbalanced iron losses and the lack of bioavailable iron in the diet. The bioavailability of non heme iron is influenced by the composition of the diet. The effect of promotors of iron absorption, such as meat, amino acids, polycarbonic acids and ascorbate is opposed by the influence of inhibitors, such as bran, soya products, vegetables and egg-dishes. Iron losses are mainly due to blood losses. Thus, the wide distribution of hookworm diseases in tropical areas contributes significantly to the endemic iron-deficiency in these regions. A more physiological loss

  2. Rare variants in calcium homeostasis modulator 1 (CALHM1 found in early onset Alzheimer's disease patients alter calcium homeostasis.

    Directory of Open Access Journals (Sweden)

    Fanny Rubio-Moscardo

    Full Text Available Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer's disease (AD. Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca(2+-permeable channel CALHM1. A genetic polymorphism (p. P86L in CALHM1 reduces plasma membrane Ca(2+ permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD, we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H and one (p.A213T in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T behaved as wild-type CALHM1 (CALHM1-WT, a complete abolishment of the Ca(2+ influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H. Notably, the previously reported p. P86L mutation was associated with an intermediate Ca(2+ influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca(2+ dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.

  3. Metabolic Alterations Associated to Brain Dysfunction in Diabetes

    OpenAIRE

    João M N Duarte

    2015-01-01

    From epidemiological studies it is known that diabetes patients display increased risk of developing dementia. Moreover, cognitive impairment and Alzheimer’s disease (AD) are also accompanied by impaired glucose homeostasis and insulin signalling. Although there is plenty of evidence for a connection between insulin-resistant diabetes and AD, definitive linking mechanisms remain elusive. Cerebrovascular complications of diabetes, alterations in glucose homeostasis and insulin signalling, as w...

  4. Biting the Iron Bullet: Endoplasmic Reticulum Stress Adds the Pain of Hepcidin to Chronic Liver Disease

    OpenAIRE

    Messner, Donald J.; Kowdley, Kris V.

    2010-01-01

    Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin overproduction causes anemia of inflammation, whereas its deficiency leads to hemochromatosis. Inflammation and iron are known extracellular stimuli for hepcidin expression. We found that endoplasmic reticulum (ER) stress also induces hepcidin expression and causes hypoferremia and spleen iron sequestration in mice. CREBH (cyclic AMP response element-binding protein H), an ER stress-activa...

  5. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4

    OpenAIRE

    Lin, Lan; Valore, Erika V.; Nemeth, Elizabeta; Goodnough, Julia B; Gabayan, Victoria; Ganz, Tomas

    2007-01-01

    The peptide hormone hepcidin is the principal regulator of systemic iron homeostasis. We examined the pathway by which iron stimulates the production of hepcidin. In humans who ingested 65 mg of iron, the increase in transferrin saturation preceded by hours the increase in urinary hepcidin excretion. Increases in urinary hepcidin concentrations were proportional to the increment in transferrin saturation. Paradoxically, in previous studies in primary hepatocytes and cell lines, hepcidin respo...

  6. Targeting one carbon metabolism with an antimetabolite disrupts pyrimidine homeostasis and induces nucleotide overflow

    OpenAIRE

    Ser, Zheng; GAO, XIA; Johnson, Christelle; Mehrmohamadi, Mahya; Liu, Xiaojing; Li, SiQi; Locasale, Jason W.

    2016-01-01

    Anti-metabolite agents that affect nucleotide metabolism are frontline chemotherapy agents in several cancers and often successfully target one carbon metabolism. However, the precise mechanisms and resulting determinants of their therapeutic value are unknown. We show that 5-fluorouracil (5-FU), a commonly used anti-metabolite therapeutic with varying efficacy, induces specific alterations to nucleotide metabolism by disrupting pyrimidine homeostasis. An integrative metabolomics analysis of ...

  7. Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

    OpenAIRE

    Chondronikola, Maria; Volpi, Elena; Børsheim, Elisabet; Porter, Craig; Annamalai, Palam; Enerbäck, Sven; Lidell, Martin E.; Saraf, Manish K.; Sebastien M Labbe; Hurren, Nicholas M; Yfanti, Christina; Chao, Tony; Andersen, Clark R.; Cesani, Fernando; Hawkins, Hal

    2014-01-01

    Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT+) men and five BAT-negative (BAT−) men under thermon...

  8. Computational modeling and analysis of iron release from macrophages.

    Directory of Open Access Journals (Sweden)

    Alka A Potdar

    2014-07-01

    Full Text Available A major process of iron homeostasis in whole-body iron metabolism is the release of iron from the macrophages of the reticuloendothelial system. Macrophages recognize and phagocytose senescent or damaged erythrocytes. Then, they process the heme iron, which is returned to the circulation for reutilization by red blood cell precursors during erythropoiesis. The amount of iron released, compared to the amount shunted for storage as ferritin, is greater during iron deficiency. A currently accepted model of iron release assumes a passive-gradient with free diffusion of intracellular labile iron (Fe2+ through ferroportin (FPN, the transporter on the plasma membrane. Outside the cell, a multi-copper ferroxidase, ceruloplasmin (Cp, oxidizes ferrous to ferric ion. Apo-transferrin (Tf, the primary carrier of soluble iron in the plasma, binds ferric ion to form mono-ferric and di-ferric transferrin. According to the passive-gradient model, the removal of ferrous ion from the site of release sustains the gradient that maintains the iron release. Subcellular localization of FPN, however, indicates that the role of FPN may be more complex. By experiments and mathematical modeling, we have investigated the detailed mechanism of iron release from macrophages focusing on the roles of the Cp, FPN and apo-Tf. The passive-gradient model is quantitatively analyzed using a mathematical model for the first time. A comparison of experimental data with model simulations shows that the passive-gradient model cannot explain macrophage iron release. However, a facilitated-transport model associated with FPN can explain the iron release mechanism. According to the facilitated-transport model, intracellular FPN carries labile iron to the macrophage membrane. Extracellular Cp accelerates the oxidation of ferrous ion bound to FPN. Apo-Tf in the extracellular environment binds to the oxidized ferrous ion, completing the release process. Facilitated-transport model can

  9. Parkinson’s Disease: The Mitochondria-Iron Link

    Directory of Open Access Journals (Sweden)

    Yorka Muñoz

    2016-01-01

    Full Text Available Mitochondrial dysfunction, iron accumulation, and oxidative damage are conditions often found in damaged brain areas of Parkinson’s disease. We propose that a causal link exists between these three events. Mitochondrial dysfunction results not only in increased reactive oxygen species production but also in decreased iron-sulfur cluster synthesis and unorthodox activation of Iron Regulatory Protein 1 (IRP1, a key regulator of cell iron homeostasis. In turn, IRP1 activation results in iron accumulation and hydroxyl radical-mediated damage. These three occurrences—mitochondrial dysfunction, iron accumulation, and oxidative damage—generate a positive feedback loop of increased iron accumulation and oxidative stress. Here, we review the evidence that points to a link between mitochondrial dysfunction and iron accumulation as early events in the development of sporadic and genetic cases of Parkinson’s disease. Finally, an attempt is done to contextualize the possible relationship between mitochondria dysfunction and iron dyshomeostasis. Based on published evidence, we propose that iron chelation—by decreasing iron-associated oxidative damage and by inducing cell survival and cell-rescue pathways—is a viable therapy for retarding this cycle.

  10. Estrogen-dependent changes in serum iron levels as a translator of the adverse effects of estrogen during infection: a conceptual framework.

    Science.gov (United States)

    Hamad, Mawieh; Awadallah, Samir

    2013-12-01

    Elevated levels of estrogen often associate with increased susceptibility to infection. This has been attributed to the ability of estrogen to concomitantly enhance the growth and virulence of pathogens and suppress host immunity. But the exact mechanism of how estrogen mediates such effects, especially in cases where the pathogen and/or the immune components in question do not express estrogen receptors, has yet to be elucidated. Here we propose that translating the adverse effects of estrogen during infection is dependent to a significant degree upon its ability to manipulate iron homeostasis. For elevated levels of estrogen alter the synthesis and/or activity of several factors involved in iron metabolism including hypoxia inducible factor 1α (HIF-1α) and hepcidin among others. This leads to the inhibition of hepcidin synthesis in hepatocytes and the maintenance of ferroportin (FPN) integrity on the surface of iron-releasing duodenal enterocytes, hepatocytes, and macrophages. Intact FPN permits the continuous efflux of dietary and stored iron into the circulation, which further enhances pathogen growth and virulence on the one hand and suppresses host immunity on the other. This new conceptual framework may help explain a multitude of disparate clinical and experimental observations pertinent to the relationship between estrogen and infection. PMID:24211145

  11. Iron and Your Child

    Science.gov (United States)

    ... Story" 5 Things to Know About Zika & Pregnancy Iron and Your Child KidsHealth > For Parents > Iron and ... enough iron in their daily diets. How Much Iron Do Kids Need? Kids require different amounts of ...

  12. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... have enough iron in your body. Low iron levels usually are due to blood loss, poor diet, ... iron supplements and multivitamins to improve her iron levels. Susan also made changes to her diet, such ...

  13. Iron deficiency

    DEFF Research Database (Denmark)

    Schou, Morten; Bosselmann, Helle; Gaborit, Freja;

    2015-01-01

    BACKGROUND: Both iron deficiency (ID) and cardiovascular biomarkers are associated with a poor outcome in heart failure (HF). The relationship between different cardiovascular biomarkers and ID is unknown, and the true prevalence of ID in an outpatient HF clinic is probably overlooked. OBJECTIVES.......043). CONCLUSION: ID is frequent in an outpatient HF clinic. ID is not associated with cardiovascular biomarkers after adjustment for traditional confounders. Inflammation, but not neurohormonal activation is associated with ID in systolic HF. Further studies are needed to understand iron metabolism in elderly HF...

  14. ROS Homeostasis Regulates Somatic Embryogenesis via the Regulation of Auxin Signaling in Cotton.

    Science.gov (United States)

    Zhou, Ting; Yang, Xiyan; Guo, Kai; Deng, Jinwu; Xu, Jiao; Gao, Wenhui; Lindsey, Keith; Zhang, Xianlong

    2016-06-01

    Somatic embryogenesis (S.E.) is a versatile model for understanding the mechanisms of plant embryogenesis and a useful tool for plant propagation. To decipher the intricate molecular program and potentially to control the parameters affecting the frequency of S.E., a proteomics approach based on two-dimensional gel electrophoresis (2-DE) combined with MALDI-TOF/TOF was used. A total of 149 unique differentially expressed proteins (DEPs) were identified at different stages of cotton S.E. compared with the initial control (0 h explants). The expression profile and functional annotation of these DEPs revealed that S.E. activated stress-related proteins, including several reactive oxygen species (ROS)-scavenging enzymes. Proteins implicated in metabolic, developmental, and reproductive processes were also identified. Further experiments were performed to confirm the role of ROS-scavenging enzymes, suggesting the involvement of ROS homeostasis during S.E. in cotton. Suppressing the expression of specifically identified GhAPX proteins resulted in the inhibition of dedifferentiation. Accelerated redifferentiation was observed in the suppression lines of GhAPXs or GhGSTL3 in parallel with the alteration of endogenous ascorbate metabolism and accumulation of endogenous H2O2 content. Moreover, disrupting endogenous redox homeostasis through the application of high concentrations of DPI, H2O2, BSO, or GSH inhibited the dedifferentiation of cotton explants. Mild oxidation induced through BSO treatment facilitated the transition from embryogenic calluses (ECs) to somatic embryos. Meanwhile, auxin homeostasis was altered through the perturbation of ROS homeostasis by chemical treatments or suppression of ROS-scavenging proteins, along with the activating/suppressing the transcription of genes related to auxin transportation and signaling. These results show that stress responses are activated during S.E. and may regulate the ROS homeostasis by interacting with auxin signaling

  15. Trace element status and zinc homeostasis differ in breast and formula-fed piglets

    Science.gov (United States)

    Miousse, Isabelle R; Mason, Andrew Z; Sharma, Neha; Blackburn, Michael L; Badger, Thomas M

    2015-01-01

    Differences in trace element composition and bioavailability between breast milk and infant formulas may affect metal homeostasis in neonates. However, there is a paucity of controlled studies in this area. Here, piglets were fed soy infant formula (soy), cow’s milk formula (milk), or were allowed to suckle from the sow from PND2 to PND21. Serum iron concentrations were higher in formula-fed compared to breastfed piglets (P supplementation, allows strong causal inference that significant differences in serum zinc after cow’s milk formula compared to soy formula consumption result in compensatory changes in expression of zinc transporters, binding proteins, and zinc-regulated genes. PMID:25179632

  16. Imbalanced immune homeostasis in immune thrombocytopenia.

    Science.gov (United States)

    Yazdanbakhsh, Karina

    2016-04-01

    Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder resulting from low platelet counts caused by inadequate production as well as increased destruction by autoimmune mechanisms. As with other autoimmune disorders, chronic ITP is characterized by perturbations of immune homeostasis with hyperactivated effector cells as well as defective regulatory arm of the adaptive immune system, which will be reviewed here. Interestingly, some ITP treatments are associated with restoring the regulatory imbalance, although it remains unclear whether the immune system is redirected to a state of tolerance once treatment is discontinued. Understanding the mechanisms that result in breakdown of immune homeostasis in ITP will help to identify novel pathways for restoring tolerance and inhibiting effector cell responses. This information can then be translated into developing therapies for averting autoimmunity not only in ITP but also many autoimmune disorders. PMID:27312156

  17. Homeostasis as the Mechanism of Evolution.

    Science.gov (United States)

    Torday, John S

    2015-01-01

    Homeostasis is conventionally thought of merely as a synchronic (same time) servo-mechanism that maintains the status quo for organismal physiology. However, when seen from the perspective of developmental physiology, homeostasis is a robust, dynamic, intergenerational, diachronic (across-time) mechanism for the maintenance, perpetuation and modification of physiologic structure and function. The integral relationships generated by cell-cell signaling for the mechanisms of embryogenesis, physiology and repair provide the needed insight to the scale-free universality of the homeostatic principle, offering a novel opportunity for a Systems approach to Biology. Starting with the inception of life itself, with the advent of reproduction during meiosis and mitosis, moving forward both ontogenetically and phylogenetically through the evolutionary steps involved in adaptation to an ever-changing environment, Biology and Evolution Theory need no longer default to teleology. PMID:26389962

  18. Homeostasis as the Mechanism of Evolution

    Directory of Open Access Journals (Sweden)

    John S. Torday

    2015-09-01

    Full Text Available Homeostasis is conventionally thought of merely as a synchronic (same time servo-mechanism that maintains the status quo for organismal physiology. However, when seen from the perspective of developmental physiology, homeostasis is a robust, dynamic, intergenerational, diachronic (across-time mechanism for the maintenance, perpetuation and modification of physiologic structure and function. The integral relationships generated by cell-cell signaling for the mechanisms of embryogenesis, physiology and repair provide the needed insight to the scale-free universality of the homeostatic principle, offering a novel opportunity for a Systems approach to Biology. Starting with the inception of life itself, with the advent of reproduction during meiosis and mitosis, moving forward both ontogenetically and phylogenetically through the evolutionary steps involved in adaptation to an ever-changing environment, Biology and Evolution Theory need no longer default to teleology.

  19. THE WORLD VIEW, IDENTITY AND SOCIOCULTUR HOMEOSTASIS

    Directory of Open Access Journals (Sweden)

    Marina Yur’evna Neronova

    2016-02-01

    Full Text Available The paper presents the relationship between the phenomenon of world view and sociocultural identity both individuals and the community as a whole. The research is being carried out in the context of current crisis of world view accepted in so-called art Nouveau era. This paper also presents the identity crisis typical for modern civilized societies. A new notion of sociocultural homeostasis is introduced in connection with analyzable phenomena and their mutual relations.Purpose. Study of the relationship between the phenomenon of the world view and sociocultural identity as a structural and functional mechanism.Methodology. Phenomenological and systematic methods with the elements of historical method were employed. Cultural analysis is based on using both axiological and phenomenological approach, and also the elements of semiotic approach.Results. The dependence of identity on the world view is revealed (or is being revealed?, the phenomenon of sociocultural homeostasis is singled out (or is being singled out in the capacity of the mechanism setting up the correspondence in the contradictory unity between the world view as a subjective image and concrete reality as an objective part of this contradictory. The analysis of sociocultural homeostasis is carried out (or is being carried out and the conclusion is being drown that instability of the latter leads to serious problems in the identification of both individuals and communities as a whole. Besides, (moreover the relationship between the legitimacy level of the world view and stability of sociocultural homeostasis is established. (is being established.Practical implications: the system of education.

  20. Oxidative Stress and Autophagy in Cardiovascular Homeostasis

    OpenAIRE

    Morales, Cyndi R.; Pedrozo, Zully; Lavandero, Sergio; Hill, Joseph A.

    2014-01-01

    Significance: Autophagy is an evolutionarily ancient process of intracellular protein and organelle recycling required to maintain cellular homeostasis in the face of a wide variety of stresses. Dysregulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) leads to oxidative damage. Both autophagy and ROS/RNS serve pathological or adaptive roles within cardiomyocytes, depending on the context. Recent Advances: ROS/RNS and autophagy communicate with each other via both tra...

  1. Recent Advances in Iron Metabolism: Relevance for Health, Exercise, and Performance.

    Science.gov (United States)

    Buratti, Paolo; Gammella, Elena; Rybinska, Ilona; Cairo, Gaetano; Recalcati, Stefania

    2015-08-01

    Iron is necessary for physiological processes essential for athletic performance, such as oxygen transport, energy production, and cell division. However, an excess of "free" iron is toxic because it produces reactive hydroxyl radicals that damage biological molecules, thus leading to cell and tissue injury. Therefore, iron homeostasis is strictly regulated; and in recent years, there have been important advancements in our knowledge of the underlying processes. Hepcidin is the central regulator of systemic iron homeostasis and exerts its function by controlling the presence of the iron exporter ferroportin on the cell membrane. Hepcidin binding induces ferroportin degradation, thus leading to cellular iron retention and decreased levels of circulating iron. As iron is required for hemoglobin synthesis, the tight link between erythropoiesis and iron metabolism is particularly relevant to sports physiology. The iron needed for hemoglobin synthesis is ensured by inhibiting hepcidin to increase ferroportin activity and iron availability and hence to make certain that efficient blood oxygen transport occurs for aerobic exercise. However, hepcidin expression is also affected by exercise-associated conditions, such as iron deficiency, anemia or hypoxia, and, particularly, inflammation, which can play a role in the pathogenesis of sports anemia. Here, we review recent advances showing the relevance of iron for physical exercise and athletic performance. Low body iron levels can cause anemia and thus limit the delivery of oxygen to exercising muscle, but tissue iron deficiency may also affect performance by, for example, hampering muscle oxidative metabolism. Accordingly, a hemoglobin-independent effect of iron on exercise capacity has been demonstrated in animal models and humans. Here, we review recent advances showing the relevance of iron for physical exercise and athletic performance. PMID:25494391

  2. Regulation of energy homeostasis via GPR120

    Directory of Open Access Journals (Sweden)

    Atsuhiko eIchimura

    2014-07-01

    Full Text Available Free fatty acids (FFAs are fundamental units of key nutrients. FFAs exert various biological functions, depending on the chain length and degree of desaturation. Recent studies have shown that several FFAs act as ligands of G-protein-coupled receptors (GPCRs, activate intracellular signaling and exert physiological functions via these GPCRs. GPR120 (also known as free fatty acid receptor 4, FFAR4 is activated by unsaturated medium- to long-chain FFAs and has a critical role in various physiological homeostasis mechanisms such as incretin hormone secretion, food preference, anti-inflammation and adipogenesis. Recent studies showed that a lipid sensor GPR120 has a key role in sensing dietary fat in white adipose tissue and regulates the whole body energy homeostasis in both humans and rodents. Genetic study in human identified the loss-of-functional mutation of GPR120 associated with obesity and insulin resistance. In addition, dysfunction of GPR120 has been linked as a novel risk factor for diet-induced obesity. This review aims to provide evidence from the recent development in physiological function of GPR120 and discusses its functional roles in regulation of energy homeostasis and its potential as drug targets.

  3. Glucose homeostasis in Egyptian children and adolescents with β-Thalassemia major: Relationship to oxidative stress

    Directory of Open Access Journals (Sweden)

    Kotb Abbass Metwalley

    2014-01-01

    alteration in oxidant-antioxidant status and increase in insulin resistance. Recommendation: 1- Glucose tolerance tests, HOMA-IR, and MDA should be an integral part of the long-term follow-up of children and adolescents with β-thalassemia major. 2- Regular iron chelation and antioxidant therapy should be advised for thalassemic patients to improve glucose hemostasis.

  4. Metformin regulates glycemic homeostasis in patients with type 2 diabetes mellitus as an NO donor

    Directory of Open Access Journals (Sweden)

    Ivan Sergeevich Kuznetsov

    2013-11-01

    Full Text Available Aim. To evaluate the influence of metformin on nitric oxide bioavailability in patients with type 2 diabetes mellitus (T2DM regarding glycemic homeostasis, and to investigate a correlation between metformin dosage and NO levels in vivo.Materials and Methods. Two groups – primary and control – were assembled for the clinical section of this study. Patients with newly diagnosed T2DM on metformin therapy were included to the primary group, while drug-naïve T2DM patients were enrolled as control subjects. Glycemic parameters and NO bioavailability was tested in both groups prior to and after the follow-up period. Experimental section was dedicated to the elucidation of potential dose-dependent effects of metformin on NO bioavailability. Mice were intraperitoneally infused with metformin at 0.5; 1.1; 5.6 mg per subject. Tissue detection of NO was performed with diethyldithiocarbamate (DETC iron complexes to form mononitrosyl iron compounds (MIC with paramagnetic properties. Control rodents were intraperitoneally infused with metformin without spin trapping.Results. We found nitrite and methaemoglobin (a marker for NO bioavailability to increase in parallel along with glycemic compensation in the primary but not control group. In vivo rodent models showed linear correlation between accumulation of DETC/MIC and dose of metformin, as well as formation of dinitrosyl iron complexes, known as endogenous NO transporters.Conclusion. Our data suggests that metformin benefits glycemic homeostasis in T2DM as an NO donor via formation of dinitrosyl iron complexes.

  5. Bacterial iron-sulfur cluster sensors in mammalian pathogens

    Science.gov (United States)

    Miller, Halie K.; Auerbuch, Victoria

    2015-01-01

    Iron-sulfur clusters act as important cofactors for a number of transcriptional regulators in bacteria, including many mammalian pathogens. The sensitivity of iron-sulfur clusters to iron availability, oxygen tension, and reactive oxygen and nitrogen species enables bacteria to use such regulators to adapt their gene expression profiles rapidly in response to changing environmental conditions. In this review, we discuss how the [4Fe-4S] or [2Fe-2S] cluster-containing regulators FNR, Wbl, aconitase, IscR, NsrR, SoxR, and AirSR contribute to bacterial pathogenesis through control of both metabolism and classical virulence factors. In addition, we briefly review mammalian iron homeostasis as well as oxidative/nitrosative stress to provide context for understanding the function of bacterial iron-sulfur cluster sensors in different niches within the host. PMID:25738802

  6. Human iron transporters

    OpenAIRE

    Garrick, Michael D.

    2010-01-01

    Human iron transporters manage iron carefully because tissues need iron for critical functions, but too much iron increases the risk of reactive oxygen species. Iron acquisition occurs in the duodenum via divalent metal transporter (DMT1) and ferroportin. Iron trafficking depends largely on the transferrin cycle. Nevertheless, non-digestive tissues have a variety of other iron transporters that may render DMT1 modestly redundant, and DMT1 levels exceed those needed for the just-mentioned task...

  7. The Application of Spectral Characteristic Space Method to the Alteration Information Extraction of Lake Superior-Type Iron Deposit%基于光谱特征空间的苏必利尔湖型铁矿高光谱遥感蚀变信息提取方法

    Institute of Scientific and Technical Information of China (English)

    黄爽; 陈圣波; 周超; 査逢丽; 路鹏; 黄唯实

    2015-01-01

    The field study of overseas iron ore deposits is difficult because of its remote location.The spectral characteristic was used to extract alteration information in view of the limitation of the traditional methods in this paper,aiming to explore altera-tion information extraction from hyperspectral images for the Lake Superior type iron ore to facilitate overseas prospecting.A two-dimensional spectral characteristic space takes on an anisotropic feature in associated distribution of two principal bands af-ter principal component analysis.The distribution is usually combined by oval clusters.The scatter points were enclosed in oval clusters of alteration information,and the mean spectra of abnormal scatter points were matched with mineral spectra from United States Geological Survey(USGS)spectral library by means of spectral feature fitting to ensure the type of alteration minerals.Spectral characteristic space method was described with the instance of Lake Superior-type iron deposit—Aguas Clar-as iron area in Brazil.Hematite,chlorite and other minerals were extracted in this study.It is found that the type and distribu-tion of extracted altered minerals were consistent well with geological condition.%由于境外铁矿床位置偏远,现场研究困难,旨在探讨苏必利尔湖型铁矿的高光谱遥感蚀变信息提取方法,为境外找矿提供依据。鉴于传统蚀变信息提取方法的局限性,研究了在二维光谱特征空间中提取蚀变信息的方法。高光谱影像经主成分变换后,包含较多地物信息的两个主成分的二维光谱特征空间体现了各向异性的特点,不同地物的聚类常呈类似椭圆分布。在蚀变信息的聚类椭圆中圈定散点,并应用波谱特征拟合,将异常散点的平均光谱与美国地质调查局(United States Geological Sur-vey,USGS)光谱库中的矿物光谱匹配,确定蚀变矿物类型。以苏必利尔湖型铁矿———巴西 Aguas Claras 铁矿区为例,提取了

  8. Iron bioavailability from commercially available iron supplements

    OpenAIRE

    Christides, Tatiana; Wray, David; McBride, Richard; Fairweather, Rose; Sharp, Paul

    2015-01-01

    Purpose Iron deficiency anaemia (IDA) is a global public health problem. Treatment with the standard of care ferrous iron salts may be poorly tolerated, leading to non-compliance and ineffective correction of IDA. Employing supplements with higher bioavailability might permit lower doses of iron to be used with fewer side effects, thus improving treatment efficacy. Here, we compared the iron bioavailability of ferrous sulphate tablets with alternative commercial iron products, including th...

  9. The commensal microbiota drives immune homeostasis

    Directory of Open Access Journals (Sweden)

    Marie-Claire eArrieta

    2012-03-01

    Full Text Available For millions of years, microbes have coexisted with eukaryotic cells at the mucosal surfaces of vertebrates in a complex, yet usually harmonious symbiosis. An ever-expanding number of reports describe how eliminating or shifting the intestinal microbiota has profound effects on the development and functionality of the mucosal and systemic immune systems. Here, we examine some of the mechanisms by which bacterial signals affect immune homeostasis. Focusing on the strategies that microbes use to keep our immune system healthy, as opposed to trying to correct the immune imbalances caused by dysbiosis, may prove to be a more astute and efficient way of treating immune-mediated disease.

  10. Potassium homeostasis in chronic kidney disease.

    Science.gov (United States)

    Palmer, Biff F

    2016-04-01

    Adaptive increases in renal and gastrointestinal excretion of K+ help to prevent hyperkalemia in patients with CKD as long as the GFR remains > 15-20 mL/min. Once the GFR falls below these values, the impact of factors known to adversely affect K+ homeostasis is significantly magnified. Impaired renal K+ excretion can be the result of conditions that severely limit distal Na+ delivery, decreased mineralocorticoid levels or activity, or a distal tubular defect (Table 2). In clinical practice, hyperkalemia is usually the result of a combination of factors superimposed on renal dysfunction.

  11. Nickel metallomics: general themes guiding nickel homeostasis.

    Science.gov (United States)

    Sydor, Andrew M; Zamble, Deborah B

    2013-01-01

    The nickel metallome describes the distribution and speciation of nickel within the cells of organisms that utilize this element. This distribution is a consequence of nickel homeostasis, which includes import, storage, and export of nickel, incorporation into metalloenzymes, and the modulation of these and associated cellular systems through nickel-regulated transcription. In this chapter, we review the current knowledge of the most common nickel proteins in prokaryotic organisms with a focus on their coordination environments. Several underlying themes emerge upon review of these nickel systems, which illustrate the common principles applied by nature to shape the nickel metallome of the cell.

  12. The molecular physiology of uric acid homeostasis.

    Science.gov (United States)

    Mandal, Asim K; Mount, David B

    2015-01-01

    Uric acid, generated from the metabolism of purines, has proven and emerging roles in human disease. Serum uric acid is determined by production and the net balance of reabsorption or secretion by the kidney and intestine. A detailed understanding of epithelial absorption and secretion of uric acid has recently emerged, aided in particular by the results of genome-wide association studies of hyperuricemia. Novel genetic and regulatory networks with effects on uric acid homeostasis have also emerged. These developments promise to lead to a new understanding of the various diseases associated with hyperuricemia and to novel, targeted therapies for hyperuricemia. PMID:25422986

  13. Epididymis cholesterol homeostasis and sperm fertilizing ability

    Institute of Scientific and Technical Information of China (English)

    Fabrice Saez; Aurélia Ouvrier; Jo(e)l R Drevet

    2011-01-01

    Cholesterol, being the starting point of steroid hormone synthesis, is a long known modulator of both female and male reproductive physiology especially at the level of the gonads and the impact cholesterol has on gametogenesis. Less is known about the effects cholesterol homeostasis may have on postgonadic reproductive functions. Lately, several data have been reported showing how imbalanced cholesterol levels may particularly affect the post-testicular events of sperm maturation that lead to fully fertile male gametes. This review will focus on that aspect and essentially centers on how cholesterol is important for the physiology of the mammalian epididymis and spermatozoa.

  14. Altered metal metabolism in patients with HCV-related cirrhosis and hepatic encephalopathy.

    Science.gov (United States)

    Marano, Massimo; Vespasiani Gentilucci, Umberto; Altamura, Claudia; Siotto, Mariacristina; Squitti, Rosanna; Bucossi, Serena; Quintiliani, Livia; Migliore, Simone; Greco, Federico; Scarciolla, Laura; Quattrocchi, Carlo Cosimo; Picardi, Antonio; Vernieri, Fabrizio

    2015-12-01

    Dysfunctional metal homeostasis contributes to oxidative stress and neuronal damage. These have been implicated in hepatic encephalopathy pathogenesis. To investigate whether altered metal metabolism is associated with hepatic encephalopathy. Twenty-one controls and 34 HCV-cirrhotic patients (ENC/NEC patients according to presence/absence of previous overt episodes of hepatic encephalopathy) and a control group were studied. Serum iron, copper, ceruloplasmin, ceruloplasmin activity, transferrin, and ceruloplasmin/transferrin ratio were determined. Neuropsychological tests were performed by the repeatable battery of neuropsychological status. Magnetic resonance assessed basal ganglia volumes and metal deposition (pallidal index and T2*). Cirrhotic patients performed worse than controls at cognitive tests, especially ENC patients,. At biochemical analysis copper concentrations, ceruloplasmin activity and transferrin levels were lower in ENC than in NEC patients and controls (p < 0.05 and p < 0.01, respectively). Ceruloplasmin/transferrin ratio was higher in ENC compared to NEC patients (p < 0.05), and controls (p < 0.01). By brain magnetic resonance, ENC patients showed reduced caudate and globus pallidus volumes compared to controls (p < 0.05), and ENC and NEC patients an increased pallidal index compared to controls (p < 0.01). In ENC patients, ceruloplasmin activity correlated with caudate volume and pallidal index (ρ = 0.773 and ρ = -0.683, p < 0.05). Altered metal metabolism likely contributes to cirrhotic hepatic encephalopathy. PMID:26307419

  15. 新疆西天山智博铁矿床蚀变矿物学、矿物化学特征及矿床成因探讨%Alteration mineralogy, mineral chemistry and genesis of Zhibo iron deposit in western Tianshan Mountains, Xinjiang

    Institute of Scientific and Technical Information of China (English)

    蒋宗胜; 张作衡; 王志华; 李凤鸣; 田敬全

    2012-01-01

    The Zhibo iron deposit is one of the recently-discovered large magnetite deposits in the Awulale iron metal-logenic belt, which is located at the eastern corner of western Tianshan Mountains. The ore bodies are hosted mainly by volcanic and volcaniclastic rocks of the Lower Carboniferous Dahalajunshan Formation. The wall rocks of the Zhibo iron deposit have been strongly altered. Three stages of alteration assemblages and associated mineralization have been recognized: Stage I , dominantly composed of pyroxene + albite + magnetite; Stage II , characterized by amphibole + K-feldspars + epidote + magnetite + pyrite; and Stage HI, dominated by epidote + chlorite + cal-cite + quartz + pyrite + hematite ± chalcopyrite. Electron microprobe analyses indicate that the Zhibo deposit have compositional features of mineral assemblages similar to many other magmatic-hydrothermal iron oxide deposits. Pyroxene consists mainly of diopside (Di = 62.97% ~ 83.56% ) , with minor hedenbergite (Hd = 16.44% ~ 36.45%). Igneous plagioclase (Ab47.57-57.82 An415.51.87 Or0.56-0.68) has been altered into albite (Ab77.89-99.33 An0.46-2.48 Or0.21-20.3)- K-feldspar related to late hydrothermal alteration is superimposed upon the pre-existing associations. Amphiboles are entirely of actinolite composition. Abundant Fe-epidote [Fe/(Fe + Al) = 0.22~ 0.36) and minor chlorite have pervasively replaced early mineral assemblages. In contrast with high titanium (3.08% TiO2) magnetite in volcanic rocks, most magnetite from the ore bodies has lower w(TiO2) (0.23%). A small amount of disseminated magnetite has a ω(V2O5) similar to the magnetite from volcanic rocks, suggesting minor iron movement from the wall rock during the early metasomatism. Mineralogy and mineral chemistry of the altered minerals indicate that metasomatic replacement played an important role in mineralization. In addition, the Zhibo iron deposit also has some textural features suggestive of an Fe-rich melt origin for the deposit

  16. Abnormal chloride homeostasis in the substancia nigra pars reticulata contributes to locomotor deficiency in a model of acute liver injury.

    Directory of Open Access Journals (Sweden)

    Yan-Ling Yang

    Full Text Available BACKGROUND: Altered chloride homeostasis has been thought to be a risk factor for several brain disorders, while less attention has been paid to its role in liver disease. We aimed to analyze the involvement and possible mechanisms of altered chloride homeostasis of GABAergic neurons within the substantia nigra pars reticulata (SNr in the motor deficit observed in a model of encephalopathy caused by acute liver failure, by using glutamic acid decarboxylase 67 - green fluorescent protein knock-in transgenic mice. METHODS: Alterations in intracellular chloride concentration in GABAergic neurons within the SNr and changes in the expression of two dominant chloride homeostasis-regulating genes, KCC2 and NKCC1, were evaluated in mice with hypolocomotion due to hepatic encephalopathy (HE. The effects of pharmacological blockade and/or activation of KCC2 and NKCC1 functions with their specific inhibitors and/or activators on the motor activity were assessed. RESULTS: In our mouse model of acute liver injury, chloride imaging indicated an increase in local intracellular chloride concentration in SNr GABAergic neurons. In addition, the mRNA and protein levels of KCC2 were reduced, particularly on neuronal cell membranes; in contrast, NKCC1 expression remained unaffected. Furthermore, blockage of KCC2 reduced motor activity in the normal mice and led to a further deteriorated hypolocomotion in HE mice. Blockade of NKCC1 was not able to normalize motor activity in mice with liver failure. CONCLUSION: Our data suggest that altered chloride homeostasis is likely involved in the pathophysiology of hypolocomotion following HE. Drugs aimed at restoring normal chloride homeostasis would be a potential treatment for hepatic failure.

  17. Iron deposition in modern and archaeological teeth

    Energy Technology Data Exchange (ETDEWEB)

    Williams, A.-M.M., E-mail: AnneMarie.Williams@utas.edu.au [School of Medicine, Private Bag 34, University of Tasmania, Hobart 7001 (Australia); Siegele, R. [Australian Nuclear Science and Technology Organisation, PMB 1, Menai, NSW 2234 (Australia)

    2014-09-15

    Iron surface concentrations and profile maps were measured on the enamel of archaeological and modern teeth to determine how iron is deposited in tooth enamel and if it was affected by the post-mortem environment. Teeth from Australian children who died in the second half of the 19th century were compared with contemporary teeth extracted for orthodontic purposes. Surface analysis of the teeth was performed using the 3 MV Van Der Graff Accelerator at The Australian Nuclear Science and Technology Organisation (ANSTO), Sydney, Australia. A small sample of teeth were then cut in the mid sagittal plane and analysed using ANSTO High Energy Heavy Ion Microprobe. Maps and linear profiles were produced showing the distribution of iron across the enamel. Results show that both the levels and distribution of iron in archaeological teeth is quite different to contemporary teeth, raising the suggestion that iron has been significantly altered by the post-mortem environment.

  18. Impact of metal ion homeostasis of genetically modified Escherichia coli Nissle 1917 and K12 (W3110) strains on colonization properties in the murine intestinal tract.

    Science.gov (United States)

    Kupz, Andreas; Fischer, André; Nies, Dietrich H; Grass, Gregor; Göbel, Ulf B; Bereswill, Stefan; Heimesaat, Markus M

    2013-09-01

    Metal ions are integral parts of pro- as well as eukaryotic cell homeostasis. Escherichia coli proved a valuable in vitro model organism to elucidate essential mechanisms involved in uptake, storage, and export of metal ions. Given that E. coli Nissle 1917 is able to overcome murine colonization resistance, we generated several E. coli Nissle 1917 mutants with defects in zinc, iron, copper, nickel, manganese homeostasis and performed a comprehensive survey of the impact of metal ion transport and homeostasis for E. coli colonization capacities within the murine intestinal tract. Seven days following peroral infection of conventional mice with E. coli Nissle 1917 strains exhibiting defined defects in zinc or iron uptake, the respective mutant and parental strains could be cultured at comparable, but low levels from the colonic lumen. We next reassociated gnotobiotic mice in which the microbiota responsible for colonization resistance was abrogated by broad-spectrum antibiotics with six different E. coli K12 (W3110) mutants. Seven days following peroral challenge, each mutant and parental strain stably colonized duodenum, ileum, and colon at comparable levels. Taken together, defects in zinc, iron, copper, nickel, and manganese homeostasis do not compromise colonization capacities of E. coli in the murine intestinal tract.

  19. Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.

    Directory of Open Access Journals (Sweden)

    Viola Nordström

    Full Text Available Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase. As a major mechanism of central nervous system (CNS metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV-mediated Ugcg delivery to the arcuate nucleus (Arc significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis.

  20. Lipoproteins, cholesterol homeostasis and cardiac health

    Directory of Open Access Journals (Sweden)

    Tyler F. Daniels, Karen M. Killinger, Jennifer J. Michal, Raymond W. Wright Jr., Zhihua Jiang

    2009-01-01

    Full Text Available Cholesterol is an essential substance involved in many functions, such as maintaining cell membranes, manufacturing vitamin D on surface of the skin, producing hormones, and possibly helping cell connections in the brain. When cholesterol levels rise in the blood, they can, however, have dangerous consequences. In particular, cholesterol has generated considerable notoriety for its causative role in atherosclerosis, the leading cause of death in developed countries around the world. Homeostasis of cholesterol is centered on the metabolism of lipoproteins, which mediate transport of the lipid to and from tissues. As a synopsis of the major events and proteins that manage lipoprotein homeostasis, this review contributes to the substantial attention that has recently been directed to this area. Despite intense scrutiny, the majority of phenotypic variation in total cholesterol and related traits eludes explanation by current genetic knowledge. This is somewhat disappointing considering heritability estimates have established these traits as highly genetic. Thus, the continued search for candidate genes, mutations, and mechanisms is vital to our understanding of heart disease at the molecular level. Furthermore, as marker development continues to predict risk of vascular illness, this knowledge has the potential to revolutionize treatment of this leading human disease.

  1. Apoptosis signaling pathways and lymphocyte homeostasis

    Institute of Scientific and Technical Information of China (English)

    Guangwu Xu; Yufang Shi

    2007-01-01

    It has been almost three decades since the term "apoptosis" was first coined to describe a unique form of cell death that involves orderly, gene-dependent cell disintegration. It is now well accepted that apoptosis is an essential life process for metazoan animals and is critical for the formation and function of tissues and organs. In the adult mammalian body, apoptosis is especially important for proper functioning of the immune system. In recent years, along with the rapid advancement of molecular and cellular biology, great progress has been made in understanding the mechanisms leading to apoptosis. It is generally accepted that there are two major pathways of apoptotic cell death induction: extrinsic signaling through death receptors that leads to the formation of the death-inducing signaling complex (DISC), and intrinsic signaling mainly through mitochondria which leads to the formation of the apoptosome. Formation of the DISC or apoptosome, respectively, activates initiator and common effector caspases that execute the apoptosis process. In the immune system, both pathways operate; however, it is not known whether they are sufficient to maintain lymphocyte homeostasis. Recently, new apoptotic mechanisms including caspase-independent pathways and granzyme-initiated pathways have been shown to exist in lymphocytes. This review will summarize our understanding of the mechanisms that control the homeostasis of various lymphocyte populations.

  2. Intestinal barrier homeostasis in inflammatory bowel disease.

    Science.gov (United States)

    Goll, Rasmus; van Beelen Granlund, Atle

    2015-01-01

    The single-cell thick intestinal epithelial cell (IEC) lining with its protective layer of mucus is the primary barrier protecting the organism from the harsh environment of the intestinal lumen. Today it is clear that the balancing act necessary to maintain intestinal homeostasis is dependent on the coordinated action of all cell types of the IEC, and that there are no passive bystanders to gut immunity solely acting as absorptive or regenerative cells: Mucin and antimicrobial peptides on the epithelial surface are continually being replenished by goblet and Paneth's cells. Luminal antigens are being sensed by pattern recognition receptors on the enterocytes. The enteroendocrine cells sense the environment and coordinate the intestinal function by releasing neuropeptides acting both on IEC and inflammatory cells. All this while cells are continuously and rapidly being regenerated from a limited number of stem cells close to the intestinal crypt base. This review seeks to describe the cell types and structures of the intestinal epithelial barrier supporting intestinal homeostasis, and how disturbance in these systems might relate to inflammatory bowel disease.

  3. MAVS maintains mitochondrial homeostasis via autophagy

    Science.gov (United States)

    Sun, Xiaofeng; Sun, Liwei; Zhao, Yuanyuan; Li, Ying; Lin, Wei; Chen, Dahua; Sun, Qinmiao

    2016-01-01

    Mitochondrial antiviral signalling protein (MAVS) acts as a critical adaptor protein to transduce antiviral signalling by physically interacting with activated RIG-I and MDA5 receptors. MAVS executes its functions at the outer membrane of mitochondria to regulate downstream antiviral signalling, indicating that the mitochondria provides a functional platform for innate antiviral signalling transduction. However, little is known about whether and how MAVS-mediated antiviral signalling contributes to mitochondrial homeostasis. Here we show that the activation of MAVS is sufficient to induce autophagic signalling, which may mediate the turnover of the damaged mitochondria. Importantly, we find MAVS directly interacts with LC3 through its LC3-binding motif ‘YxxI’, suggesting that MAVS might act as an autophagy receptor to mediate mitochondrial turnover upon excessive activation of RLR signalling. Furthermore, we provide evidence that both MAVS self-aggregation and its interaction with TRAF2/6 proteins are important for MAVS-mediated mitochondrial turnover. Collectively, our findings suggest that MAVS acts as a potential receptor for mitochondria-associated autophagic signalling to maintain mitochondrial homeostasis. PMID:27551434

  4. MAVS maintains mitochondrial homeostasis via autophagy.

    Science.gov (United States)

    Sun, Xiaofeng; Sun, Liwei; Zhao, Yuanyuan; Li, Ying; Lin, Wei; Chen, Dahua; Sun, Qinmiao

    2016-01-01

    Mitochondrial antiviral signalling protein (MAVS) acts as a critical adaptor protein to transduce antiviral signalling by physically interacting with activated RIG-I and MDA5 receptors. MAVS executes its functions at the outer membrane of mitochondria to regulate downstream antiviral signalling, indicating that the mitochondria provides a functional platform for innate antiviral signalling transduction. However, little is known about whether and how MAVS-mediated antiviral signalling contributes to mitochondrial homeostasis. Here we show that the activation of MAVS is sufficient to induce autophagic signalling, which may mediate the turnover of the damaged mitochondria. Importantly, we find MAVS directly interacts with LC3 through its LC3-binding motif 'YxxI', suggesting that MAVS might act as an autophagy receptor to mediate mitochondrial turnover upon excessive activation of RLR signalling. Furthermore, we provide evidence that both MAVS self-aggregation and its interaction with TRAF2/6 proteins are important for MAVS-mediated mitochondrial turnover. Collectively, our findings suggest that MAVS acts as a potential receptor for mitochondria-associated autophagic signalling to maintain mitochondrial homeostasis. PMID:27551434

  5. Consciousness, endogenous generation of goals and homeostasis

    Science.gov (United States)

    Tsitolovsky, Lev E.

    2015-08-01

    Behaviour can be both unpredictable and goal directed, as animals act in correspondence with their motivation. Motivation arises when neurons in specific brain areas leave the state of homeostatic equilibrium and are injured. The basic goal of organisms and living cells is to maintain their life and their functional state is optimal if it does not lead to physiological damage. This can somehow be sensed by neurons and the occurrence of damage elicits homeostatic protection to recover excitability and the ability to produces spikes. It can be argued that the neuron's activity is guided on the scale of "damage-protection" and it behaves as an object possessing minimum awareness. The approach of death increases cellular efforts to operate. Thus, homeostasis may evidently produce both maintenance of life and will. The question is - how does homeostasis reach the optimum? We have no possibility of determining how the cell evaluates its own states, e.g. as "too little free energy" or in terms of "threat" to life. In any case, the approach of death increases cellular efforts to operate. For the outside observer, this is reminiscent of intentional action and a manifestation of will.

  6. Brain glycogen and its role in supporting glutamate and GABA homeostasis in a type 2 diabetes rat model

    DEFF Research Database (Denmark)

    Sickmann, Helle Mark; Waagepetersen, Helle S.; Schousboe, Arne;

    2012-01-01

    diabetic state. Also, our objective was to elucidate the contribution of glycogen to support neurotransmitter glutamate and GABA homeostasis. A glycogen phosphorylase (GP) inhibitor was administered to Sprague-Dawley (SprD) and Zucker Diabetic Fatty (ZDF) rats in vivo and after one day of treatment [1......-(13)C]glucose was used to monitor metabolism. Brain levels of (13)C labeling in glucose, lactate, alanine, glutamate, GABA, glutamine and aspartate were determined. Our results show that inhibition of brain glycogen metabolism reduced the amounts of glutamate in both the control and type 2 diabetes......The number of people suffering from diabetes is hastily increasing and the condition is associated with altered brain glucose homeostasis. Brain glycogen is located in astrocytes and being a carbohydrate reservoir it contributes to glucose homeostasis. Furthermore, glycogen has been indicated to be...

  7. Hepatic iron overload following liver transplantation of a C282y homozygous allograft: a case report and literature review.

    LENUS (Irish Health Repository)

    Dwyer, Jeremy P

    2011-11-01

    Hereditary haemochromatosis is a common genetic disease associated with progressive iron overload and parenchymal organ damage including liver, pancreas and heart. We report a case of inadvertent transplantation of a liver from a haemochromatosis donor to a 56-year-old Asian female. Progressive iron overload occurred over a 2 year follow up as assessed by liver biopsy and iron studies in the absence of a secondary cause of iron overload, supporting a primary role of liver rather than small intestine in the regulation of iron homeostasis in hereditary haemochromatosis.

  8. Iron Sucrose Injection

    Science.gov (United States)

    Iron sucrose injection is used treat iron-deficiency anemia (a lower than normal number of red blood cells due ... may cause the kidneys to stop working). Iron sucrose injection is in a class of medications called ...

  9. Steam iron cleaner poisoning

    Science.gov (United States)

    ... cleaner is a substance used to clean steam irons. Poisoning occurs when someone swallows steam iron cleaner. This ... Below are symptoms of steam iron cleaner poisoning in different ... AND THROAT Severe pain in the throat Severe pain in the mouth ...

  10. Taking iron supplements

    Science.gov (United States)

    ... medlineplus.gov/ency/article/007478.htm Taking iron supplements To use the sharing features on this page, ... levels. You may also need to take iron supplements as well to rebuild iron stores in your ...

  11. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... refers to a condition in which your blood has a lower than normal number of red blood ... iron, your body starts using the iron it has stored. Soon, the stored iron gets used up. ...

  12. Tfp1 is required for ion homeostasis, fluconazole resistance and N-Acetylglucosamine utilization in Candida albicans.

    Science.gov (United States)

    Jia, Chang; Zhang, Kai; Yu, Qilin; Zhang, Bing; Xiao, Chenpeng; Dong, Yijie; Chen, Yulu; Zhang, Biao; Xing, Laijun; Li, Mingchun

    2015-10-01

    The vacuolar-type H+-ATPase (V-ATPase) is crucial for the maintenance of ion homeostasis. Dysregulation of ion homeostasis affects various aspects of cellular processes. However, the importance of V-ATPase in Candida albicans is not totally clear. In this study, we demonstrated the essential roles of V-ATPase through Tfp1, a putative V-ATPase subunit. Deletion of TFP1 led to generation of an iron starvation signal and reduced total iron content, which was associated with mislocalization of Fet34p that was finally due to disorders in copper homeostasis. Furthermore, the tfp1∆/∆ mutant exhibited weaker growth and lower aconitase activity on nonfermentable carbon sources, and iron or copper addition partially rescued the growth defect. In addition, the tfp1∆/∆ mutant also showed elevated cytosolic calcium levels in normal or low calcium medium that were relevant to calcium release from vacuole. Kinetics of cytosolic calcium response to an alkaline pulse and VCX1 (VCX1 encodes a putative vacuolar Ca2+/H+ exchanger) overexpression assays indicated that the cytosolic calcium status was in relation to Vcx1 activity. Spot assay and concentration-kill curve demonstrated that the tfp1∆/∆ mutant was hypersensitive to fluconazole, which was attributed to reduced ergosterol biosynthesis and CDR1 efflux pump activity, and iron/calcium dysregulation. Interestingly, carbon source utilization tests found the tfp1∆/∆ mutant was defective for growth on N-Acetylglucosamine (GlcNAc) plate, which was associated with ATP depletion due to the decreased ability to catabolize GlcNAc. Taken together, our study gives new insights into functions of Tfp1, and provides the potential to better exploit V-ATPase as an antifungal target.

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

    Directory of Open Access Journals (Sweden)

    Salvatore eBozzaro

    2013-09-01

    Full Text Available 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 defence 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

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

    Science.gov (United States)

    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.

  15. Affected chromosome homeostasis and genomic instability of clonal yeast cultures.

    Science.gov (United States)

    Adamczyk, Jagoda; Deregowska, Anna; Panek, Anita; Golec, Ewelina; Lewinska, Anna; Wnuk, Maciej

    2016-05-01

    Yeast cells originating from one single colony are considered genotypically and phenotypically identical. However, taking into account the cellular heterogeneity, it seems also important to monitor cell-to-cell variations within a clone population. In the present study, a comprehensive yeast karyotype screening was conducted using single chromosome comet assay. Chromosome-dependent and mutation-dependent changes in DNA (DNA with breaks or with abnormal replication intermediates) were studied using both single-gene deletion haploid mutants (bub1, bub2, mad1, tel1, rad1 and tor1) and diploid cells lacking one active gene of interest, namely BUB1/bub1, BUB2/bub2, MAD1/mad1, TEL1/tel1, RAD1/rad1 and TOR1/tor1 involved in the control of cell cycle progression, DNA repair and the regulation of longevity. Increased chromosome fragility and replication stress-mediated chromosome abnormalities were correlated with elevated incidence of genomic instability, namely aneuploid events-disomies, monosomies and to a lesser extent trisomies as judged by in situ comparative genomic hybridization (CGH). The tor1 longevity mutant with relatively balanced chromosome homeostasis was found the most genomically stable among analyzed mutants. During clonal yeast culture, spontaneously formed abnormal chromosome structures may stimulate changes in the ploidy state and, in turn, promote genomic heterogeneity. These alterations may be more accented in selected mutated genetic backgrounds, namely in yeast cells deficient in proper cell cycle regulation and DNA repair.

  16. Zeolite A effect on calcium homeostasis in growing goats.

    Science.gov (United States)

    Schwaller, D; Wilkens, M R; Liesegang, A

    2016-04-01

    The purpose of this study was to investigate the influence of 2 different concentrations of zeolite A on calcium homeostasis. Seventeen growing goats were divided into 3 groups. Whereas the control group (5 animals) received no supplementation, 2 treatment groups were supplemented with zeolite A at either 1.2 (6 animals) or 1.6 g/kg BW (6 animals), respectively. Blood and urine samples were continually drawn and bone mineral density was measured weekly by peripheral quantitative computed tomography. After 3 wks, the animals were slaughtered and samples were taken from the rumen, duodenum, and kidneys. Plasma concentrations of phosphate ( Ussing chamber technique and quantification of RNA and protein expression of genes known to be involved in active calcium absorption did not reveal any stimulating effect of zeolite. Plasma calcium concentrations were not altered, probably because of the sufficient dietary calcium supply. However due to the effects of zeolite on 1,25 dihydroxycholecalciferol, bone metabolism and serum concentrations of phosphate and magenesium shown in the present study, potential negative long-termin effects on the animals should be considered whenever rations with zeolite are designed. PMID:27136016

  17. Genetics Home Reference: iron-refractory iron deficiency anemia

    Science.gov (United States)

    ... refractory iron deficiency anemia iron-refractory iron deficiency anemia Enable Javascript to view the expand/collapse boxes. ... All Close All Description Iron-refractory iron deficiency anemia is one of many types of anemia , which ...

  18. Smectite alteration

    International Nuclear Information System (INIS)

    This report contains the proceedings of a second workshop in Washington DC December 8-9, 1983 on the alteration of smectites intended for use as buffer materials in the long-term containment of nuclear wastes. It includes extended summaries of all presentations and a transcript of the detailed scientific discussion. The discussions centered on three main questions: What is the prerequisite for and what is the precise mechanism by which smectite clays may be altered to illite. What are likly sources of potassium with respect to the KBS project. Is it likely that the conversion of smectite to illite will be of importance in the 10 5 to the 10 6 year time frame. The workshop was convened to review considerations and conclusions in connection to these questions and also to broaden the discussion to consider the use of smectite clays as buffer materials for similar applications in different geographical and geological settings. SKBF/KBS technical report 83-03 contains the proceedings from the first workshop on these matters that was held at the State University of New York, Buffalo May 26-27, 1982. (Author)

  19. Iron and stony-iron meteorites

    DEFF Research Database (Denmark)

    Benedix, Gretchen K.; Haack, Henning; McCoy, T. J.

    2014-01-01

    Without iron and stony-iron meteorites, our chances of ever sampling the deep interior of a differentiated planetary object would be next to nil. Although we live on a planet with a very substantial core, we will never be able to sample it. Fortunately, asteroid collisions provide us with a rich...... sampling of the deep interiors of differentiated asteroids. Iron and stony-iron meteorites are fragments of a large number of asteroids that underwent significant geological processing in the early solar system. Parent bodies of iron and some stony-iron meteorites completed a geological evolution similar...... to that continuing on Earth – although on much smaller length- and timescales – with melting of the metal and silicates; differentiation into core, mantle, and crust; and probably extensive volcanism. Iron and stony-iron meteorites are our only available analogues to materials found in the deep interiors of Earth...

  20. Environmental stresses disrupt telomere length homeostasis.

    Directory of Open Access Journals (Sweden)

    Gal Hagit Romano

    Full Text Available Telomeres protect the chromosome ends from degradation and play crucial roles in cellular aging and disease. Recent studies have additionally found a correlation between psychological stress, telomere length, and health outcome in humans. However, studies have not yet explored the causal relationship between stress and telomere length, or the molecular mechanisms underlying that relationship. Using yeast as a model organism, we show that stresses may have very different outcomes: alcohol and acetic acid elongate telomeres, whereas caffeine and high temperatures shorten telomeres. Additional treatments, such as oxidative stress, show no effect. By combining genome-wide expression measurements with a systematic genetic screen, we identify the Rap1/Rif1 pathway as the central mediator of the telomeric response to environmental signals. These results demonstrate that telomere length can be manipulated, and that a carefully regulated homeostasis may become markedly deregulated in opposing directions in response to different environmental cues.

  1. PACAP in the Defense of Energy Homeostasis.

    Science.gov (United States)

    Rudecki, Alexander P; Gray, Sarah L

    2016-09-01

    The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) mediates diverse physiology from neuroprotection to thermoregulation. PACAP is well established as a master regulator of the stress response, regulating psychological and physiological equilibrium via the autonomic nervous system. Neuroanatomical and functional evidence support a role for PACAP in energy metabolism, including thermogenesis, activity, mobilization of energy stores, and appetite. Through integration of this evidence we suggest PACAP be included in the growing list of neuropeptides that mediate energy homeostasis. Future work to uncover the intricacies of PACAP expression and the molecular pathways responsible for PACAP signaling may show potential for this neuropeptide as a therapeutic target as well as further elucidate the complex neuroanatomical networks involved in defending energy balance. PMID:27166671

  2. Interference between nanoparticles and metal homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Petit, A N; Catty, P; Charbonnier, P; Cuillel, M; Mintz, E; Moulis, J M; Niviere, V; Choudens, S Ollagnier de [Laboratoire de Chimie et Biologie des Metaux UMR 5249 CEA-CNRS-UJF, 17 rue des Martyrs, 38054 Grenoble Cedex 09 (France); Garcia, C Aude; Candeias, S; Chevallet, M; Collin-Faure, V; Lelong, C; Luche, S; Rabilloud, T [Laboratoire de Biochimie et Biophysique des Systemes Integres UMR 5092 CNRS-CEA-UJF, 17 rue des martyrs, 38054 Grenoble Cedex 09 (France); Casanova, A; Herlin-Boime, N [Laboratoire Edifices Nanometriques URA 2453 CEA-CNRS-IRAMIS, 91191 Gif-sur-Yvette (France); Douki, T; Ravanat, J L; Sauvaigo, S, E-mail: isabelle.michaud-soret@cea.fr [Laboratoire Lesions des Acides Nucleiques UMR E3 CEA-UJF, 17 rue des Martyrs, 38054 Grenoble Cedex 09 (France)

    2011-07-06

    The TiO{sub 2} nanoparticles (NPs) are now produced abundantly and widely used in a variety of consumer products. Due to the important increase in the production of TiO{sub 2}-NPs, potential widespread exposure of humans and environment may occur during both the manufacturing process and final use. Therefore, the potential toxicity of TiO{sub 2}-NPs on human health and environment has attracted particular attention. Unfortunately, the results of the large number of studies on the toxicity of TiO{sub 2}-NPs differ significantly, mainly due to an incomplete characterization of the used nanomaterials in terms of size, shape and crystalline structure and to their unknown state of agglomeration/aggregation. The purpose of our project entitled NanoBioMet is to investigate if interferences between nanoparticles and metal homeostasis could be observed and to study the toxicity mechanisms of TiO{sub 2}-NPs with well-characterized physicochemical parameters, using proteomic and molecular approaches. A perturbation of metal homeostasis will be evaluated upon TiO{sub 2}-NPs exposure which could generate reactive oxygen species (ROS) production. Moreover, oxidative stress consequences such as DNA damage and lipid peroxidation will be studied. The toxicity of TiO{sub 2}-NPs of different sizes and crystalline structures will be evaluated both in prokaryotic (E. coli) and eukaryotic cells (A549 human pneumocytes, macrophages, and hepatocytes). First results of the project will be presented concerning the dispersion of TiO{sub 2}-NPs in bacterial medium, proteomic studies on total extracts of macrophages and genotoxicity on pneumocytes.

  3. Serum PBDE levels in exposed rats in relation to effects on thyroxine homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Darnerud, P.O.; Aune, M.; Larsson, L.; Hallgren, S. [National Food Administration, Uppsala (Sweden)

    2004-09-15

    Brominated flame retardants (BFRs) is a group of environmental chemicals for which lately both interest and knowledge have increased considerably. Among the BFRs, the polybrominated diphenyl ethers (PBDEs) have attained special interest. Much data on environmental and human levels have been presented and several toxicological reviews are now published. Among interesting results is the difference in human PBDE levels that seem to exist between U.S.A. and Europe, results that suggest differences in exposure but without being able to pin-point the exact sources. In experimental studies PBDEs alter serum thyroxin levels, an effect seen both in rats and in mice. The mechanism(s) are still not completely clarified, but are thought to include alterations in serum transport, induced enzymatic degradation and possibly also direct effects on the thyroid gland. As perinatal alterations in thyroid homeostasis could affect brain development, early effects on thyroid hormones may be of special concern. Indeed, PBDEs have been shown to affect behaviour and learning in mice, when given neonatally. The aim of the present study was to relate the serum levels of PBDEs in rats to effects of these compounds on thyroxine homeostasis in these animals. Specifically, the relation between serum PBDE levels and effects on serum thyroxine levels was investigated, after two weeks of daily oral exposure. The result may have consequences for the future risk assessment activities on PBDE and specifically in finding the critical serum PBDE concentration at which the effect on thyroid hormone levels begin to occur.

  4. Iron from Zealandic bog iron ore -

    DEFF Research Database (Denmark)

    Lyngstrøm, Henriette Syrach

    2011-01-01

    og geologiske materiale, metallurgiske analyser og eksperimentel arkæologiske forsøg - konturerne af en jernproduktion med udgangspunkt i den sjællandske myremalm. The frequent application by archaeologists of Werner Christensen’s distribution map for the occurrence of bog iron ore in Denmark (1966...... are sketched of iron production based on bog iron ore from Zealand....

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

    Science.gov (United States)

    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.

  6. Impaired Bile Acid Homeostasis in Children with Severe Acute Malnutrition.

    Directory of Open Access Journals (Sweden)

    Ling Zhang

    Full Text Available Severe acute malnutrition (SAM is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work was to investigate whether SAM is associated with clinically relevant changes in bile acid homeostasis.An initial discovery cohort with 5 healthy controls and 22 SAM-patients was used to identify altered bile acid homeostasis. A follow up cohort of 40 SAM-patients were then studied on admission and 3 days after clinical stabilization to assess recovery in bile acid metabolism. Recruited children were 6-60 months old and admitted for SAM in Malawi. Clinical characteristics, feces and blood were collected on admission and prior to discharge. Bile acids, 7α-hydroxy-4-cholesten-3-one (C4 and FGF-19 were quantified.On admission, total serum bile acids were higher in children with SAM than in healthy controls and glycine-conjugates accounted for most of this accumulation with median and interquartile range (IQR of 24.6 μmol/L [8.6-47.7] compared to 1.9 μmol/L [1.7-3.3] (p = 0.01 in controls. Total serum bile acid concentrations did not decrease prior to discharge. On admission, fecal conjugated bile acids were lower and secondary bile acids higher at admission compared to pre- discharge, suggesting increased bacterial conversion. FGF19 (Fibroblast growth factor 19, a marker of intestinal bile acid signaling, was higher on admission and was associated with decreased C4 concentrations as a marker of bile acid synthesis. Upon recovery, fecal calprotectin, a marker of intestinal inflammation, was lower.SAM is associated with increased serum bile acid levels despite reduced synthesis rates. In SAM, there tends to be increased deconjugation of bile acids and conversion from primary to secondary bile acids, which may contribute to the development of liver disease.

  7. Helicobacter pylori and CagA under conditions of iron deficiency.

    Science.gov (United States)

    Noto, Jennifer M; Peek, Richard M

    2015-01-01

    Iron deficiency is the most common nutritional deficiency worldwide and compelling evidence has demonstrated that this condition heightens the risk of gastric cancer. Infection with Helicobacter pylori is the strongest known risk factor for the development of gastric adenocarcinoma. Recent work has demonstrated that, under conditions of iron deficiency, H. pylori-induced gastric carcinogenesis is augmented through increased formation of the strain-specific cag type IV secretion system and enhanced delivery of the bacterial oncoprotein CagA into host cells. Although CagA is a potent virulence factor that promotes oncogenic responses, additional studies have now demonstrated that CagA modulates host cell iron homeostasis in vitro and fundamental metabolic functions of the bacterial cell in vivo. Here we discuss these findings and describe working models by which CagA exerts its effects on gastric epithelial cells, with particular emphasis on its potential role in modulation of host iron homeostasis.

  8. IL-4 and TGF-β1 Counterbalance One Another while Regulating Mast Cell Homeostasis

    OpenAIRE

    Macey, Matthew R.; Sturgill, Jamie L.; Morales, Johanna K.; Falanga, Yves T.; Morales, Joshua; Norton, Sarah K.; Yerram, Nitin; Shim, Hoon; Fernando, Josephine; Gifillan, Alasdair M.; Gomez, Gregorio; Schwartz, Lawrence; Oskeritzian, Carole; Spiegel, Sarah; Conrad, Daniel

    2010-01-01

    Mast cell responses can be altered by cytokines, including those secreted by Th2 and regulatory T cells (Treg). Given the important role of mast cells in Th2-mediated inflammation and recent demonstrations of Treg-mast cell interactions, we examined the ability of IL-4 and TGF-β1 to regulate mast cell homeostasis. Using in vitro and in vivo studies of mouse and human mast cells, we demonstrate that IL-4 suppresses TGF-β1 receptor expression and signaling, and vice versa. In vitro studies demo...

  9. Iceland as a Model for Chemical Alteration on Mars

    Science.gov (United States)

    Bishop, Janice L.; Schiffman, P.; Murad, E.; Southard, R.; DeVincenzi, Donald L. (Technical Monitor)

    2001-01-01

    Subglacial volcanic activity on Iceland has led to the formation of a variety of silicate and iron oxide-rich alteration products that may serve as a model for chemical alteration on Mars. Multiple palagonitic tuffs, altered pillow lavas, hydrothermal springs and alteration at glacial run-off streams were observed during a recent field trip in Iceland. Formation of alteration products and ferrihydrite in similar environments on Mars may have contributed to the ferric oxide-rich surface material there. The spectral and chemical properties of Icelandic alteration products and ferrihydrites are presented here.

  10. Hydrothermal Mobilization and Enrichment of Iron in the Iron Deposits of the Middle—Lower Yangtze Valley District

    Institute of Scientific and Technical Information of China (English)

    顾连兴; 阮惠础

    1993-01-01

    There are two main types of iron deposits in the Middle-Lower Yangtze Valley district.Both of them underwent post-magmatic hydrothermal processes during ore formation.Iron in the hydrothermal ore bodies was derived largely through mobilization from substantially consolidated diroitic intrusives.Wall-roch alteration zonation indicates that iron-mobilizing hydrothermal fluids evolved in a trend of decreasing alkalinity,which is suggested by regularly distributed wall-rock alterations formed by iron-mobilizing hydrothermal fluids and is in contradiction with the current chloride,chloride complex and bicarbonate models for iron mobilization.The close association of carbonatization with iron ores and the high concentrations of reduced gases such as CO,CH4 and H2 in fluid inclusions suggest that iron is most probably transported in the form of iron carbonyls during post-magmatic hydrothermal processes. In the light of the iron carbonyl mobilization model,explanations are made of the constraints on ores of some geologic factors such as melanocratic alteration,carbonatization,carbonate strata,structural fractures,cyptoexplosive pipes and embryo ores.

  11. Staphylococcus aureus redirects central metabolism to increase iron availability.

    Directory of Open Access Journals (Sweden)

    David B Friedman

    2006-08-01

    Full Text Available Staphylococcus aureus pathogenesis is significantly influenced by the iron status of the host. However, the regulatory impact of host iron sources on S. aureus gene expression remains unknown. In this study, we combine multivariable difference gel electrophoresis and mass spectrometry with multivariate statistical analyses to systematically cluster cellular protein response across distinct iron-exposure conditions. Quadruplicate samples were simultaneously analyzed for alterations in protein abundance and/or post-translational modification state in response to environmental (iron chelation, hemin treatment or genetic (Deltafur alterations in bacterial iron exposure. We identified 120 proteins representing several coordinated biochemical pathways that are affected by changes in iron-exposure status. Highlighted in these experiments is the identification of the heme-regulated transport system (HrtAB, a novel transport system which plays a critical role in staphylococcal heme metabolism. Further, we show that regulated overproduction of acidic end-products brought on by iron starvation decreases local pH resulting in the release of iron from the host iron-sequestering protein transferrin. These findings reveal novel strategies used by S. aureus to acquire scarce nutrients in the hostile host environment and begin to define the iron and heme-dependent regulons of S. aureus.

  12. The immune system, natural autoantibodies and general homeostasis in health and disease.

    Science.gov (United States)

    Poletaev, A; Boura, P

    2011-10-01

    It is generally accepted that the destination of the immune system is not only to discriminate between self and non-self but also to mount responses against non-self. During the last decades, it became evident that weak self-reactivity is a necessary condition for immune homeostasis. Natural self reactivity and the internal image created by autoantibodies, participate greatly to the maintenance of homeostasis. Under conditions of increased or altered antigenic pressure, the homeostatic status is disrupted and the organism becomes vulnerable to the emergence of diseases. "Immunculus" is the self-reactive and interconnected entity of the immune system, provided by a complicated network of natural autoantibobies of different specificity, as a mosaic picture. Quantitative changes in each part of the image are related to variations of expression of relative antigens. The immune system takes in account image information from the continuous screening of the antigenic status and compares between presented state and the desired (optimal) one. Substantial and prolonged deviations from the optimal state, triggers the induction of compensatory and reparative processes, aiming to restore molecular and functional homeostasis. So, natural autoimmunity through the ability of natural a-Abs to induce mechanisms of natural and acquired immunity, aims to prevent pathogenic processes and maintain or restore health status. PMID:24391407

  13. Zinc and Copper Homeostasis in Head and Neck Cancer: Review and Meta-Analysis.

    Science.gov (United States)

    Ressnerova, Alzbeta; Raudenska, Martina; Holubova, Monika; Svobodova, Marketa; Polanska, Hana; Babula, Petr; Masarik, Michal; Gumulec, Jaromir

    2016-01-01

    Metals are known for playing essential roles in human physiology. Copper and zinc are trace elements closely dependent on one another and are involved in cell proliferation, growth, gene expression, apoptosis and other processes. Their homeostasis is crucial and tightly controlled by a resourceful system of transporters and transport proteins which deliver copper and zinc ions to their target sites. Abnormal zinc and copper homeostasis can be seen in a number of malignancies and also in head and neck cancer. Imbalance in this homeostasis is observed as an elevation or decrease of copper and zinc ions in serum or tissue levels in patients with cancer. In head and neck cancer these altered levels stand out from those of other malignancies which makes them an object of interest and therefore zinc and copper ions might be a good target for further research of head and neck cancer development and progression. This review aims to summarize the physiological roles of copper and zinc, its binding and transport mechanisms, and based on those, its role in head and neck cancer. To provide stronger evidence, dysregulation of levels is analysed by a meta-analytical approach.

  14. Nutritional iron deficiency

    NARCIS (Netherlands)

    Zimmermann, M.B.; Hurrell, R.F.

    2007-01-01

    Iron deficiency is one of the leading risk factors for disability and death worldwide, affecting an estimated 2 billion people. Nutritional iron deficiency arises when physiological requirements cannot be met by iron absorption from diet. Dietary iron bioavailability is low in populations consuming

  15. Special thermite cast irons

    OpenAIRE

    Yu. Zhiguts; I. Kurytnik

    2008-01-01

    The given paper deals with the problems of the synthesis of cast iron by metallothermy synthesis. On the basis of investigated method of calculations structures of charges have been arranged and cast iron has been synthesized further. Peculiarities metallothermic smelting were found, mechanical properties and structure of received cast iron were investigated and different technologies for cast iron receiving were worked out.

  16. Mechanosensitive subcellular rheostasis drives emergent single-cell mechanical homeostasis

    Science.gov (United States)

    Weng, Shinuo; Shao, Yue; Chen, Weiqiang; Fu, Jianping

    2016-09-01

    Mechanical homeostasis--a fundamental process by which cells maintain stable states under environmental perturbations--is regulated by two subcellular mechanotransducers: cytoskeleton tension and integrin-mediated focal adhesions (FAs). Here, we show that single-cell mechanical homeostasis is collectively driven by the distinct, graduated dynamics (rheostasis) of subcellular cytoskeleton tension and FAs. Such rheostasis involves a mechanosensitive pattern wherein ground states of cytoskeleton tension and FA determine their distinct reactive paths through either relaxation or reinforcement. Pharmacological perturbations of the cytoskeleton and molecularly modulated integrin catch-slip bonds biased the rheostasis and induced non-homeostasis of FAs, but not of cytoskeleton tension, suggesting a unique sensitivity of FAs in regulating homeostasis. Theoretical modelling revealed myosin-mediated cytoskeleton contractility and catch-slip-bond-like behaviours in FAs and the cytoskeleton as sufficient and necessary mechanisms for quantitatively recapitulating mechanosensitive rheostasis. Our findings highlight the previously underappreciated physical nature of the mechanical homeostasis of cells.

  17. A conceptual framework for homeostasis: development and validation.

    Science.gov (United States)

    McFarland, Jenny; Wenderoth, Mary Pat; Michael, Joel; Cliff, William; Wright, Ann; Modell, Harold

    2016-06-01

    We have developed and validated a conceptual framework for understanding and teaching organismal homeostasis at the undergraduate level. The resulting homeostasis conceptual framework details critical components and constituent ideas underlying the concept of homeostasis. It has been validated by a broad range of physiology faculty members from community colleges, primarily undergraduate institutions, research universities, and medical schools. In online surveys, faculty members confirmed the relevance of each item in the framework for undergraduate physiology and rated the importance and difficulty of each. The homeostasis conceptual framework was constructed as a guide for teaching and learning of this critical core concept in physiology, and it also paves the way for the development of a concept inventory for homeostasis. PMID:27105740

  18. Targeting iron assimilation to develop new antibacterials

    Science.gov (United States)

    Foley, Timothy L.; Simeonov, Anton

    2012-01-01

    Introduction Since the first application of antibiotics to treat bacterial infections, the development and spread of resistance has been a persistent threat. An ever-evolving pipeline of next-generation therapeutics is required for modern medicine to remain one step ahead of pathogens. Areas covered in this review This review describes recent efforts to develop drugs that interrupt the assimilation of iron by bacteria, a process that is vital to cellular homeostasis and is not currently targeted by antibiotics used in the clinic. We cover the mechanisms through which bacteria acquire iron for their environment and detail efforts to intervene in these processes with small molecule inhibitors that target key steps in these pathways, with a special emphasis on recent advances published during the 2010–2012 period. Expert Opinion For decades, the routes used by bacteria to assimilate iron from host and environmental settings have been the subject of intense study. While numerous investigations have identified inhibitors of these pathways, many have stopped short of translating the in vitro results to in vivo proof of concept experiments. Extension of preliminary findings in this manner to validate the clinical potential of iron assimilation pathways for therapeutic development will significantly increase the impact of the field. PMID:22812521

  19. O-GlcNAcase expression is sensitive to changes in O-GlcNAc homeostasis

    Directory of Open Access Journals (Sweden)

    ZHEN eZHANG

    2014-12-01

    Full Text Available O-linked N-acetylglucosamine (O-GlcNAc is a post-translational modification involving an attachment of a single β-N-acetylglucosamine moiety to serine or threonine residues in nuclear and cytoplasmic proteins. Cellular O-GlcNAc levels are regulated by two enzymes: O-GlcNAc transferase (OGT and O-GlcNAcase (OGA, which add and remove the modification respectively. The levels of O-GlcNAc can rapidly change in response to fluctuations in the extracellular environment; however, O-GlcNAcylation returns to a baseline level quickly after stimulus removal. This process termed O-GlcNAc homeostasis appears to be critical to the regulation of many cellular functions including cell cycle progress, stress response, and gene transcription. Disruptions in O-GlcNAc homeostasis are proposed to lead to the development of diseases such as cancer, diabetes, and Alzheimer’s disease. O-GlcNAc homeostasis is correlated with the expression of OGT and OGA. We reason that alterations in O-GlcNAc levels affect OGA and OGT transcription. We treated several human cell lines with Thiamet-G (TMG, an OGA inhibitor to increase overall O-GlcNAc levels resulting in decreased OGT protein expression and increased OGA protein expression. OGT transcript levels slightly declined with TMG treatment, but OGA transcript levels were significantly increased. Pretreating cells with protein translation inhibitor cycloheximide (CHX did not stabilize OGT or OGA protein expression in the presence of TMG; nor did TMG stabilize OGT and OGA mRNA levels when cells were treated with RNA transcription inhibitor actinomycin D (AMD. Finally, we performed RNA Polymerase II chromatin immunoprecipitation (ChIP at the OGA promoter and found RNA Pol II occupancy at the transcription start site (TSS was lower after prolonged TMG treatment. Together, these data suggest that OGA transcription was sensitive to changes in O-GlcNAc homeostasis and was potentially regulated by O-GlcNAc.

  20. Breast milk, microbiota, and intestinal immune homeostasis.

    Science.gov (United States)

    Walker, W Allan; Iyengar, Rajashri Shuba

    2015-01-01

    Newborns adjust to the extrauterine environment by developing intestinal immune homeostasis. Appropriate initial bacterial colonization is necessary for adequate intestinal immune development. An environmental determinant of adequate colonization is breast milk. Although the full-term infant is developmentally capable of mounting an immune response, the effector immune component requires bacterial stimulation. Breast milk stimulates the proliferation of a well-balanced and diverse microbiota, which initially influences a switch from an intrauterine TH2 predominant to a TH1/TH2 balanced response and with activation of T-regulatory cells by breast milk-stimulated specific organisms (Bifidobacteria, Lactobacillus, and Bacteroides). As an example of its effect, oligosaccharides in breast milk are fermented by colonic bacteria producing an acid milieu for bacterial proliferation. In addition, short-chain fatty acids in breast milk activate receptors on T-reg cells and bacterial genes, which preferentially mediate intestinal tight junction expression and anti-inflammation. Other components of breast milk (defensins, lactoferrin, etc.) inhibit pathogens and further contribute to microbiota composition. The breast milk influence on initial intestinal microbiota also prevents expression of immune-mediated diseases (asthma, inflammatory bowel disease, type 1 diabetes) later in life through a balanced initial immune response, underscoring the necessity of breastfeeding as the first source of nutrition. PMID:25310762

  1. DYSREGULATION OF ION HOMEOSTASIS BY ANTIFUNGAL AGENTS

    Directory of Open Access Journals (Sweden)

    Yongqiang eZhang

    2012-04-01

    Full Text Available Ion signaling and transduction networks are central to fungal development and virulence because they regulate gene expression, filamentation, host association and invasion, pathogen stress response and survival. Dysregulation of ion homeostasis rapidly mediates cell death, forming the mechanistic basis by which a growing number of amphipathic but structurally unrelated compounds elicit antifungal activity. Included in this group is carvacrol, a terpenoid phenol that is a prominent component of oregano and other plant essential oils. Carvacrol triggers an early dose dependent Ca2+ burst and long lasting pH changes in the model yeast S. cerevisiae. The distinct phases of ionic transients and a robust transcriptional response that overlaps with Ca2+ stress and nutrient starvation point to specific signaling events elicited by plant terpenoid phenols, rather than a non-specific lesion of the membrane as was previously considered. We discuss the potential use of plant essential oils and other agents that disrupt ion signaling pathways as chemosensitizers to augment conventional antifungal therapy, and to convert fungistatic drugs with strong safety profiles into fungicides.

  2. Cellular Auxin Homeostasis:Gatekeeping Is Housekeeping

    Institute of Scientific and Technical Information of China (English)

    Michel Ruiz Rosquete; Elke Barbez; Jürgen Kleine-Vehn

    2012-01-01

    The phytohormone auxin is essential for plant development and contributes to nearly every aspect of the plant life cycle.The spatio-temporal distribution of auxin depends on a complex interplay between auxin metabolism and cell-to-cell auxin transport.Auxin metabolism and transport are both crucial for plant development;however,it largely remains to be seen how these processes are integrated to ensure defined cellular auxin levels or even gradients within tissues or organs.In this review,we provide a glance at very diverse topics of auxin biology,such as biosynthesis,conjugation,oxidation,and transport of auxin.This broad,but certainly superficial,overview highlights the mutual importance of auxin metabolism and transport.Moreover,it allows pinpointing how auxin metabolism and transport get integrated to jointly regulate cellular auxin homeostasis.Even though these processes have been so far only separately studied,we assume that the phytohormonal crosstalk integrates and coordinates auxin metabolism and transport.Besides the integrative power of the global hormone signaling,we additionally introduce the hypothetical concept considering auxin transport components as gatekeepers for auxin responses.

  3. Snx3 regulates recycling of the transferrin receptor and iron assimilation.

    Science.gov (United States)

    Chen, Caiyong; Garcia-Santos, Daniel; Ishikawa, Yuichi; Seguin, Alexandra; Li, Liangtao; Fegan, Katherine H; Hildick-Smith, Gordon J; Shah, Dhvanit I; Cooney, Jeffrey D; Chen, Wen; King, Matthew J; Yien, Yvette Y; Schultz, Iman J; Anderson, Heidi; Dalton, Arthur J; Freedman, Matthew L; Kingsley, Paul D; Palis, James; Hattangadi, Shilpa M; Lodish, Harvey F; Ward, Diane M; Kaplan, Jerry; Maeda, Takahiro; Ponka, Prem; Paw, Barry H

    2013-03-01

    Sorting of endocytic ligands and receptors is critical for diverse cellular processes. The physiological significance of endosomal sorting proteins in vertebrates, however, remains largely unknown. Here we report that sorting nexin 3 (Snx3) facilitates the recycling of transferrin receptor (Tfrc) and thus is required for the proper delivery of iron to erythroid progenitors. Snx3 is highly expressed in vertebrate hematopoietic tissues. Silencing of Snx3 results in anemia and hemoglobin defects in vertebrates due to impaired transferrin (Tf)-mediated iron uptake and its accumulation in early endosomes. This impaired iron assimilation can be complemented with non-Tf iron chelates. We show that Snx3 and Vps35, a component of the retromer, interact with Tfrc to sort it to the recycling endosomes. Our findings uncover a role of Snx3 in regulating Tfrc recycling, iron homeostasis, and erythropoiesis. Thus, the identification of Snx3 provides a genetic tool for exploring erythropoiesis and disorders of iron metabolism.

  4. Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice.

    Science.gov (United States)

    Viatte, Lydie; Lesbordes-Brion, Jeanne-Claire; Lou, Dan-Qing; Bennoun, Myriam; Nicolas, Gaël; Kahn, Axel; Canonne-Hergaux, François; Vaulont, Sophie

    2005-06-15

    Evidence is accumulating that hepcidin, a liver regulatory peptide, could be the common pathogenetic denominator of all forms of iron overload syndromes including HFE-related hemochromatosis, the most prevalent genetic disorder characterized by inappropriate iron absorption. To understand the mechanisms whereby hepcidin controls iron homeostasis in vivo, we have analyzed the level of iron-related proteins by Western blot and immunohistochemistry in hepcidin-deficient mice, a mouse model of severe hemochromatosis. These mice showed important increased levels of duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), and ferroportin compared with control mice. Interestingly, the level of ferroportin was coordinately up-regulated in the duodenum, the spleen, and the liver (predominantly in the Kupffer cells). Finally, we also evidenced a decrease of ceruloplasmin in the liver of hepcidin-deficient mice. We hypothesized that the deregulation of these proteins might be central in the pathogenesis of iron overload, providing key therapeutic targets for iron disorders. PMID:15713792

  5. Scavenging iron: a novel mechanism of plant immunity activation by microbial siderophores.

    Science.gov (United States)

    Aznar, Aude; Chen, Nicolas W G; Rigault, Martine; Riache, Nassima; Joseph, Delphine; Desmaële, Didier; Mouille, Grégory; Boutet, Stéphanie; Soubigou-Taconnat, Ludivine; Renou, Jean-Pierre; Thomine, Sébastien; Expert, Dominique; Dellagi, Alia

    2014-04-01

    Siderophores are specific ferric iron chelators synthesized by virtually all microorganisms in response to iron deficiency. We have previously shown that they promote infection by the phytopathogenic enterobacteria Dickeya dadantii and Erwinia amylovora. Siderophores also have the ability to activate plant immunity. We have used complete Arabidopsis transcriptome microarrays to investigate the global transcriptional modifications in roots and leaves of Arabidopsis (Arabidopsis thaliana) plants after leaf treatment with the siderophore deferrioxamine (DFO). Physiological relevance of these transcriptional modifications was validated experimentally. Immunity and heavy-metal homeostasis were the major processes affected by DFO. These two physiological responses could be activated by a synthetic iron chelator ethylenediamine-di(o-hydroxyphenylacetic) acid, indicating that siderophores eliciting activities rely on their strong iron-chelating capacity. DFO was able to protect Arabidopsis against the pathogenic bacterium Pseudomonas syringae pv tomato DC3000. Siderophore treatment caused local modifications of iron distribution in leaf cells visible by ferrocyanide and diaminobenzidine-H₂O₂ staining. Metal quantifications showed that DFO causes a transient iron and zinc uptake at the root level, which is presumably mediated by the metal transporter iron regulated transporter1 (IRT1). Defense gene expression and callose deposition in response to DFO were compromised in an irt1 mutant. Consistently, plant susceptibility to D. dadantii was increased in the irt1 mutant. Our work shows that iron scavenging is a unique mechanism of immunity activation in plants. It highlights the strong relationship between heavy-metal homeostasis and immunity. PMID:24501001

  6. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation.

    Science.gov (United States)

    Nicolas, Gaël; Chauvet, Caroline; Viatte, Lydie; Danan, Jean Louis; Bigard, Xavier; Devaux, Isabelle; Beaumont, Carole; Kahn, Axel; Vaulont, Sophie

    2002-10-01

    The present study was aimed at determining whether hepcidin, a recently identified peptide involved in iron metabolism, plays a role in conditions associated with both iron overload and iron deficiency. Hepcidin mRNA levels were assessed in two models of anemia, acute hemolysis provoked by phenylhydrazine and bleeding provoked by repeated phlebotomies. Hepcidin response to hypoxia was also studied, both ex vivo, in human hepatoma cells, and in vivo. Anemia and hypoxia were associated with a dramatic decrease in liver hepcidin gene expression, which may account for the increase in iron release from reticuloendothelial cells and increase in iron absorption frequently observed in these situations. A single injection of turpentine for 16 hours induced a sixfold increase in liver hepcidin mRNA levels and a twofold decrease in serum iron. The hyposideremic effect of turpentine was completely blunted in hepcidin-deficient mice, revealing hepcidin participation in anemia of inflammatory states. These modifications of hepcidin gene expression further suggest a key role for hepcidin in iron homeostasis under various pathophysiological conditions, which may support the pharmaceutical use of hepcidin agonists and antagonists in various iron homeostasis disorders. PMID:12370282

  7. Investigating the role of two iron-regulated small RNAs of Pseudomonas syringae

    Science.gov (United States)

    Small RNAs (sRNAs) have emerged as important components of many regulatory pathways and have been shown to have key roles in the regulation of iron homeostasis in a number of bacteria. To date, only a few sRNAs have been described for the bacterial plant pathogen Pseudomonas syringae pathovar tomat...

  8. Molecular responses of ceruloplasmin to Edwardsiella ictaluri infection and iron overload in channel catfish (Ictalurus punctatus)

    Science.gov (United States)

    Ceruloplasmin is a serum ferroxidase that carries more than 90% of the copper in plasma and has documented roles in iron homeostasis as well as antioxidative functions. In our previous studies, it has been shown that the ceruloplasmin gene is strongly up-regulated in catfish during challenge with Ed...

  9. The Role of Copper Chaperone Atox1 in Coupling Redox Homeostasis to Intracellular Copper Distribution

    Science.gov (United States)

    Hatori, Yuta; Lutsenko, Svetlana

    2016-01-01

    Human antioxidant protein 1 (Atox1) is a small cytosolic protein with an essential role in copper homeostasis. Atox1 functions as a copper carrier facilitating copper transfer to the secretory pathway. This process is required for activation of copper dependent enzymes involved in neurotransmitter biosynthesis, iron efflux, neovascularization, wound healing, and regulation of blood pressure. Recently, new cellular roles for Atox1 have emerged. Changing levels of Atox1 were shown to modulate response to cancer therapies, contribute to inflammatory response, and protect cells against various oxidative stresses. It has also become apparent that the activity of Atox1 is tightly linked to the cellular redox status. In this review, we summarize biochemical information related to a dual role of Atox1 as a copper chaperone and an antioxidant. We discuss how these two activities could be linked and contribute to establishing the intracellular copper balance and functional identity of cells during differentiation. PMID:27472369

  10. Iron Metabolism Regulates p53 Signaling through Direct Heme-p53 Interaction and Modulation of p53 Localization, Stability, and Function

    Directory of Open Access Journals (Sweden)

    Jia Shen

    2014-04-01

    Full Text Available Iron excess is closely associated with tumorigenesis in multiple types of human cancers, with underlying mechanisms yet unclear. Recently, iron deprivation has emerged as a major strategy for chemotherapy, but it exerts tumor suppression only on select human malignancies. Here, we report that the tumor suppressor protein p53 is downregulated during iron excess. Strikingly, the iron polyporphyrin heme binds to p53 protein, interferes with p53-DNA interactions, and triggers both nuclear export and cytosolic degradation of p53. Moreover, in a tumorigenicity assay, iron deprivation suppressed wild-type p53-dependent tumor growth, suggesting that upregulation of wild-type p53 signaling underlies the selective efficacy of iron deprivation. Our findings thus identify a direct link between iron/heme homeostasis and the regulation of p53 signaling, which not only provides mechanistic insights into iron-excess-associated tumorigenesis but may also help predict and improve outcomes in iron-deprivation-based chemotherapy.

  11. Anti-CD25 monoclonal antibody Fc variants differentially impact regulatory T cells and immune homeostasis.

    Science.gov (United States)

    Huss, David J; Pellerin, Alex F; Collette, Brian P; Kannan, Arun K; Peng, Liaomin; Datta, Abhishek; Wipke, Brian T; Fontenot, Jason D

    2016-07-01

    Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its non-redundant role in regulatory T (Treg) cell biology. There is major interest in therapeutic modulation of the IL-2 pathway to promote immune activation in the context of tumour immunotherapy or to enhance immune suppression in the context of transplantation, autoimmunity and inflammatory diseases. Antibody-mediated targeting of the high-affinity IL-2 receptor α chain (IL-2Rα or CD25) offers a direct mechanism to target IL-2 biology and is being actively explored in the clinic. In mouse models, the rat anti-mouse CD25 clone PC61 has been used extensively to investigate the biology of IL-2 and Treg cells; however, there has been controversy and conflicting data on the exact in vivo mechanistic function of PC61. Engineering antibodies to alter Fc/Fc receptor interactions can significantly alter their in vivo function. In this study, we re-engineered the heavy chain constant region of an anti-CD25 monoclonal antibody to generate variants with highly divergent Fc effector function. Using these anti-CD25 Fc variants in multiple mouse models, we investigated the in vivo impact of CD25 blockade versus depletion of CD25(+) Treg cells on immune homeostasis. We report that immune homeostasis can be maintained during CD25 blockade but aberrant T-cell activation prevails when CD25(+) Treg cells are actively depleted. These results clarify the impact of PC61 on Treg cell biology and reveal an important distinction between CD25 blockade and depletion of CD25(+) Treg cells. These findings should inform therapeutic manipulation of the IL-2 pathway by targeting the high-affinity IL-2R. PMID:27012310

  12. Lack of glucagon receptor signaling and its implications beyond glucose homeostasis.

    Science.gov (United States)

    Charron, Maureen J; Vuguin, Patricia M

    2015-03-01

    Glucagon action is transduced by a G protein-coupled receptor located in liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart, pancreatic β-cells, and placenta. Genetically modified animal models have provided important clues about the role of glucagon and its receptor (Gcgr) beyond glucose control. The PubMed database was searched for articles published between 1995 and 2014 using the key terms glucagon, glucagon receptor, signaling, and animal models. Lack of Gcgr signaling has been associated with: i) hypoglycemic pregnancies, altered placentation, poor fetal growth, and increased fetal-neonatal death; ii) pancreatic glucagon cell hyperplasia and hyperglucagonemia; iii) altered body composition, energy state, and protection from diet-induced obesity; iv) impaired hepatocyte survival; v) altered glucose, lipid, and hormonal milieu; vi) altered metabolic response to prolonged fasting and exercise; vii) reduced gastric emptying and increased intestinal length; viii) altered retinal function; and ix) prevention of the development of diabetes in insulin-deficient mice. Similar phenotypic findings were observed in the hepatocyte-specific deletion of Gcgr. Glucagon action has been involved in the modulation of sweet taste responsiveness, inotropic and chronotropic effects in the heart, satiety, glomerular filtration rate, secretion of insulin, cortisol, ghrelin, GH, glucagon, and somatostatin, and hypothalamic signaling to suppress hepatic glucose production. Glucagon (α) cells under certain conditions can transdifferentiate into insulin (β) cells. These findings suggest that glucagon signaling plays an important role in multiple organs. Thus, treatment options designed to block Gcgr activation in diabetics may have implications beyond glucose homeostasis.

  13. Early Iron Deficiency Has Brain and Behavior Effects Consistent with Dopaminergic Dysfunction123

    OpenAIRE

    Lozoff, Betsy

    2011-01-01

    To honor the late John Beard’s many contributions regarding iron and dopamine biology, this review focuses on recent human studies that test specific hypotheses about effects of early iron deficiency on dopamine system functioning. Short- and long-term alterations associated with iron deficiency in infancy can be related to major dopamine pathways (mesocortical, mesolimbic, nigrostriatal, tuberohypophyseal). Children and young adults who had iron deficiency anemia in infancy show poorer inhib...

  14. Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure.

    Science.gov (United States)

    Liakath-Ali, Kifayathullah; Vancollie, Valerie E; Lelliott, Christopher J; Speak, Anneliese O; Lafont, David; Protheroe, Hayley J; Ingvorsen, Camilla; Galli, Antonella; Green, Angela; Gleeson, Diane; Ryder, Ed; Glover, Leanne; Vizcay-Barrena, Gema; Karp, Natasha A; Arends, Mark J; Brenn, Thomas; Spiegel, Sarah; Adams, David J; Watt, Fiona M; van der Weyden, Louise

    2016-07-01

    The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1-deficient (Acer1(-/-) ) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1(-/-) mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1(-/-) skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1(-/-) mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole-body energy homeostasis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID:27126290

  15. Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure.

    Science.gov (United States)

    Liakath-Ali, Kifayathullah; Vancollie, Valerie E; Lelliott, Christopher J; Speak, Anneliese O; Lafont, David; Protheroe, Hayley J; Ingvorsen, Camilla; Galli, Antonella; Green, Angela; Gleeson, Diane; Ryder, Ed; Glover, Leanne; Vizcay-Barrena, Gema; Karp, Natasha A; Arends, Mark J; Brenn, Thomas; Spiegel, Sarah; Adams, David J; Watt, Fiona M; van der Weyden, Louise

    2016-07-01

    The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1-deficient (Acer1(-/-) ) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1(-/-) mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1(-/-) skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1(-/-) mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole-body energy homeostasis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

  16. Caffeine and glucose homeostasis during rest and exercise in diabetes mellitus.

    Science.gov (United States)

    Zaharieva, Dessi P; Riddell, Michael C

    2013-08-01

    Caffeine is a substance that has been used in our society for generations, primarily for its effects on the central nervous system that causes wakefulness. Caffeine supplementation has become increasingly more popular as an ergogenic aid for athletes and considerable scientific evidence supports its effectiveness. Because of their potential to alter energy metabolism, the effects of coffee and caffeine on glucose metabolism in diabetes have also been studied both epidemiologically and experimentally. Predominantly targeting the adenosine receptors, caffeine causes alterations in glucose homeostasis by decreasing glucose uptake into skeletal muscle, thereby causing elevations in blood glucose concentration. Caffeine intake has also been proposed to increase symptomatic warning signs of hypoglycemia in patients with type 1 diabetes and elevate blood glucose levels in patients with type 2 diabetes. Other effects include potential increases in glucose counterregulatory hormones such as epinephrine, which can also decrease peripheral glucose disposal. Despite these established physiological effects, increased coffee intake has been associated with reduced risk of developing type 2 diabetes in large-scale epidemiological studies. This review paper highlights the known effects of caffeine on glucose homeostasis and diabetes metabolism during rest and exercise. PMID:23855268

  17. Altered Calcium and Vitamin D Homeostasis in First-Time Calcium Kidney Stone-Formers.

    Directory of Open Access Journals (Sweden)

    Hemamalini Ketha

    Full Text Available Elevated serum 1,25-dihydroxyvitamin D (1,25(OH2D concentrations have been reported among cohorts of recurrent calcium (Ca kidney stone-formers and implicated in the pathogenesis of hypercalciuria. Variations in Ca and vitamin D metabolism, and excretion of urinary solutes among first-time male and female Ca stone-formers in the community, however, have not been defined.In a 4-year community-based study we measured serum Ca, phosphorus (P, 25-hydroxyvitamin D (25(OHD, 1,25(OH2D, 24,25-dihydroxyvitamin D (24,25(OH2D, parathyroid hormone (PTH, and fibroblast growth factor-23 (FGF-23 concentrations in first-time Ca stone-formers and age- and gender frequency-matched controls.Serum Ca and 1,25(OH2D were increased in Ca stone-formers compared to controls (P = 0.01 and P = 0.001. Stone-formers had a lower serum 24,25(OH2D/25(OHD ratio compared to controls (P = 0.008. Serum PTH and FGF-23 concentrations were similar in the groups. Urine Ca excretion was similar in the two groups (P = 0.82. In controls, positive associations between serum 25(OHD and 24,25(OH2D, FGF-23 and fractional phosphate excretion, and negative associations between serum Ca and PTH, and FGF-23 and 1,25(OH2D were observed. In SF associations between FGF-23 and fractional phosphate excretion, and FGF-23 and 1,25(OH2D, were not observed. 1,25(OH2D concentrations associated more weakly with FGF-23 in SF compared with C (P <0.05.Quantitative differences in serum Ca and 1,25(OH2D and reductions in 24-hydroxylation of vitamin D metabolites are present in first-time SF and might contribute to first-time stone risk.

  18. Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis

    NARCIS (Netherlands)

    Sepulveda-Falla, Diego; Barrera-Ocampo, Alvaro; Hagel, Christian; Korwitz, Anne; Vinueza-Veloz, Maria Fernanda; Zhou, Kuikui; Schonewille, Martijn; Zhou, Haibo; Velazquez-Perez, Luis; Rodriguez-Labrada, Roberto; Villegas, Andres; Ferrer, Isidro; Lopera, Francisco; Langer, Thomas; De Zeeuw, Chris I; Glatzel, Markus

    2014-01-01

    Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia w

  19. Tissue-specific alterations in thyroid hormone homeostasis in combined Mct10 and Mct8 deficiency

    NARCIS (Netherlands)

    J. Müller (Julia); S. Mayerl (Steffen); T.J. Visser (Ton); V.M. Darras (Veerle); A. Boelen (Anita); L. Frappart (Lucien); L. Mariotta (Luca); F. Verrey; H. Heuer (Heike)

    2014-01-01

    textabstractThe monocarboxylate transporter Mct10 (Slc16a10; T-type amino acid transporter) facilitates the cellular transport of thyroid hormone (TH) and shows an overlapping expression with the wellestablished TH transporter Mct8. Because Mct8 deficiency is associated with distinct tissue-specific

  20. Altered telomere homeostasis and resistance to skin carcinogenesis in Suv39h1 transgenic mice

    OpenAIRE

    Petti, Eleonora; Jordi, Fabian; Buemi, Valentina; Dinami, Roberto; Benetti, Roberta; Blasco, Maria A.; Schoeftner, Stefan

    2015-01-01

    The Suv39h1 and Suv39h2 H3K9 histone methyltransferases (HMTs) have a conserved role in the formation of constitutive heterochromatin and gene silencing. Using a transgenic mouse model system we demonstrate that elevated expression of Suv39h1 increases global H3K9me3 levels in vivo. More specifically, Suv39h1 overexpression enhances the imposition of H3K9me3 levels at constitutive heterochromatin at telomeric and major satellite repeats in primary mouse embryonic fibroblasts. Chromatin compac...

  1. ALTERED MICROGLIAL COPPER HOMEOSTASIS IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

    OpenAIRE

    Zheng, Zhiqiang; White, Carine; Lee, Jaekwon; Peterson, Troy S.; Ashley I. Bush; Sun, Grace; Gary A Weisman; Petris, Michael J.

    2010-01-01

    Alzheimer’s disease (AD) is characterized by progressive neurodegeneration associated with the aggregation and deposition of β-amyloid (Aβ40 and Aβ42) peptide in senile plaques. Recent studies suggest that copper may play an important role in AD pathology. Copper concentrations are elevated in amyloid plaques and copper binds with high affinity to the Aβ peptide and promotes Aβ oligomerization and neurotoxicity. Despite this connection between copper and AD, it is unknown whether the expressi...

  2. Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B–null mice

    OpenAIRE

    Choi, Young Hun; Park, Sunhee; Hockman, Steven; Zmuda-Trzebiatowska, Emilia; Svennelid, Fredrik; Haluzik, Martin; Gavrilova, Oksana; Ahmad, Faiyaz; Pepin, Laurent; Napolitano, Maria; Taira, Masato; Sundler, Frank; Stenson Holst, Lena; Degerman, Eva; Manganiello, Vincent C.

    2006-01-01

    Cyclic nucleotide phosphodiesterase 3B (PDE3B) has been suggested to be critical for mediating insulin/IGF-1 inhibition of cAMP signaling in adipocytes, liver, and pancreatic β cells. In Pde3b-KO adipocytes we found decreased adipocyte size, unchanged insulin-stimulated phosphorylation of protein kinase B and activation of glucose uptake, enhanced catecholamine-stimulated lipolysis and insulin-stimulated lipogenesis, and blocked insulin inhibition of catecholamine-stimulated lipolysis. Glucos...

  3. Prions, protein homeostasis, and phenotypic diversity

    OpenAIRE

    Halfmann, Randal; Alberti, Simon; Lindquist, Susan

    2010-01-01

    Prions are fascinating but often misunderstood protein aggregation phenomena. The traditional association of the mammalian prion protein with disease has overshadowed a potentially more interesting attribute of prions: their ability to create protein-based molecular memories. In fungi, prions alter the relationship between genotype and phenotype in a heritable way that diversifies clonal populations. Recent findings in yeast indicate that prions might be much more common than previously real...

  4. The influence of intermittent hypobaric hypoxia on the brain iron metabolism in adult Sprague dawley rats

    Institute of Scientific and Technical Information of China (English)

    Wu Qiong; Li Yaru; Chang Yanzhong

    2015-01-01

    Objective:Iron is an essential element in all living organisms and is required as a cofactor for oxygen-binding proteins. Iron metabolism, oxygen homeostasis and erythropoiesis are consequently strongly inter-connected. In mammalian cells, exposure to a low-oxygen environment triggers a hypoxic response pathway cen-tered on the regulated expression of the hypoxia-inducible transcription factor ( HIF) . Hypoxia has been shown to increase the expression of a variety of proteins involved in iron homeostasis. However, little is known about brain iron metabolism after intermittent hypobaric hypoxia ( IHH) treatment. In this study, adult Sprague dawley ( SD) rats were treated with IHH for 28 days, 8h per day and then we detected iron homeostasis in different brain areas of SD rats. Results:The protein level of hippocampus transferrin receptor 1 ( TfR1 ) , divalent metal transporter 1 (DMT1) with IRE, DMT1 (-IRE), ferritin-H, iron regulatory protein (IRP) 2 and ceruloplasmin (CP) is ele-vated significantly while ferritin-L decreased. We have also found the down regulation of IRP1. We observe the same results in the cerebral cortex in the brain. Conclusions:We first discover that IHH has an influence on the brain iron homeostasis and the decreased ferritin-L corresponds to the down regulation of IRP1 indicating hypoxia can affect the expression of ferritin-L through IRE/IRP system. Although there is a marked increase in TfR1 ex-pression that would lead to the raised level of LIP in cells. It can finally result in the higher ROS which can damage the cells. The concerned mechanisms involved in it remain to be deliberated.

  5. Calcium homeostasis modulator (CALHM) ion channels.

    Science.gov (United States)

    Ma, Zhongming; Tanis, Jessica E; Taruno, Akiyuki; Foskett, J Kevin

    2016-03-01

    Calcium homeostasis modulator 1 (CALHM1), formerly known as FAM26C, was recently identified as a physiologically important plasma membrane ion channel. CALHM1 and its Caenorhabditis elegans homolog, CLHM-1, are regulated by membrane voltage and extracellular Ca(2+) concentration ([Ca(2+)]o). In the presence of physiological [Ca(2+)]o (∼1.5 mM), CALHM1 and CLHM-1 are closed at resting membrane potentials but can be opened by strong depolarizations. Reducing [Ca(2+)]o increases channel open probability, enabling channel activation at negative membrane potentials. Together, voltage and Ca(2+) o allosterically regulate CALHM channel gating. Through convergent evolution, CALHM has structural features that are reminiscent of connexins and pannexins/innexins/LRRC8 (volume-regulated anion channel (VRAC)) gene families, including four transmembrane helices with cytoplasmic amino and carboxyl termini. A CALHM1 channel is a hexamer of CALHM1 monomers with a functional pore diameter of ∼14 Å. CALHM channels discriminate poorly among cations and anions, with signaling molecules including Ca(2+) and ATP able to permeate through its pore. CALHM1 is expressed in the brain where it plays an important role in cortical neuron excitability induced by low [Ca(2+)]o and in type II taste bud cells in the tongue that sense sweet, bitter, and umami tastes where it functions as an essential ATP release channel to mediate nonsynaptic neurotransmitter release. CLHM-1 is expressed in C. elegans sensory neurons and body wall muscles, and its genetic deletion causes locomotion defects. Thus, CALHM is a voltage- and Ca(2+) o-gated ion channel, permeable to large cations and anions, that plays important roles in physiology. PMID:26603282

  6. Maintaining homeostasis by decision-making.

    Directory of Open Access Journals (Sweden)

    Christoph W Korn

    2015-05-01

    Full Text Available Living organisms need to maintain energetic homeostasis. For many species, this implies taking actions with delayed consequences. For example, humans may have to decide between foraging for high-calorie but hard-to-get, and low-calorie but easy-to-get food, under threat of starvation. Homeostatic principles prescribe decisions that maximize the probability of sustaining appropriate energy levels across the entire foraging trajectory. Here, predictions from biological principles contrast with predictions from economic decision-making models based on maximizing the utility of the endpoint outcome of a choice. To empirically arbitrate between the predictions of biological and economic models for individual human decision-making, we devised a virtual foraging task in which players chose repeatedly between two foraging environments, lost energy by the passage of time, and gained energy probabilistically according to the statistics of the environment they chose. Reaching zero energy was framed as starvation. We used the mathematics of random walks to derive endpoint outcome distributions of the choices. This also furnished equivalent lotteries, presented in a purely economic, casino-like frame, in which starvation corresponded to winning nothing. Bayesian model comparison showed that--in both the foraging and the casino frames--participants' choices depended jointly on the probability of starvation and the expected endpoint value of the outcome, but could not be explained by economic models based on combinations of statistical moments or on rank-dependent utility. This implies that under precisely defined constraints biological principles are better suited to explain human decision-making than economic models based on endpoint utility maximization.

  7. WSB1: from homeostasis to hypoxia.

    Science.gov (United States)

    Haque, Moinul; Kendal, Joseph Keith; MacIsaac, Ryan Matthew; Demetrick, Douglas James

    2016-01-01

    The wsb1 gene has been identified to be important in developmental biology and cancer. A complex transcriptional regulation of wsb1 yields at least three functional transcripts. The major expressed isoform, WSB1 protein, is a substrate recognition protein within an E3 ubiquitin ligase, with the capability to bind diverse targets and mediate ubiquitinylation and proteolytic degradation. Recent data suggests a new role for WSB1 as a component of a neuroprotective pathway which results in modification and aggregation of neurotoxic proteins such as LRRK2 in Parkinson's Disease, via an unusual mode of protein ubiquitinylation.WSB1 is also involved in thyroid hormone homeostasis, immune regulation and cellular metabolism, particularly glucose metabolism and hypoxia. In hypoxia, wsb1 is a HIF-1 target, and is a regulator of the degradation of diverse proteins associated with the cellular response to hypoxia, including HIPK2, RhoGDI2 and VHL. Major roles are to both protect HIF-1 function through degradation of VHL, and decrease apoptosis through degradation of HIPK2. These activities suggest a role for wsb1 in cancer cell proliferation and metastasis. As well, recent work has identified a role for WSB1 in glucose metabolism, and perhaps in mediating the Warburg effect in cancer cells by maintaining the function of HIF1. Furthermore, studies of cancer specimens have identified dysregulation of wsb1 associated with several types of cancer, suggesting a biologically relevant role in cancer development and/or progression.Recent development of an inducible expression system for wsb1 could aid in the further understanding of the varied functions of this protein in the cell, and roles as a potential oncogene and neuroprotective protein. PMID:27542736

  8. Suppressing Farnesyl Diphosphate Synthase Alters Chloroplast Development and Triggers Sterol-Dependent Induction of Jasmonate- and Fe-Related Responses.

    Science.gov (United States)

    Manzano, David; Andrade, Paola; Caudepón, Daniel; Altabella, Teresa; Arró, Montserrat; Ferrer, Albert

    2016-09-01

    Farnesyl diphosphate synthase (FPS) catalyzes the synthesis of farnesyl diphosphate from isopentenyl diphosphate and dimethylallyl diphosphate. Arabidopsis (Arabidopsis thaliana) contains two genes (FPS1 and FPS2) encoding FPS. Single fps1 and fps2 knockout mutants are phenotypically indistinguishable from wild-type plants, while fps1/fps2 double mutants are embryo lethal. To assess the effect of FPS down-regulation at postembryonic developmental stages, we generated Arabidopsis conditional knockdown mutants expressing artificial microRNAs devised to simultaneously silence both FPS genes. Induction of silencing from germination rapidly caused chlorosis and a strong developmental phenotype that led to seedling lethality. However, silencing of FPS after seed germination resulted in a slight developmental delay only, although leaves and cotyledons continued to show chlorosis and altered chloroplasts. Metabolomic analyses also revealed drastic changes in the profile of sterols, ubiquinones, and plastidial isoprenoids. RNA sequencing and reverse transcription-quantitative polymerase chain reaction transcriptomic analysis showed that a reduction in FPS activity levels triggers the misregulation of genes involved in biotic and abiotic stress responses, the most prominent one being the rapid induction of a set of genes related to the jasmonic acid pathway. Down-regulation of FPS also triggered an iron-deficiency transcriptional response that is consistent with the iron-deficient phenotype observed in FPS-silenced plants. The specific inhibition of the sterol biosynthesis pathway by chemical and genetic blockage mimicked these transcriptional responses, indicating that sterol depletion is the primary cause of the observed alterations. Our results highlight the importance of sterol homeostasis for normal chloroplast development and function and reveal important clues about how isoprenoid and sterol metabolism is integrated within plant physiology and development. PMID

  9. Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans.

    Science.gov (United States)

    Lennerz, Belinda S; Vafai, Scott B; Delaney, Nigel F; Clish, Clary B; Deik, Amy A; Pierce, Kerry A; Ludwig, David S; Mootha, Vamsi K

    2015-01-01

    Sodium benzoate is a widely used preservative found in many foods and soft drinks. It is metabolized within mitochondria to produce hippurate, which is then cleared by the kidneys. We previously reported that ingestion of sodium benzoate at the generally regarded as safe (GRAS) dose leads to a robust excursion in the plasma hippurate level [1]. Since previous reports demonstrated adverse effects of benzoate and hippurate on glucose homeostasis in cells and in animal models, we hypothesized that benzoate might represent a widespread and underappreciated diabetogenic dietary exposure in humans. Here, we evaluated whether acute exposure to GRAS levels of sodium benzoate alters insulin and glucose homeostasis through a randomized, controlled, cross-over study of 14 overweight subjects. Serial blood samples were collected following an oral glucose challenge, in the presence or absence of sodium benzoate. Outcome measurements included glucose, insulin, glucagon, as well as temporal mass spectrometry-based metabolic profiles. We did not find a statistically significant effect of an acute oral exposure to sodium benzoate on glucose homeostasis. Of the 146 metabolites targeted, four changed significantly in response to benzoate, including the expected rise in benzoate and hippurate. In addition, anthranilic acid, a tryptophan metabolite, exhibited a robust rise, while acetylglycine dropped. Although our study shows that GRAS doses of benzoate do not have an acute, adverse effect on glucose homeostasis, future studies will be necessary to explore the metabolic impact of chronic benzoate exposure.

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

    Science.gov (United States)

    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 erythropoietin (p 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

  11. Effects of environmental pollutants on cellular iron homeostasis and ultimate links to human disease

    Science.gov (United States)

    Chronic disease has increased in the last several decades, and environmental pollutants have been implicated. The magnitude and variety of diseases indicate the malfunctioning of some basic mechanism underlying human health. Environmental pollutants demonstrate a capability to co...

  12. Research on the Relationship between Exercise and Iron Homeostasis%运动与铁稳态

    Institute of Scientific and Technical Information of China (English)

    漆正堂; 贺杰; 罗艳蕊

    2006-01-01

    机体对运动的不适应不仅可能导致铁的丢失,还可能导致铁转运障碍,铁在储铁组织(肝脏、肌肉)蓄积过多,而在耗铁组织(骨髓)又相对缺乏.这种贫富悬殊的铁分布可能是运动性贫血的发病机理之一.长期运动训练后,如果机体产生运动适应,上调转铁蛋白及其受体的表达或增强非Tf结合铁的转运,那么就会克服铁的紊乱分布,将富铁组织的铁转运到贫铁的骨髓,有利于运动性贫血发生后血红蛋白与红细胞比容的恢复,这可能是运动性贫血呈现一过性、长期运动训练后机体出现低铁而不贫血状态的原因所在.

  13. Changed iron regulation in scrapie-infected neuroblastoma cells.

    Science.gov (United States)

    Fernaeus, Sandra; Hälldin, Jonas; Bedecs, Katarina; Land, Tiit

    2005-02-18

    Prion diseases are characterized by the conversion of the normal cellular prion protein PrP(C) into a pathogenic isoform, PrP(Sc). The mechanisms involved in neuronal cell death in prion diseases are largely unknown, but accumulating evidence has demonstrated oxidative impairment along with metal imbalances in scrapie-infected brains. In this study, we report changes in cellular iron metabolism in scrapie-infected mouse neuroblastoma N2a cells (ScN2a). We detected twofold lower total cellular iron and calcein-chelatable cytosolic labile iron pool (LIP) in ScN2a cells as compared to the N2a cells. We also measured in ScN2a cells significantly lower activities of iron regulatory proteins 1 and 2 (IRP1 and IRP2, respectively), regulators of cellular iron by sensing cytosolic free iron levels and controlling posttranscriptionally the expression of the major iron transport protein transferrin receptor 1 (TfR1) and the iron sequestration protein ferritin. IRP1 and IRP2 protein levels were decreased by 40% and 50%, respectively, in ScN2a cells. TfR1 protein levels were fourfold reduced and ferritin levels were threefold reduced in ScN2a cells. TfR1 and ferritin mRNA levels were significantly reduced in ScN2a cells. ScN2a cells responded normally to iron and iron chelator treatment with respect to the activities of IRP1 and IRP2, and biosynthesis of TfR1 and ferritin. However, the activities of IRP1 and IRP2, and protein levels of TfR1 and ferritin, were still significantly lower in iron-depleted ScN2a cells as compared to the N2a cells, suggesting lower need for iron in ScN2a cells. Our results demonstrate that scrapie infection leads to changes in cellular iron metabolism, affecting both total cellular and cytosolic free iron, and the activities and expression of major regulators of cellular iron homeostasis. PMID:15710243

  14. Autophagy in Skeletal Muscle Homeostasis and in Muscular Dystrophies

    OpenAIRE

    Paolo Bonaldo; Paolo Grumati

    2012-01-01

    Skeletal muscles are the agent of motion and one of the most important tissues responsible for the control of metabolism. The maintenance of muscle homeostasis is finely regulated by the balance between catabolic and anabolic process. Macroautophagy (or autophagy) is a catabolic process that provides the degradation of protein aggregation and damaged organelles through the fusion between autophagosomes and lysosomes. Proper regulation of the autophagy flux is fundamental for the homeostasis o...

  15. The GARP complex is required for cellular sphingolipid homeostasis

    DEFF Research Database (Denmark)

    Fröhlich, Florian; Petit, Constance; Kory, Nora;

    2015-01-01

    (GARP) complex, which functions in endosome-to-Golgi retrograde vesicular transport, as a critical player in sphingolipid homeostasis. GARP deficiency leads to accumulation of sphingolipid synthesis intermediates, changes in sterol distribution, and lysosomal dysfunction. A GARP complex mutation...... the phenotypes of GARP-deficient yeast or mammalian cells. Together, these data show that GARP is essential for cellular sphingolipid homeostasis and suggest a therapeutic strategy for the treatment of PCCA2....

  16. Lung Stem and Progenitor Cells in Tissue Homeostasis and Disease

    OpenAIRE

    Leeman, Kristen T.; Fillmore, Christine M.; Kim, Carla F.

    2014-01-01

    The mammalian lung is a complex organ containing numerous putative stem/progenitor cell populations that contribute to region-specific tissue homeostasis and repair. In this review, we discuss recent advances in identifying and studying these cell populations in the context of lung homeostasis and disease. Genetically engineered mice now allow for lineage tracing of several lung stem and progenitor cell populations in vivo during different types of lung injury repair. Using specific sets of c...

  17. Sex differences in metabolic homeostasis, diabetes, and obesity

    OpenAIRE

    Mauvais-Jarvis, Franck

    2015-01-01

    There are fundamental aspects of the control of metabolic homeostasis that are regulated differently in males and females. This sex asymmetry represents an evolutionary paradigm for females to resist the loss of energy stores. This perspective discusses the most fundamental sex differences in metabolic homeostasis, diabetes, and obesity. Together, the role of genetic sex, the programming effect of testosterone in the prenatal period in males, and the activational role of sex hormones at puber...

  18. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... intravenous iron therapy. Rate This Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the National Heart, Lung, and Blood ...

  19. Total iron binding capacity

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/003489.htm Total iron binding capacity To use the sharing features on this page, please enable JavaScript. Total iron binding capacity (TIBC) is a blood test to ...

  20. Iron supplements (image)

    Science.gov (United States)

    The mineral iron is an essential nutrient for humans because it is part of blood cells, which carry oxygen to all body cells. There is no conclusive evidence that iron supplements contribute to heart attacks.

  1. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... This Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video— ... treatment. For more information about living with and managing iron-deficiency anemia, go to the Health Topics ...

  2. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... levels usually are due to blood loss, poor diet, or an inability to absorb enough iron from ... iron levels. Susan also made changes to her diet, such as focusing more on green leafy vegetables, ...

  3. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... iron-rich protein that carries oxygen from the lungs to the rest of the body. Iron-deficiency ... 2011 This video—presented by the National Heart, Lung, and Blood Institute, part of the National Institutes ...

  4. Oxidative stress response in neural stem cells exposed to different superparamagnetic iron oxide nanoparticles.

    Science.gov (United States)

    Pongrac, Igor M; Pavičić, Ivan; Milić, Mirta; Brkić Ahmed, Lada; Babič, Michal; Horák, Daniel; Vinković Vrček, Ivana; Gajović, Srećko

    2016-01-01

    Biocompatibility, safety, and risk assessments of superparamagnetic iron oxide nanoparticles (SPIONs) are of the highest priority in researching their application in biomedicine. One improvement in the biological properties of SPIONs may be achieved by different functionalization and surface modifications. This study aims to investigate how a different surface functionalization of SPIONs - uncoated, coated with d-mannose, or coated with poly-l-lysine - affects biocompatibility. We sought to investigate murine neural stem cells (NSCs) as important model system for regenerative medicine. To reveal the possible mechanism of toxicity of SPIONs on NSCs, levels of reactive oxygen species, intracellular glutathione, mitochondrial membrane potential, cell-membrane potential, DNA damage, and activities of SOD and GPx were examined. Even in cases where reactive oxygen species levels were significantly lowered in NSCs exposed to SPIONs, we found depleted intracellular glutathione levels, altered activities of SOD and GPx, hyperpolarization of the mitochondrial membrane, dissipated cell-membrane potential, and increased DNA damage, irrespective of the surface coating applied for SPION stabilization. Although surface coating should prevent the toxic effects of SPIONs, our results showed that all of the tested SPION types affected the NSCs similarly, indicating that mitochondrial homeostasis is their major cellular target. Despite the claimed biomedical benefits of SPIONs, the refined determination of their effects on various cellular functions presented in this work highlights the need for further safety evaluations. This investigation helps to fill the knowledge gaps on the criteria that should be considered in evaluating the biocompatibility and safety of novel nanoparticles. PMID:27217748

  5. Special thermite cast irons

    Directory of Open Access Journals (Sweden)

    Yu. Zhiguts

    2008-07-01

    Full Text Available The given paper deals with the problems of the synthesis of cast iron by metallothermy synthesis. On the basis of investigated method of calculations structures of charges have been arranged and cast iron has been synthesized further. Peculiarities metallothermic smelting were found, mechanical properties and structure of received cast iron were investigated and different technologies for cast iron receiving were worked out.

  6. Alternative iron making routes

    Energy Technology Data Exchange (ETDEWEB)

    Kaushik, P.; Sharma, T. [Indian School of Mines, Dhanbad (India)

    2002-07-01

    The versatile route of iron production 'blast furnace' technique is being replaced by widely accepted Corex technology, Midrex process using Fastmelt ironmaking, eco-friendly Romelt process, more innovative Ausmelt & Hismelt technology, TATA KORF Mini blast furnace improvement, 'quickest iron through Orbiting Plasma', Direct iron ore smelting process, Conred, AISI-Hyl, Inred processes, Direct iron ore reduction methods, their comparison and proposed modifications. 18 refs., 11 figs., 14 tabs.

  7. The interplay between iron accumulation, mitochondrial dysfunction and inflammation during the execution step of neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Pamela J. Urrutia

    2014-03-01

    Full Text Available A growing set of observations points to mitochondrial dysfunction, iron accumulation, oxidative damage and chronic inflammation as common pathognomonic signs of a number of neurodegenerative diseases that includes Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, Friedrich’s ataxia and Parkinson’s disease. Particularly relevant for neurodegenerative processes is the relationship between mitochondria and iron. The mitochondrion upholds the synthesis of iron-sulfur clusters and heme, the most abundant iron-containing prosthetic groups in a large variety of proteins, so a fraction of incoming iron must go through this organelle before reaching its final destination. In turn, the mitochondrial respiratory chain is the source of reactive oxygen species (ROS derived from leaks in the electron transport chain. The co-existence of both iron and ROS in the secluded space of the mitochondrion makes this organelle particularly prone to hydroxyl radical-mediated damage. In addition, a connection between the loss of iron homeostasis and inflammation is starting to emerge; thus, inflammatory cytokines like TNF-alpha and IL-6 induce the synthesis of the divalent metal transporter 1 and promote iron accumulation in neurons and microglia. Here, we review the recent literature on mitochondrial iron homeostasis and the role of inflammation on mitochondria dysfunction and iron accumulation on the neurodegenerative process that lead to cell death in Parkinson’s disease. We also put forward the hypothesis that mitochondrial dysfunction, iron accumulation and inflammation are part of a synergistic self-feeding cycle that ends in apoptotic cell death, once the antioxidant cellular defense systems are finally overwhelmed.

  8. Is the iron regulatory hormone hepcidin a risk factor for alcoholic liver disease?

    Institute of Scientific and Technical Information of China (English)

    Duygu Dee Harrison-Findik

    2009-01-01

    Despite heavy consumption over a long period of time,only a small number of alcoholics develop alcoholic liver disease. This alludes to the possibility that other factors,besides alcohol, may be involved in the progression of the disease. Over the years, many such factors have indeed been identified, including iron. Despite being crucial for various important biological processes, iron can also be harmful due to its ability to catalyze Fenton chemistry. Alcohol and iron have been shown to interact synergistically to cause liver injury. Iron-mediated cell signaling has been reported to be involved in the pathogenesis of experimental alcoholic liver disease. Hepcidin is an iron-regulatory hormone synthesized by the liver,which plays a pivotal role in iron homeostasis. Both acute and chronic alcohol exposure suppress hepcidin expression in the liver. The sera of patients with alcoholic liver disease, particularly those exhibiting higher serum iron indices, have also been reported to display reduced prohepcidin levels. Alcohol-mediated oxidative stress is involved in the inhibition of hepcidin promoter activity and transcription in the liver. This in turn leads to an increase in intestinal iron transport and liver iron storage. Hepcidin is expressed primarily in hepatocytes.It is noteworthy that both hepatocytes and Kupffer cells are involved in the progression of alcoholic liver disease. However, the activation of Kupffer cells and TNF-α signaling has been reported not to be involved in the down-regulation of hepcidin expression by alcohol in the liver. Alcohol acts within the parenchymal cells of the liver to suppress the synthesis of hepcidin. Due to its crucial role in the regulation of body iron stores, hepcidin may act as a secondary risk factor in the progression of alcoholic liver disease. The clarification of the mechanisms by which alcohol disrupts iron homeostasis will allow for further understanding of the pathogenesis of alcoholic liver disease.

  9. Iron-Deficiency Anemia

    Science.gov (United States)

    ... page from the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, ... Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by ...

  10. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the body. Iron-deficiency anemia usually develops over time if your body doesn't have enough iron ... Institutes of Health—shows how Susan, a full-time worker and student, has coped with having iron- ...

  11. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, easily ... Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the ...

  12. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... body. Low iron levels usually are due to blood loss, poor diet, or an inability to absorb enough iron from food. Overview Iron-deficiency anemia is a common type of anemia . The term "anemia" usually refers to ...

  13. New Insights on Iron Study in Myelodysplasia

    Directory of Open Access Journals (Sweden)

    Noha M. El Husseiny

    2014-12-01

    Full Text Available OBJECTIVE: Hepcidin plays a pivotal role in iron homeostasis. It is predominantly produced by hepatocytes and inhibits iron release from macrophages and iron uptake by intestinal epithelial cells. Competitive ELISA is the current method of choice for the quantification of serum hepcidin because of its lower detection limit, low costs, and high throughput. This study aims to discuss the role of hepcidin in the pathogenesis of iron overload in recently diagnosed myelodysplasia (MDS cases. METHODS: The study included 21 recently diagnosed MDS patients and 13 healthy controls. Ferritin, hepcidin, and soluble transferrin receptor (sTFR were measured in all subjects. RESULTS: There were 7 cases of hypocellular MDS, 8 cases of refractory cytopenia with multilineage dysplasia, and 6 cases of refractory anemia with excess blasts. No difference was observed among the 3 MDS subtypes in terms of hepcidin, sTFR, and ferritin levels (p>0.05. Mean hepcidin levels in the MDS and control groups were 55.8±21.5 ng/mL and 19.9±2.6 ng/ mL, respectively. Mean sTFR was 45.7±8.8 nmol/L in MDS patients and 31.1±5.6 nmol/L in the controls. Mean ferritin levels were significantly higher in MDS patients than in controls (539.14±83.5 ng/mL vs. 104.6±42.9 ng/mL, p0.05. CONCLUSION: Hepcidin may not be the main cause of iron overload in MDS. Further studies are required to test failure of production or peripheral unresponsiveness to hepcidin in MDS cases.

  14. Rice OsYSL15 is an iron-regulated iron(III)-deoxymugineic acid transporter expressed in the roots and is essential for iron uptake in early growth of the seedlings.

    Science.gov (United States)

    Inoue, Haruhiko; Kobayashi, Takanori; Nozoye, Tomoko; Takahashi, Michiko; Kakei, Yusuke; Suzuki, Kazumasa; Nakazono, Mikio; Nakanishi, Hiromi; Mori, Satoshi; Nishizawa, Naoko K

    2009-02-01

    Graminaceous plants take up iron through YS1 (yellow stripe 1) and YS1-like (YSL) transporters using iron-chelating compounds known as mugineic acid family phytosiderophores. We examined the expression of 18 rice (Oryza sativa L.) YSL genes (OsYSL1-18) in the epidermis/exodermis, cortex, and stele of rice roots. Expression of OsYSL15 in root epidermis and stele was induced by iron deficiency and showed daily fluctuation. OsYSL15 restored a yeast mutant defective in iron uptake when supplied with iron(III)-deoxymugineic acid and transported iron(III)-deoxymugineic acid in Xenopus laevis oocytes. An OsYSL15-green fluorescent protein fusion was localized to the plasma membrane when transiently expressed in onion epidermal cells. OsYSL15 promoter-beta-glucuronidase analysis revealed that OsYSL15 expression in roots was dominant in the epidermis/exodermis and phloem cells under conditions of iron deficiency and was detected only in phloem under iron sufficiency. These results strongly suggest that OsYSL15 is the dominant iron(III)-deoxymugineic acid transporter responsible for iron uptake from the rhizosphere and is also responsible for phloem transport of iron. OsYSL15 was also expressed in flowers, developing seeds, and in the embryonic scutellar epithelial cells during seed germination. OsYSL15 knockdown seedlings showed severe arrest in germination and early growth and were rescued by high iron supply. These results demonstrate that rice OsYSL15 plays a crucial role in iron homeostasis during the early stages of growth. PMID:19049971

  15. Iron and the liver.

    Science.gov (United States)

    Pietrangelo, Antonello

    2016-01-01

    Humans have evolved to retain iron in the body and are exposed to a high risk of iron overload and iron-related toxicity. Excess iron in the blood, in the absence of increased erythropoietic needs, can saturate the buffering capacity of serum transferrin and result in non-transferrin-bound highly reactive forms of iron that can cause damage, as well as promote fibrogenesis and carcinogenesis in the parenchymatous organs. A number of hereditary or acquired diseases are associated with systemic or local iron deposition or iron misdistribution in organs or cells. Two of these, the HFE- and non-HFE hemochromatosis syndromes represent the paradigms of genetic iron overload. They share common clinical features and the same pathogenic basis, in particular, a lack of synthesis or activity of hepcidin, the iron hormone. Before hepcidin was discovered, the liver was simply regarded as the main site of iron storage and, as such, the main target of iron toxicity. Now, as the main source of hepcidin, it appears that the loss of the hepcidin-producing liver mass or genetic and acquired factors that repress hepcidin synthesis in the liver may also lead to iron overload. Usually, there is low-grade excess iron which, through oxidative stress, is sufficient to worsen the course of the underlying liver disease or other chronic diseases that are apparently unrelated to iron, such as chronic metabolic and cardiovascular diseases. In the future, modulation of hepcidin synthesis and activity or hepcidin hormone-replacing strategies may become therapeutic options to cure iron-related disorders.

  16. Ethylene is critical to the maintenance of primary root growth and Fe homeostasis under Fe stress in Arabidopsis.

    Science.gov (United States)

    Li, Guangjie; Xu, Weifeng; Kronzucker, Herbert J; Shi, Weiming

    2015-04-01

    Iron (Fe) is an essential microelement but is highly toxic when in excess. The response of plant roots to Fe toxicity and the nature of the regulatory pathways engaged are poorly understood. Here, we examined the response to excess Fe exposure in Arabidopsis wild type and ethylene mutants with a focus on primary root growth and the role of ethylene. We showed that excess Fe arrested primary root growth by decreasing both cell elongation and division, and principally resulteds from direct external Fe contact at the root tip. Pronounced ethylene, but not abscisic acid, evolution was associated with excess Fe exposure. Ethylene antagonists intensified root growth inhibition in the wild type, while the inhibition was significantly reduced in ethylene-overproduction mutants. We showed that ethylene plays a positive role in tissue Fe homeostasis, even in the absence of iron-plaque formation. Ethylene reduced Fe concentrations in the stele, xylem, and shoot. Furthermore, ethylene increased the expression of genes encoding Fe-sequestering ferritins. Additionally, ethylene significantly enhanced root K(+) status and upregulated K(+)-transporter (HAK5) expression. Our findings highlight the important role of ethylene in tissue Fe and K homeostasis and primary root growth under Fe stress in Arabidopsis.

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

    Science.gov (United States)

    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 Effects of Dietary Fat and Iron Interaction on Brain Regional Iron Contents and Stereotypical Behaviors in Male C57BL/6J Mice

    Science.gov (United States)

    Liu, Lumei; Byrd, Aria; Plummer, Justin; Erikson, Keith M.; Harrison, Scott H.; Han, Jian

    2016-01-01

    Adequate brain iron levels are essential for enzyme activities, myelination, and neurotransmitter synthesis in the brain. Although systemic iron deficiency has been found in genetically or dietary-induced obese subjects, the effects of obesity-associated iron dysregulation in brain regions have not been examined. The objective of this study was to examine the effect of dietary fat and iron interaction on brain regional iron contents and regional-associated behavior patterns in a mouse model. Thirty C57BL/6J male weanling mice were randomly assigned to six dietary treatment groups (n = 5) with varying fat (control/high) and iron (control/high/low) contents. The stereotypical behaviors were measured during the 24th week. Blood, liver, and brain tissues were collected at the end of the 24th week. Brains were dissected into the hippocampus, midbrain, striatum, and thalamus regions. Iron contents and ferritin heavy chain (FtH) protein and mRNA expressions in these regions were measured. Correlations between stereotypical behaviors and brain regional iron contents were analyzed at the 5% significance level. Results showed that high-fat diet altered the stereotypical behaviors such as inactivity and total distance traveled (P iron contents and FtH protein and mRNA expressions in a regional-specific manner: (1) high-fat diet significantly decreased the brain iron content in the striatum (P iron content and sleeping in midbrain (P iron also decreased brain iron content and FtH protein expression in a regionally specific manner. The effect of interaction between dietary fat and iron was observed in brain iron content and behaviors. All these findings will lay foundations to further explore the links among obesity, behaviors, and brain iron alteration. PMID:27493939

  19. Curcumin inhibits growth of Saccharomyces cerevisiae through iron chelation.

    Science.gov (United States)

    Minear, Steven; O'Donnell, Allyson F; Ballew, Anna; Giaever, Guri; Nislow, Corey; Stearns, Tim; Cyert, Martha S

    2011-11-01

    Curcumin, a polyphenol derived from turmeric, is an ancient therapeutic used in India for centuries to treat a wide array of ailments. Interest in curcumin has increased recently, with ongoing clinical trials exploring curcumin as an anticancer therapy and as a protectant against neurodegenerative diseases. In vitro, curcumin chelates metal ions. However, although diverse physiological effects have been documented for this compound, curcumin's mechanism of action on mammalian cells remains unclear. This study uses yeast as a model eukaryotic system to dissect the biological activity of curcumin. We found that yeast mutants lacking genes required for iron and copper homeostasis are hypersensitive to curcumin and that iron supplementation rescues this sensitivity. Curcumin penetrates yeast cells, concentrates in the endoplasmic reticulum (ER) membranes, and reduces the intracellular iron pool. Curcumin-treated, iron-starved cultures are enriched in unbudded cells, suggesting that the G(1) phase of the cell cycle is lengthened. A delay in cell cycle progression could, in part, explain the antitumorigenic properties associated with curcumin. We also demonstrate that curcumin causes a growth lag in cultured human cells that is remediated by the addition of exogenous iron. These findings suggest that curcumin-induced iron starvation is conserved from yeast to humans and underlies curcumin's medicinal properties.

  20. Hepcidin: an emerging biomarker for iron disorders, inflammatory diseases, and infections

    Science.gov (United States)

    Westerman, Mark E.; Olbina, Gordana; Ostland, Vaughn E.; Nemeth, Elizabeta; Ganz, Tomas

    2010-04-01

    The peptide hormone hepcidin, has emerged as the master regulator of iron homeostasis. Dysregulation of hepcidin is a principal or contributing factor in most genetic and acquired systemic iron disorders, including anemia of inflammation (anemia of chronic disease). Hepcidin maintains healthy blood iron levels by regulating dietary iron absorption and transport from body iron stores to plasma. High serum hepcidin levels observed in chronic and acute inflammatory conditions can cause anemia by limiting plasma iron available for erythropoiesis. Chronically low serum hepcidin levels cause iron-overload and ultimately, accumulation of iron in liver and heart. We recently validated the first immunoassay for serum hepcidin and established the normal ranges in adults. Hepcidin has excellent potential as a biomarker and has a known mechanism of action, good stability, and rapid response to iron stores, inflammatory stimuli, and bacterial infections. Hepcidin can be measured in blood, urine, and saliva, and is generally not measurable in iron deficient/anemic patients and highly elevated in inflammatory diseases and infections. Intrinsic LifeSciences (ILS) is developing second generation hepcidin immunoassays and lateral-flow POC devices for hepcidin, a well characterized multi-purpose biomarker with applications in global health security.