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1
SAITO, HIROSHI. "METABOLISM OF IRON STORES". Nagoya University School of Medicine, 2014. http://hdl.handle.net/2237/20543.
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2
Alvarez-Hernandez, J. "Iron metabolism in macrophages". Thesis, University of Glasgow, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375442.
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3
Xue, Yue 1978. "Iron metabolism in mammalian cells". Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=79216.
Testo completoAbstract (sommario):
Iron, known for its versatility, is an essential element in the metabolism of mammalian cells. One of the most common iron disorders is autosomal recessive disease---hereditary hemochromatosis, which leads to the iron overload in population of northern European descent. During years of my graduate research, I focused on the study of Hemochromatosis gene Hfe and a point mutation C282Y that leads to more than 80% of all hemochromatosis cases.Iron Regulatory Proteins (IRPs), which serve as main posttranscriptional regulators of cellular iron homeostasis, are the other interest of research. Iron regulatory proteins reversibly interact with iron regulatory elements (IREs) within ferritin and transferrin receptor (TfR) mRNAs. The binding ability of IRPs is under tight control so that they respond to the changes in the intracellular iron requirements in a coordinate manner by differentially regulating ferritin mRNA translational efficiency and TfR mRNA stability. Besides intracellular iron levels, some other stimuli, such as oxidative stress, are capable of regulating this RNA-protein interactions.
4
Whitnall, Megan. "Iron metabolism, chelation and disease". Thesis, The University of Sydney, 2011. https://hdl.handle.net/2123/28914.
Testo completoAbstract (sommario):
Organisms depend on iron to survive. This fact is underscored by the critical requirement for iron during DNA synthesis and as a cofactor in proteins involved in respiration and oxygen transport. However, when present in excess of cellular requirements, iron can be toxic, due to its ability to generate reactive oxygen species and induce oxidative stress. The physiological significance of iron renders it a target for the development of iron chelators as therapeutic agents and highlights the potential problems that can occur when iron regulatory pathways are disturbed in disease.
The rapid rate of neoplastic cell replication and the involvement of iron in cell cycle progression and DNA synthesis, highlight the potential for using iron chelators for cancer treatment. Chapter 3 of this thesis demonstrates the broad-spectrum in vitro and in vivo anti-tumour activity of the novel iron chelator, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) (Whitnall et.al., Proc Natl Acad Sci USA 2006; 103:14901-6). In vitro results illustrate the potency of Dp44mT over the clinically used chemotherapeutic agent, doxorubicin, and the ability of Dp44mT to overcome multidrug resistance. The unique ability of Dp44mT to up-regulate the tumour growth and metastasis suppressor, Ndrgl in in vivo experiments, may account for this ligands selective anti-tumour activity (Whitnall et al., 2006). Collectively, these studies demonstrate that iron chelators such as Dp44mT, may be valuable anti-cancer compounds, particularly considering the emergence of multi-drug resistance in tumours.
There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich 's ataxia (FA). The identification of potentially toxic mitochondrial iron deposits in FA suggests iron plays a role in its pathogenesis and merits the use of iron chelation therapy for the treatment of FA. Studies in Chapters 4 and 5 used the muscle creatine kinase (MCK) frataxin mutant mouse model that reproduces the classical traits associated with cardiomyopathy in FA, to study the molecular alterations which underlie the pathogenesis of this disease and assess the use of iron chelation therapy (Whitnall et.al., Proc Natl Acad Sci USA 2008; 105:9757-62). Studies specifically in Chapter 4 show that the increased mitochondrial iron in the myocardium of mutants was due to marked transferrin-iron uptake, which was the result of enhanced transferrin receptor 1 (TfRl) expression. 1n contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic iron were decreased in mutant mice, indicating the cytosol was iron deficient. These studies demonstrate that loss of frataxin alters cardiac iron metabolism due to pronounced changes in iron trafficking away from the cytosol to the mitochondrion.
Further work in Chapter 4 showed that the mitochondrial-permeable ligand, pyridoxal isonicotinoyl hydrazone, in combination with the hydrophilic chelator, desferrioxamine, prevented cardiac iron loading and limited cardiac hypertrophy in mutants, but did not lead to overt cardiac iron depletion or toxicity (Whitnall et al., 2008). However, iron chelation did not prevent decreased succinate dehydrogenase expression in the mutants nor loss of cardiac function, indicating that frataxin function must also be replaced in addition to removing the excess mitochondrial iron. In summary, for the first time, studies in this thesis demonstrate that frataxin deficiency markedly alters cellular iron trafficking and that iron chelation limits myocardial hypertrophy in the MCK mutant model of FA.
To address the cytosolic iron deficiency in the cardiomyocytes of mutant mice, in Chapter 5, mice were fed a high iron diet aimed at reconstituting the iron deprived cytosolic compartment. From these studies, a significant decrease in cardiac hypertrophy was observed in high iron diet fed mice. Interestingly, while wild-type (WT) mice responded to the high iron diet by decreasing cardiac TfRl expression, no such compensation was observed in high-compared to normal-iron iron diet fed mutants. Similarly, activity of iron regulatory protein 2 (i.e., IRP2 RNA-binding activity) was not decreased in high iron diet fed mutants. These findings demonstrate the mutant heart does not respond to increased iron levels as does the WT animal. An intriguing and important outcome of dietary iron loading investigations, was the marked increase in iron concentration observed in the liver, spleen and kidney of mutant mice that were fed a normal iron diet. The MCK mutant mouse experiences deletion of frataxin in the heart only, and hence, the increase in iron levels observed in frataxin intact tissues such as the liver, indicated that the heart is able to influence systemic iron metabolism. Supporting this, changes were observed in iron-metabolism proteins such as hemojuvelin and TfRl not only in the heart, but in the liver. Collectively, these results indicate that frataxin knockout in the heart and the alterations in iron metabolism which lead to cytosolic iron deficiency in the heart, activate a systemic signalling mechanism, most likely to communicate its need for iron within the cytosolic compartment.
In the final section of Chapter 5, transmission electron microscopy and magnetic susceptibility measurements were used to assess the molecular composition of accumulated iron in the MCK mutants. These studies showed that the iron accumulating in the mutant heart is not present within ferritin, but in well crystallised antiferromagnetic mineral aggregates.
In conclusion, the investigations described within this thesis demonstrate the potential for iron chelators to be used for the treatment of cancer and FA. Moreover, they also begin to elucidate the marked alterations in the pathways of iron metabolism that occur on both a cellular and systemic level in FA. ln terms of contributing to our understanding of basic physiological iron homeostasis, they also identify that cardiac iron status is able to markedly influence systemic iron metabolism.
5
Ekins, Andrew John. "Iron acquisition by Histophilus ovis". Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=38481.
Testo completoAbstract (sommario):
Five strains (9L, 642A, 714, 5688T and 3384Y) of Histophilus ovis were investigated with respect to iron acquisition. All strains used ovine, bovine and goat, but not porcine or human, transferrins (Tfs) as iron sources for growth. In solid phase binding assays, total membranes from only two (9L and 642A) of the five strains, grown under iron-restricted conditions, were able to bind Tfs (ovine, bovine and goat, but not porcine or human). However, when the organisms were grown under iron-restricted conditions in the presence of bovine Tf, total membranes from all strains exhibited Tf binding (as above); competition experiments demonstrated that all three Tfs (ovine, bovine and goat) were bound by the same receptor(s). An affinity isolation procedure allowed the isolation of two putative Tf-binding polypeptides (78 and 66 kDa) from total membranes of strains 9L and 642A grown under iron-restricted conditions, and from membranes of all strains if the growth medium also contained Tf. A gene encoding a Pasteurella multocida TbpA homologue was shown to be present in each of two representative strains (9L and 3384Y); these genes were sequenced and determined to be the structural genes encoding the 78-kDa Tf-binding polypeptides. The identification of a fur homologue and a Fur box within the promoter region of tbpA in both strains indicated that Fur (and iron) is responsible for the iron-repressible nature of Tf-binding activity. Although tbpA transcripts were detected by reverse transcription (RT)-PCR with RNA isolated from strains 9L and 3384Y grown under iron-restricted conditions, with strain 3384Y, and depending on the primer pair, tbpA transcripts were detected by RT-PCR predominantly when the RNA was isolated from cells grown under conditions of iron-restriction in the presence of Tf. The presence of an additional G in the tbpA gene of strain 3384Y grown under iron-replete conditions, compared to organisms grown under iron-restricted conditions plus bovine Tf, is
6
Sritharan, Manjula. "Studies in iron metabolism of mycobacteria". Thesis, University of Hull, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278446.
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Lopes, Tiago Jose da Silva. "Systems biology analysis of iron metabolism". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2011. http://dx.doi.org/10.18452/16417.
Testo completoAbstract (sommario):
Jede Zelle des Säugetierorganismus benötigt Eisen als Spurenelement für zahlreiche oxidativ-reduktive Elektronentransfer-Reaktionen und für Transport und Speicherung von Sauerstoff. Der Organismus unterhält daher ein komplexes Regulationsnetzwerk für die Aufnahme, Verteilung und Ausscheidung von Eisen. Die intrazelluläre Regulation in den verschiedenen Zelltypen des Körpers ist mit einer globalen hormonellen Signalstruktur verzahnt. Sowohl Eisenmangel wie Eisenüberschuss sind häufige und ernste menschliche Krankheitsbilder. Sie betreffen jede Zelle, aber auch den Organismus als Ganzes. In dieser Dissertation wird ein mathematisches Modell des Eisenstoffwechsels der erwachsenen Maus vorgestellt. In ihm wird die Flussbilanz des Eisens in den wichtigsten Zelltypen in Form von transmembranalen und intrazellulären kinetischen Gleichungen dargestellt, und es werden diese Zellmodelle mit dem zentralen Eisenaustausch-Kompartiment (Blutplasma) des Körpers integriert. Der Eisenstatus wird charakterisiert als Gehalt an labil gebundenen Eisen und an ferritin-gebundenen Eisen für jede Zelle. Der Stoffwechsel wird als Netzwerk von Flussdynamik formuliert. Der experimentelle Input in dieses Modells stammt von verschiedenen Quellen. Radioaktive Tracerdaten, gemessen am intakten Tier (Mausstamm C57BL6 – das am intensivsten studierte Tiermodell) unter varrierten physiologischen Bedingungen lieferten den experimentellen Hintergrund, von dem aus Clearance-Parameter durch numerisches Fitting ermittelt wurden. Es wird gezeigt, dass das Modell mit entsprechend adaptierten Parametersätzen die wichtigsten metabolischen und regulatorischen Ereignisse in Übereinstimmung mit den Messungen darstellen kann. In Zukunft soll die quantitative Übereinstimmung mit Daten aus weiteren genetischen Rekonstruktionen (globale und zell-spezifische knock-outs und konstitutive Expression relevanter Gene des Modellorganismus Maus) hergestellt werden.Every cell of the mammalian organism needs iron as trace element in numerous oxido-reductive processes as well as for transport and storage of oxygen. The mammalian organism maintains therefore a complex regulatory network of iron uptake, excretion and intra-body distribution. Here a mathematical model of iron metabolism of the adult mouse is presented. It formulates the iron flux balance of the most important cell types of the organism in the form of transmembraneous and intracellular kinetic equations and integrates these cell models with the central exchange compartment (blood plasma) of the body. The iron status is represented as content of labile iron and of ferritin-bound iron in every cell type, and the metabolism is formulated as a network of flux dynamics. The experimental input into the model stems from different sources. Radioactive tracer data measured in the intact animal (mouse strain C57BL6 - the most intensively studied animal model) under various physiological conditions provided the experimental background from which clearance parameters could be obtained by numerical parameter fitting. Future research should render more precise the quantitative representation of genetic reconstructions (global and cell-type-addressed knock-out and constitutive expression of relevant genes of the model mouse strain).
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Bahrami, Fariborz. "Iron acquisition in Actinobacillus suis". Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85880.
Testo completoAbstract (sommario):
Seven strains of Actinobacillus suis (ATCC 15557, B49, C84, H89-1173, H91-0380, SO4 and VSB 3714) were investigated with respect to iron acquisition from animal transferrins (Tfs) and haemoglobins (Hbs). Growth assays with porcine, bovine and human Tfs and Hbs revealed that all seven strains could use porcine (but not human or bovine) Tf and all three Hbs as iron sources. In solid phase binding assays, membranes derived from all strains exhibited strong binding of porcine Tf and each of the Hbs. Competition binding assays indicated that all three Hbs were bound by the same receptor(s). Affinity procedures allowed the isolation and identification of iron repressible Tf-binding (~100 kDa and ~63 kDa) and Hb-binding (~105 kDa) polypeptides from all strains. Nucleotide sequence analyses revealed that A. suis strains SO4 and C84 possess genes that encode homologues of the Actinobacillus pleuropneumoniae Tf-binding proteins, TbpA and TbpB, and Hb-binding protein, HgbA. In both strains, tbpB was located immediately upstream of tbpA and was shown to be preceded by tonB, exbB and exbD homologues; hgbA was shown to be preceded by a hugZ homologue. Putative promoter and Fur box sequences were located upstream of tonB and hugZ and RT-PCR revealed that the genes in each of these clusters (tonB-exbB-exbD-tbpB-tbpA; hugZ-hgbA) are co-transcribed and iron-repressible. The molecular masses of the predicted mature TbpA, TbpB and HgbA proteins were calculated to be 104.3, 63.4 and 105.0 kDa, respectively, suggesting that the affinity-isolated, ~100 kDa and ~63 kDa Tf-binding polypeptides represent TbpA and TbpB, respectively, and that the ~105 kDa Hb-binding polypeptide represents HgbA. TbpB of A. suis was expressed in Escherichia coli and the recombinant TbpB (rTbpB) was identified by immunoblotting using swine sera raised against recombinant TbpB (A. pleuropneumoniae). It is envisaged that the acquisition of Tf- and Hb-bound iron by A. suis involves mechan
9
Bae, Dong-Hun. "The Effects of Iron Levels on the Interaction between Polyamine Metabolism and Iron Metabolism in Neoplastic Cells". Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18081.
Testo completoAbstract (sommario):
Iron is a crucial element that is associated with many metabolic pathways important for life sustaining processes. Polyamines are small positively charged polycations involved in various physiological functions. Both iron and polyamines levels are known to be high in cancer cells which suggests a possible unexplored link between the two metabolic pathways. For the first time, we demonstrate that iron-depletion robustly regulates the expression of 13 polyamine pathway proteins. Iron-depletion also decreased polyamine and S-adenosylmethionine levels (required for spermidine/spermine biosynthesis) and decreased 3H-spermidine uptake in accordance with expression of the polyamine importer, SLC22A16. The “reprogramming” of polyamine metabolism by iron-depletion showed dependence on the proto-oncogene, c-Myc, and tumour suppressor, p53 expression. Furthermore, the ability of iron chelators to inhibit proliferation can be rescued by polyamine supplementation. Collectively, these data demonstrate that iron and polyamine metabolism are closely linked at multiple levels. Moreover, we have identified that the mRNA and protein expression of the iron-containing enzyme, aci-reductone dioxygenase 1 (ADI1), was regulated by iron levels. Cellular iron depletion or deficient ADI1 metalation by the iron chaperone, PCBP1, promotes the proteasomal degradation of ADI1. Collectively, this demonstrates that cellular iron regulates ADI1 stability, a key enzyme involved in methionine salvage, polyamine biosynthesis and proliferation. In addition to regulating ADI1, poly(rC)-binding proteins (PCBPs) have been reported to function as iron-binding chaperones that deliver iron to ferritin. We observed that PCBP2 enhances, while PCBP1 inhibits ferritin 59Fe-loading and ferritin protein expression. Our results suggest that the regulation of ferritin iron-loading by PCBPs may involve a combination of translational regulation and/or iron chaperone activity. Overall this study has demonstrated for the first time the direct interaction between iron metabolism and polyamine metabolism, which is important in understanding how cancer cells can survive adverse environments.
10
Tremblay, Yannick. "Acquisition of haemoglobin-bound iron by Histophilus somni". Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82441.
Testo completoAbstract (sommario):
Ovine (strains 9L and 3384Y) and bovine (strains 649, 2336 and 8025) isolates of Histophilus somni were investigated for their ability to acquire iron from haemoglobin (Hb). Bovine isolates were capable of utilizing bovine, but not ovine, porcine or human Hb as a source of iron. Ovine isolates could not obtain iron from Hb. Bovine isolates bound bovine, ovine, and human Hbs by means of the same iron-repressible receptor(s) and produced a ~120-kDa iron-repressible, outer membrane protein. Using PCR approaches, an iron-regulated operon containing hugX and hugZ homologues and a gene (hgbA) that encodes a TonB-dependent, Hb-binding proteins were identified in strains 649, 9L and 3384Y. In strains 9L and 3384Y, HgbA is truncated offering a possible explanation for their lack of utilization of Hb as an iron source. In strains 2336 and 8025, expression of HgbA was also subject to a form of phase variation.
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Zetterström, Fernaeus Sandra. "Changed iron metabolism and iron toxicity in scrapie-infected neuroblastoma cells". Doctoral thesis, Stockholm University, Department of Neurochemistry, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-661.
Testo completoAbstract (sommario):
Reactions and interactions of iron and oxygen can be both beneficial and detrimental to cells and tissues. Iron is mainly found in our blood where it functions as a mediator in the transport of oxygen to the cells and is further vital for the cellular respiration reducing the oxygen to water. The flexible redox state of iron makes it ideal to contribute in single electron transfers, but may also catalyze reactions with oxygen resulting in cell damaging reactive oxygen species (ROS). Normally the cells are protected against iron toxicity by controlling iron uptake and storage. When the intracellular demand for iron increases; the iron uptake is promoted by increasing the expression of transferrin receptor (TfR) and by decreasing the expression of the iron storage protein ferritin. Ferritin has a central role in the cellular iron detoxification by keeping it in a non reactive but still bioavailable form. However, in neurodegenerative diseases like in Alzheimer’s and Parkinson’s disease the iron storage capacity is disturbed and iron induced oxidative stress adds to the pathology of the diseases. The role of iron and its possible contribution to the pathology of prion diseases, like Creutzfeldt-Jakob disease, is less explored. In the first three studies of this thesis, the iron metabolism and the mutual relation between iron and oxygen are studied in scrapie-infected mouse neuroblastoma cells (ScN2a) as compared to control cells (N2a). In the fourth study we have analyzed the expression of ferritin and TfR in response to inflammation by treating the cells with the bacterial endotoxin lipopolysaccharide (LPS). LPS promotes the expression of inducible nitric oxide synthase (iNOS), a producer of nitric oxide (NO), a well known regulator of the iron metabolism.
In the first study, the scrapie infection was found to reduce the iron levels, to reduce the mRNA and protein levels of ferritin and the TfR. In addition, reduced levels and activities of the iron regulatory proteins 1 and 2 were observed as compared to the uninfected N2a cells.
In the second study, the addition of iron to the cell medium strongly increased the level of ROS and decreased the cell viability of the ScN2a cells, whereas the N2a cells were unaffected. The ferritin expression in N2a cells in response to the iron treatment was strongly increased and the concomitant measurement of the labile iron pool (LIP) revealed the LIP to be normalized within four hours. In the ScN2a cells the induction of ferritin expression was lower resulting in elevations in LIP that lasted up to 16 h, indicating that the increased ROS levels were iron catalyzed.
In the third study, the cells were challenged with hydrogen peroxide (H2O2) to elevate the oxidative stress and to analyze the effects on the LIP and cell viability. The ScN2a cells were sensitive to the increased oxidative stress according to the cell viability test, and responded to the treatment with marked increase in the LIP levels, probably derived from an intra-cellular source. The cell viability could be reset by the co-addition of an iron chelator to the cell media. The N2a cells did not elevate the LIP and resisted higher concentrations of H2O2 than the ScN2a cells, according to the cell viability assay.
In the fourth study, the LPS treatment resulted in increased mRNA levels of the heavy chain of ferritin, increased the protein levels of ferritin light chain and decreased the protein levels of the TfR in N2a cells, but no effects were observed in the ScN2a cells. Co-treatment with LPS and the iNOS inhibitor aminoguanidine did not affect the LPS induced decrease of TfR in N2a cells, whereas the free radical scavenger N-acetyl-L-cysteine reversed the effect of LPS on TfR expression, indicating that the changes were mediated by an oxidative rather than a nitric oxide mechanism in the N2a cells.
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Zetterström, Fernaeus Sandra. "Changed iron metabolism and iron toxicity in scrapie-infected neuroblastoma cells /". Stockholm : Dept. of neurochemistry, Stockholm university, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-661.
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Åkesson, Agneta. "Cadmium exposure and iron status /". Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4290-0/.
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Kobylarz, Marek John. "Siderophore-mediated iron metabolism in Staphylococcus aureus". Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/57023.
Testo completoAbstract (sommario):
Staphylococcus aureus requires iron as a nutrient and uses uptake systems to extract iron from the human host. S. aureus produces the iron-chelating siderophore staphyloferrin B (SB) to scavenge for available iron under conditions of low iron stress. Upon iron-siderophore re-entry into the cell, iron is separated from the siderophore complex to initiate assimilation into metabolism. To gain insight into how SB biosynthesis is integrated into S. aureus central metabolism, the three SB precursor biosynthetic proteins, SbnA, SbnB, and SbnG, were biochemically characterized. SbnG is a citrate synthase analogous to the citrate synthase enzyme present in the TCA cycle. The crystal structure of SbnG was solved and superpositions with TCA cycle citrate synthases support a model for convergent evolution in the active site architecture and a conserved catalytic mechanism. Since L-Dap is an essential precursor for SB, the biosynthetic pathway for L-Dap was elucidated. A combination of X-ray crystallography, biochemical assays and biophysical techniques were used to delineate the reaction mechanisms for SbnA and SbnB, demonstrating that SbnA performs a β-replacement reaction using O-phospho-L-serine (OPS) and L-glutamate to produce N-(1-amino-1-carboxy-2-ethyl)-glutamic acid (ACEGA). Oxidative hydrolysis of ACEGA catalyzed by SbnB produces α-ketoglutarate and L-Dap. Detailed analysis of the substrate specificity of SbnA revealed that OPS binding and conversion to the PLP-α-aminoacrylate intermediate in SbnA induced a conformational change and formation of a second substrate binding pocket for L-glutamate. Furthermore, L-cysteine was identified as a competitive inhibitor of SbnA activity, revealing a link between iron uptake and the oxidative stress response in S. aureus. IruO was examined for its role in Fe(III)-siderophore reduction. Utilizing a combination of visible spectroscopy and enzyme kinetics, a mechanism for electron transfer was proposed. IruO was demonstrated to reduce iron bound hydroxamate-type siderophores to release Fe(II) using NADPH as the electron donor. Under anaerobic conditions, IruO formed a stable FAD semiquinone intermediate that mediates a single electron transfer from the FAD to the Fe(III)-siderophore complex. These studies have shown how SB precursors are synthesized and led to the development of models for SB biosynthesis integration into central metabolism under conditions of low iron stress.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
15
Kingsley, Robert Anthony. "Iron uptake and metabolism by Salmonella enterica". Thesis, University of Leicester, 1997. http://hdl.handle.net/2381/29735.
Testo completoAbstract (sommario):
Serovars of the genus Salmonella scavenge iron (III) chelated with low molecular weight compounds called siderophores. The transport of one such group of siderophores, the ferroxamines, was investigated using sensitivity growth stimulation bioassays. Uptake of all three ferrioxamines tested was demonstrated to be dependent upon transport across the outer membrane via the FoxA protein. Wild-type levels of transport required the TonB protein, however, lower yet significant transport of iron complexed with ferroixamines B and E, but not G, appeared to occur by a TonB-independent mechanism. Transport of all three ferrioxamines across the inner membrane, like all other hydroxamate siderophores, was found to be dependent on the periplasmic binding protein-dependent inner membrane ABC transporter consisting of FhuBCD. The distribution of the foxA receptor gene within the genus Salmonella was determined by DNA hybridisation and found to be limited to S. enterica subspecies, I, II and IIIb. S. enterica serovar Typhimurium strains unable to utilise ferrixoamines B, E and G as a sole of source of iron were found to have a small but significant disadvantage in colonising rabbit ileal loops compared to the wild-type parent strain. Furthermore, a strain containing this mutation was highly attenuated in mice after oral inoculation.;A range of structurally diverse -keto and -hydroxy acids promoted growth of a number of mutants of serovars of S. enterica subspecies I by a TonB-dependent mechanism. A S. enterica serovar Typhimurium strain containing a TnphoA insertion in the gene encoding the periplasmic binding protein component of an inner membrane ABC transporter system was found to be unable to utilise -keto acids at high iron limitation. Excretion of a number of -keto acids into culture supernatants occured in response to iron limitation and was found to be regulated by Fur.
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Nixon, Gavin James. "Studies in the iron metabolism of mycobacteria". Thesis, University of Hull, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310267.
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Hoque, Rukshana. "The effects of quercetin on iron metabolism". Thesis, King's College London (University of London), 2014. https://kclpure.kcl.ac.uk/portal/en/theses/the-effects-of-quercetin-on-iron-metabolism(c3f5d9ca-eeaf-4fa7-9878-5b04552e6367).html.
Testo completoAbstract (sommario):
Polyphenols are known to be major inhibitors of dietary non-haem iron bioavailability, mainly through their action as iron chelators. In this present study Caco-2 cells were used to investigate the influence of quercetin, the most abundant flavonol in the diet, on non-haem iron bioavailability using 55Fe, and the gene expression of intestinal iron transporters as measured via qPCR. Chronic exposure to quercetin (24 hours) had no significant effect on iron uptake but iron efflux was significantly decreased. Consistent with this, qPCR analysis revealed a significant decrease in basolateral transport genes ferroportin (FPN) and hephaestin expression suggesting polyphenols may have direct gene regulatory effects. Exploring the cellular mechanisms underlying quercetin-induced FPN down-regulation, transfection of 5’FPN promoter constructs showed quercetin did not affect activity but did decrease FPN1A mRNA whilst increasing FPN1B expression; this suggests that although FPN1B is specific to intestinal epithelial cells, FPN1A remains the major isoform. FPN 3’UTR miRNA array analysis identified candidate hsa-miR-17-3p to be significantly activated by quercetin (1.5 fold) and qPCR validation confirmed up-regulation of 101 ± 25.1 -fold (p<0.01). This represents a novel mechanism of quercetin-induced miRNA-mediated regulation of FPN. In HepG2 cells quercetin stimulated hepcidin expression and inhibited ferroportin gene expression; this may provide an additional means of regulating systemic iron levels. Quercetin was shown to be both pro- and anti- proliferative/apoptotic dependent on the concentration used which may have beneficial consequences for liver pathology of iron-overload diseases. In contrast to findings in Caco-2 cells, in Thp1 macrophages quercetin caused a significant dose-dependent increase in FPN expression. Furthermore, quercetin induced both FPN1A and 1B promoter activities. This strongly implies that quercetin acts at the level of the FPN promoter to increase FPN expression - an effect specific to macrophages only. This demonstrates that quercetin has cell-specific effects and its actions on FPN are differentially regulated dependent on cell/tissue type. The results show that quercetin can have multiple effects on iron homeostasis. Given its relatively long half-life in the circulation, repeated dietary intake of quercetin could lead to plasma accumulation in vivo. This may have important consequences for conditions that are low in iron such as anaemia; alternatively it has therapeutic potential for iron overload diseases such as haemochromatosis. By deducing the mechanisms of how dietary polyphenols interact with our intake of essential nutrients such as iron, intake can be optimised to harness the potential benefits polyphenols have to offer.
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Mitchell, Simon. "A computational model of human iron metabolism". Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/a-computational-model-of-human-iron-metabolism(c3afe167-4a40-42aa-8fd8-a65e47dfe7eb).html.
Testo completoAbstract (sommario):
Iron is essential for virtually all organisms, yet it can be highly toxic if not properly regulated. Only the Lyme disease pathogen Borrelia burgdorferi has evolved to not require iron (Aguirre et al., 2013).Recent findings have characterised elements of the iron metabolism network, but understanding of systemic iron regulation remains poor. To improve understanding and provide a tool for in silico experimentation, a computational model of human iron metabolism has been constructed. COPASI was utilised to construct a model that included detailed modelling of iron metabolism in liver and intestinal cells. Inter-cellular interactions and dietary iron absorption were included to create a systemic computational model. Parameterisation was performed using a wide variety of literature data. Validation of the model was performed using published experimental and clinical findings, and the model was found to recreate quantitatively and accurately many results. Analysis of sensitivities in the model showed that, despite enterocytes being the only route of iron uptake, almost all control over the system is provided by reactions in the liver. Metabolic control analysis identified key regulatory factors and potential therapeutic targets. A virtual haemochromatosis patient was created and compared to a simulation of a healthy human. The redistribution of control in haemochromatosis was analysed in order to improve our understanding of the condition and identify promising therapeutic targets. Cellular prion protein (PrP) is an enigmatic protein, implicated in disease when misfolded, but its physiological role remains a mystery. PrP was recently found to have ferric-reductase capacity. Potential sites of ferric reduction were simulated and the findings compared to PrP knockout mice experiments. I propose that the physiological role of PrP is in the chemical reduction of endocytosed ferric iron to its ferrous form following transferrin receptor-mediated uptake.
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Xu, Xiangcong. "THE MOLECULAR MECHANISMS OF IRON AND FERRITIN METABOLISM IN". University of Sydney, 2008. http://hdl.handle.net/2123/3535.
Testo completoAbstract (sommario):
Doctor of Philosophy(PhD)Iron (Fe) is essential for cell growth and replication as many Fe-containing proteins catalyse key reactions involved in energy metabolism (cytochromes, mitochondrial aconitase and Fe-S proteins of the electron transport chain), respiration (hemoglobin and myoglobin) and DNA synthesis (ribonucleotide reductase). If not appropriately shielded, Fe could participate in one-electron transfer reactions that lead to the production of extremely toxic free radicals. The Fe storage protein, ferritin, is essential to protect cells against Fe-mediated oxidative stress by accommodating excess Fe into its protein shell (Xu et al., 2005). However, despite intensive research over the last few decades, many questions relating to intracellular Fe metabolism, e.g. Fe release from ferritin remain unanswered. Therefore, it is important to elucidate the molecular mechanisms of Fe trafficking in cells. At the beginning of my candidature, little was understood regarding the effect of anti-cancer agents, anthracyclines on the Fe-regulated genes, including transferrin receptor-1 (TfR1), N-myc downstream-regulated gene-1 (Ndrg1) and ferritin. Furthermore, the mechanisms of ferritin-Fe release and anthracycline-mediated ferritin-Fe accumulation are unclear. The work presented in Chapters 3 and 4 has addressed these issues. Apart from the studies examining the molecular interactions of anthracyclines with Fe, a mouse model with perturbed Fe metabolism was used and the marked alterations of protein expression in the heart of this knockout mouse model was discussed in Chapter 5. Chapter 3 Anthracyclines are effective anti-cancer agents. However, their use is limited by cardiotoxicity, an effect linked to their ability to chelate iron (Fe) and perturb Fe metabolism (Xu et al., 2005). These effects on Fe-trafficking remain poorly understood, but are important to decipher as treatment for anthracycline cardiotoxicity utilises the chelator, dexrazoxane. Incubation of cells with doxorubicin (DOX) up-regulated mRNA levels of the Fe-regulated genes, transferrin receptor-1 (TfR1) and N-myc downstream-regulated gene-1 (Ndrg1). This effect was mediated by Fe-depletion, as it was reversed by adding Fe and was prevented by saturating the anthracycline metal-binding site with Fe. However, DOX did not act like a typical chelator, as it did not induce cellular Fe mobilisation. In the presence of DOX and 59Fe-transferrin, Fe-trafficking studies demonstrated ferritin-59Fe accumulation and decreased cytosolic-59Fe incorporation. This could induce cytosolic Fe-deficiency and increase TfR1 and Ndrg1 mRNA. Up-regulation of TfR1 and Ndrg1 by DOX was independent of anthracycline-mediated radical generation and occurred via HIF-1α-independent mechanisms. Despite increased TfR1 and Ndrg1 mRNA after DOX treatment, this agent decreased TfR1 and Ndrg1 protein expression. Hence, the effects of DOX on Fe metabolism were complex due to its multiple effector mechanisms. Chapter 4 The Fe storage protein, ferritin, can accommodate up to 4500 atoms of Fe in its protein shell (Harrison and Arosio, 1996). However, the underlying mechanism of ferritin-Fe release remains unknown. Previous studies demonstrated that anti-cancer agents, anthracyclines, led to ferritin-59Fe accumulation (Kwok and Richardson, 2003). The increase in ferritin-59Fe was shown to be due to a decrease in the release of Fe from this protein. It could be speculated that DOX may impair the Fe release pathway by preventing the synthesis of essential ferritin partner proteins that induce Fe release. In this study, a native protein purification technique has been utilised to isolate ferritin-associated partners by combining ultra-centrifugation, anion-exchange chromatography, size exclusion chromatography and native gel electrophoresis. In addition to cells in culture (namely, SK-Mel-28 melanoma cells), liver taken from the mouse was used as a physiological in vivo model, as this organ is a major source of ferritin. Four potential partner proteins were identified along with ferritin, e.g. aldehyde dehydrogenase 1 family, member L1 (ALDH1L1). Future studies are required to clarify the relationship of these proteins with cellular Fe metabolism and ferritin-Fe release. Chapter 5 A frequent cause of death in Friedreich’s ataxia patients is cardiomyopathy, but the molecular alterations underlying this condition are unknown. We performed two dimensional electrophoresis to characterise the changes in protein expression of hearts using the muscle creatine kinase frataxin conditional knockout (KO) mouse. Pronounced changes in the protein expression profile were observed in 9-week-old KO mice with severe cardiomyopathy. In contrast, only a few proteins showed altered expression in asymptomatic 4-week-old KO mice. In hearts from frataxin KO mice, components of the iron-dependent complex-I and -II of the mitochondrial electron transport chain and enzymes involved in ATP homeostasis (creatine kinase, adenylate kinase) displayed decreased expression. Interestingly, the KO hearts exhibited increased expression of enzymes involved in the citric acid cycle, catabolism of branched-chain amino acids, ketone body utilisation and pyruvate decarboxylation. This constitutes evidence of metabolic compensation due to decreased expression of electron transport proteins. There was also pronounced up-regulation of proteins involved in stress protection, such as a variety of chaperones, as well as altered expression of proteins involved in cellular structure, motility and general metabolism. This is the first report of the molecular changes at the protein level which could be involved in the cardiomyopathy of the frataxin KO mouse.
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Gelling, Cristy Lee Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Tetrahydrofolate and iron-sulfur metabolism in Saccharomyces cerevisiae". Publisher:University of New South Wales. Biotechnology & Biomolecular Sciences, 2008. http://handle.unsw.edu.au/1959.4/43270.
Testo completoAbstract (sommario):
Tetrahydrofolate-mediated one-carbon metabolism is required for the biosynthesis of many central metabolites, including some amino acids, nucleobases, and nucleotides, and hence dysfunction of one-carbon metabolism is associated with many human diseases and disorders. The mitochondrial glycine decarboxylase complex (GDC) is an important component of one-carbon metabolism, generating 5,10-methylene-tetrahydrofolate (5,10-CH2-H??4folate) from glycine. Previous work has shown that the genes encoding the unique sub-units of the Saccharomyces cerevisiae GDC (GCV1, GCV2 and GCV3) are regulated in response to changes in the levels of cytosolic 5,10-CH2-H??4folate (Piper et al., 2000). Given the centrality of 5,10-CH2-H??4folate to many aspects of metabolism, it was hypothesised that other genes may be regulated by the same mechanism. Using microarray analysis of S. cerevisiae under a number of conditions that affect 5,10-CH2-H??4folate levels, the ??one-carbon regulon??, a group of genes that were co-regulated with the GCV genes was identified. The one-carbon regulon corresponds closely to genes whose promoters are bound by the purine biosynthesis regulator Bas1p, but not all one-carbon regulon members are significantly purine regulated. Genetic approaches demonstrated that the one-carbon unit response and the purine response are distinct, though both depend on the presence of Bas1p. This demonstrated that the close metabolic connections of one-carbon and purine metabolism are reflected in over-lapping, but separable regulatory mechanisms. The identity of the sensor of one-carbon unit depletion remains unknown, but in the course of investigation of the candidate regulator Caf17p, it was demonstrated that Caf17p is in fact involved in Fe/S cluster protein maturation. Examination of the effects of Caf17p depletion revealed that Caf17p is required for the function and maturation of the related mitochondrial Fe/S proteins aconitase and homoaconitase, as well as the function of, but not de novo iron incorporation into, the mitochondrial radical-SAM Fe/S protein biotin synthase. Because other Fe/S proteins were unaffected, Caf17p appears to be a specialised Fe/S maturation factor. The presence of a putative H4folate binding site indicates that Caf17p may constitute a metabolic link between one-carbon and iron metabolism.
21
Dzikaitė, Vijolė. "Studies of proteins in heme and iron metabolism /". Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-762-2/.
Testo completo
22
Sun, Xuesong. "Iron metabolism mediated by MtsA, transferrin and desferrioxamine". View the Table of Contents & Abstract, 2006. http://sunzi.lib.hku.hk/hkuto/record/B37552995.
Testo completo
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Sun, Xuesong, e 孫雪松. "Iron metabolism mediated by MtsA, transferrin and desferrioxamine". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B38722446.
Testo completo
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Moshtaghie, A. A. "Interrelationships between aluminium and iron metabolism in man". Thesis, University of Newcastle Upon Tyne, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380213.
Testo completo
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Ferreira, Patrícia Daniela Oliveira. "Regulation of iron metabolism in different bacterial infections". Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/14598.
Testo completoAbstract (sommario):
Mestrado em Biomedicina MolecularIron is found in almost all living organisms, playing a central role in host-pathogen interactions and being crucial for both host and pathogens. In the host, iron is a crucial element, since it plays a key role in biological processes such as oxygen transport, biosynthesis of DNA, energy production and regulation of gene expression. However, high concentrations of iron can also be toxic to cells due to the ability to generate hydroxyl radicals. Thus, vertebrates developed proteins to transport and store iron: transferrin and ferritin, respectivetly. Hepcidin is a key protein of iron metabolism, since it binds to ferroportin, the iron exporter, regulating the release of iron to the serum. On the other hand, iron is also fundamental for pathogens that required it to its growth and proliferation, to the expression of virulence factors and to metabolic processes. Thereby, during infection, the host and the pathogen compete by this metal. Pathogens developed multiple strategies to acquire iron from the host during infection. Thus, making iron unavailable for microorganisms is a central mechanism in host defense. In this work, we investigated the regulation of iron metabolism in host during infection with Listeria monocytogenes, a gram-positive bacterium and Salmonella Typhimurium, a gram-negative bacterium in order to verify whether there are alterations in host iron metabolism depending of infection type and if hepcidin have a central role in these alterations. C57BL6 male mice were infected with 104 CFU of L. monocytogenes, S. Typhimurium, or an equivalent volume of vehicle and sacrificed at different time points. Bacterial load quantification, non-heme iron determination in liver, evaluation of iron distribution in tissue, histopathologic analyses and the expression of genes related with iron metabolism were analyzed. Our results show that in both infections with L. monocytogenes and S. Typhimurium the host immune system are not able to irradiate the infection and, thus, the bacterial load increases during the experiment. Regarding the hematological and serological parameters, a reduction of red blood cells and hematocrit is observed, as well as, of serum iron levels. The levels of interleukin-6 and hepcidin increase at different time points in each infection. Additionally, non-heme iron concentration increases in liver during infection with both pathogens. Histopathological alterations were also detected during infection with L monocytogenes and S. Typhimurium. Our data suggests that both infections induce alterations in host iron metabolism. However, the infection with S. Typhimurium appears to have earlier and more severe effects in the host than infection with L. monocytogenes.
O ferro é encontrado em quase todos os seres vivos, desempenhando um papel central nas interacções entre o hospedeiro e o patógeno e sendo essencial para ambos. Para o hospedeiro, o ferro é um elemento crucial, uma vez que desempenha um papel chave em processos biológicos como o transporte de oxigénio, a biossíntese de DNA, produção de energia e regulação da expressão génica. No entanto, elevadas concentrações de ferro também podem ser tóxicas para as células devido à capacidade de gerarem radicais hidroxilo. Assim, os vertebrados possuem proteínas para transportar e armazenar o ferro, a transferrina e a ferritina respetivamente. A hepcidina é uma proteína chave do metabolismo do ferro, uma vez que se liga à ferroportina, o exportador do ferro, regulando a libertação de ferro para o soro. Por outro lado, o ferro é também fundamental para os patógenos, que o requerem para o seu crescimento e proliferação, para a expressão de factores de virulência e para vários processos metabólicos. Assim, durante a infecção, o hospedeiro e o patógeno competem por este metal. Os patógenos desenvolveram múltiplas estratégias para adquirir o ferro a partir do hospedeiro durante a infeção. Deste modo, tornar o ferro indisponível para os microrganismos é um mecanismo central na defesa do hospedeiro. Neste trabalho, investigámos a regulação do metabolismo do ferro no hospedeiro durante a infecção com Listeria monocytogenes, uma bactéria gram-positiva e com Salmonella Typhimurium, uma bactéria gram-negativa, de modo a verificar se existem alterações no metabolismo do ferro do hospedeiro dependendo do tipo de infeção e se a hepcidina tem um papel preponderante nestas alterações. Murganhos machos C57BL6 foram infectados com 104 CFU de L. monocytogenes, S. Typhimurium, ou um volume equivalente de veículo e sacrificados a diferentes tempos experimentais. A quantificação da carga bacteriana, determinação do ferro não hémico no fígado, avaliação da distribuição de ferro no tecido, análise histopatológica e a expressão de genes relacionados com o metabolismo do ferro foram analisados. Os nossos resultados mostram que tanto na infeção com L. monocytogenes como na infeção com S. Typhimurium, o sistema imunitário do hospedeiro não é capaz de irradiar a infeção e, assim, a carga bacteriana aumenta durante a experiência. Em relação aos parâmetros hematológicos e serológicos, é observada a redução da quantidade de eritrócitos e do hematócrito, bem como dos níveis de ferro no soro. Os níveis de interleucina-6 e de hepcidina aumentam em diferentes tempos experimentais em cada infeção. Adicionalmente, a concentração de ferro não hémico aumenta no fígado durante a infeção com ambos os patógenos. Foram também detetadas alterações histopatológicas aquando da infeção com L monocytogenes e S. Typhimurium. Os nossos dados sugerem que ambas as infeções induzem alterações no metabolismo do ferro do hospedeiro. Contudo, a infeção com S. Typhimurium parece ter efeitos mais precoces e mais severos no hospedeiro do que a infeção com L. monocytogenes.
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Govus, Andrew. "The regulation of human iron metabolism in hypoxia". Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2015. https://ro.ecu.edu.au/theses/1719.
Testo completoAbstract (sommario):
Athletes commonly use altitude exposure in an attempt to improve their aerobic performance at sea level. Altitude exposure enhances erythropoiesis and iron-dependent oxidative and glycolytic enzyme production, for this reason, athletes must maintain a healthy iron balance at altitude. A negative iron balance at altitude may limit such physiological adaptations, potentially reducing the performance benefits of altitude exposure.
This thesis examined the regulation of iron metabolism during acute (~31 min, Study One) and prolonged altitude exposure (14 days, Study Two). Finally, Study Three examined how daily oral iron supplementation influenced haemoglobin mass (Hbmass) and iron parameter responses to prolonged, moderate altitude exposure in a large cohort of elite athletes. Specifically, Study One found acute (~31 min) interval exercise [5 × 4 min at 90% of the maximal aerobic running velocity (vVO2max)] increased post-exercise interleukin-6 (IL-6) production and elevated hepcidin production 3 h thereafter in both normoxia (fraction of inspired oxygen (FIO2) = 0.2093) and normobaric hypoxia (i.e. 3,000 m simulated altitude; FIO2 = 0.1450). These results suggest exercise performed in acute hypoxia does not alter the post-exercise hepcidin response, relative to exercise in normoxia, possibly owing to the short duration of the hypoxic stimulus.
Prolonged altitude exposure suppresses resting hepcidin levels in sojourning mountaineers, but its influence on the post-exercise hepcidin response exercise has not yet been investigated. Therefore, Study Two investigated how 14 days of live high: train low (LHTL) (exposure to 3,000 m simulated altitude for 14 h.d-1) influenced resting levels of hepcidin, erythropoietin (EPO) and blood iron parameters. Study Two also examined the post-exercise hepcidin and iron parameter responses to interval exercise (5 × 1,000 m at 90% of the maximal aerobic running velocity) performed in normoxia (600 m natural altitude) and normobaric hypoxia (i.e. ~3,000 m simulated altitude), following 11 and 14 days of LHTL. The post-exercise hepcidin response was compared with interval exercise performed at a matched exercise intensity in normoxia or hypoxia before LHTL. Here, LHTL suppressed resting hepcidin levels after two days of exposure, but the post-exercise hepcidin response to interval exercise was similar in normoxia and hypoxia, both before and after LHTL. Additionally, Hbmass increased by 2.2% and plasma ferritin levels decreased following LHTL. In conclusion, prolonged, moderate altitude exposure suppresses resting hepcidin levels, which likely ensures more iron can be transported to the erythron to support accelerated erythropoiesis.
Prolonged altitude exposure places a large burden on body iron stores because additional iron is required to support accelerated erythropoiesis. Accordingly, athletes often ingest oral iron supplements during altitude exposure to ensure they maintain a healthy iron balance. By analysing ten years of haematological data collected from welltrained athletes who undertook two-to-four weeks of LHTL at simulated (3,000 m) or natural (1,350-2,700 m) altitudes, Study Three established how oral iron supplement dose moderates the Hbmass, serum ferritin and transferrin saturation response to prolonged moderate altitude exposure. In general, athletes supplemented with 105 mg.d- 1 or 210 mg.d-1 of oral iron supplement increased their Hbmass from pre-altitude levels by 3.3% and 4.0% respectively. Serum ferritin levels decreased by 33.2% in non-iron supplemented athletes and by 13.8% in athletes supplemented with 105 mg.d-1 of oral iron, however, those athletes who ingested 210 mg.d-1 markedly increased their iron storage compartment by 36.8% after moderate altitude exposure. Thus, daily oral iron supplementation at altitude assists athletes to maintain a healthy iron balance, providing them with sufficient iron to sustain accelerated erythropoiesis.
In conclusion, this thesis suggests exercise in acute hypoxia does not seem to alter the post-exercise hepcidin response relative to exercise in normoxia, but prolonged altitude exposure suppresses resting hepcidin levels and may attenuate the magnitude of postexercise hepcidin response after 14 days of LHTL. Finally, daily oral iron supplementation may support iron balance and Hbmass production in athletes undertaking prolonged moderate altitude exposure.
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Maddocks, Sarah Elizabeth. "Iron metabolism in bacteria : examination of the Feo system (Ferrous iron transporter) and Dps-iron storage proteins". Thesis, University of Reading, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434313.
Testo completo
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Danzeisen, Ruth. "Iron metabolism by BeWo cells : the role of copper and iron in the regulation of placental iron transfer". Thesis, University of Aberdeen, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364703.
Testo completoAbstract (sommario):
In this thesis, the regulation of placental Fe metabolism is investigated, using a placental choriocarcinoma cell line (BeWo). Both copper (Cu) and iron (Fe) status are examined for a possible role in the process of placental Fe transfer. Firstly, the involvement of Cu in Fe release is tested. Ceruloplasmin (Cp), a plasma Cu carrier and ferroxidase, is implicated in Fe release from a variety of cell types, but does not stimulate Fe release from BeWo cells. Instead, evidence is presented for a membrane-associated ferroxidase with homology to Cp, expressed by BeWo cells. This placental protein has a peri-nuclear location, but does not co-localise with classical markers for organelles. Expression of the placental Cu oxidase is inversely regulated by Fe status, indicating a possible role in Fe metabolism. Further, it is regulated by cellular Cu status, with protein levels and enzyme activity decreasing in Cu deficiency. In an environment of limited oxygen supply, Cu deficient BeWo cells display a decrease in Fe release, providing additional support for a role of the placental Cu oxidase in Fe release. Secondly, the role of Cu in Fe uptake in investigated. Cu status does not affect Fe uptake through transferrin-receptor mediated endocytosis. However, a non-transferrin dependent pathway of Fe uptake is up-regulated in Cu deficiency. Cu and Fe compete for uptake by this pathway, indicating that it may be mediated by a non-specific transporter, such as DMT1. Finally, the effect of Fe deficiency on Fe transfer by BeWo cells was investigated. It is demonstrated that Fe uptake and Fe release both increase in Fe deficient cells.
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Wang, Jian 1966. "Molecular control of iron metabolism in mammalian cells : new insights into iron regulatory proteins". Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86063.
Testo completoAbstract (sommario):
Iron is an essential but potentially harmful metal element. Iron regulatory protein 1 and IRP2 posttranscriptionally control cellular iron homeostasis by binding to iron-responsive elements (IREs). Binding of IRPs to single IRE within 5'-untranslated region (5'-UTR) of ferritin mRNA attenuates biosynthesis of the iron-storage protein by translational repression, while their binding to multiple IREs within 3'-UTR of transferrin receptor 1 (TfR1) mRNA stimulates that of the iron-acquisition protein through mRNA stabilization. IRP1 and IRP2 share extensive homology, but respond to levels of cellular iron by distinct mechanisms. According to cellular iron status, IRP1 is switched between the states of RNA-binding and cytosolic (c-)aconitase by reversible assembly of a cubane [4Fe-4S] cluster. In contrast, IRP2 is mainly regulated through iron-dependent proteasomal degradation. Previous studies have identified constitutive IRP mutants. Substitution of any IRP1 cluster-coordinating cysteine residue with serine rendered the mutant (such as IRP1C437S) constitutively active for IRE-binding. In the case of IRP2, replacement of cysteines at positions of 168, 174 and 178 within an IRP2-specific, 73-amino-acid fragment (73 aa) was reported to yield an apparently stable mutant (IRP23CS). This project was initially designed to study the functional characteristics of IRPs in vivo by stably expressing constitutive IRP mutants in human cells. To this end, we first established clones of human lung (H1299) and breast (MCF7) cancer cells that express epitope-tagged IRP1C437S in a tetracycline-dependent manner and characterized the biological effects associated with IRP1C437S expression (Chapter II). In agreement with the commonly accepted regulatory model of IRE/IRP regulatory system, we demonstrated that IRP1C437S stimulates TfR1 by stabilizing its mRNA, resulting in increased uptake of cellular iron from 59Fe-transferrin. However, we observed a more complex
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Stys, Agnieska. "Role of iron regulatory proteins in the regulation of iron metabolism by nitric oxide". Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T056.
Testo completoAbstract (sommario):
Les Iron Regulatory Proteins 1 (IRP1/2) sont des protéines cytosoliques qui contrôlent l’homéostasie du fer chez les mammifères. Elles régulent la concentration de fer intracellulaire au niveau post-transcriptionnel, en interagissant spécifiquement avec des motifs appelés iron responsive élément (IREs). Ces motifs sont localisés dans les régions non traduites des ARNm codant notamment pour la ferritine (Ft), la ferroportine (Fpn) et le récepteur de la transferrine (TfR1). L’IRP1 est une protéine bifonctionnelle, majoritairement exprimée sous une forme contenant un centre [4Fe-4S] qui présente une activité aconitase. Les deux activités de l’IRP1 (aconitase/trans-régulateur) s’excluent mutuellement par la présence ou non du centre Fe-S. L’IRP2 est exprimée constitutivement sous une forme liant les IREs. Le monoxyde d’azote (NO), une importante molécule de signalisation impliquée dans les défenses immunitaires, cible le centre Fe-S de l’IRP1 et permet la conversion de l’IRP1 de sa forme aconitase vers sa forme liant les séquences IREs. Il a également été rapporté que l’IRP2 détecterait NO, cependant la fonction intrinsèque de l’IRP1 et de l’IRP2 dans le contrôle du métabolisme du fer intracellulaire en réponse à NO reste à ce jour non élucidée. Dans cette étude, nous avons identifié le régulateur principal du métabolisme du fer intracellulaire en réponse à NO, en utilisant des modèles de souris déficients pour les gènes IRP1 et/ou IRP2 et testé la contribution de la tension en oxygène dans cette régulation. Ainsi, nous avons exposé des macrophages primaires issus de la moelle osseuse de souris Irp1-/-, Irp2-/- et de souris Irp1-/- Irp2-/- de la lignée macrophagique à une source de NO, sous différentes tensions en oxygène. Les activités IRPs, l’expression des gènes Ft, Fpn et TfR1 ainsi que l’activité d’une protéine à centre Fe-S (l’aconitase mitochondriale) ont été mesurées après fractionnement cellulaire. Nous avons montré qu’en normoxie, la conversion de l’aconitase cytosolique en apo-IRP1 par NO est entièrement responsable de la régulation post-transcriptionnelle des ferritines (L-Ft et H-Ft), de la Fpn et du TfR1. En augmentant le transport du fer intracellulaire et en diminuant le stockage et l’export, l’activation de l’IRP1 par NO servirait à maintenir des taux de fer intracellulaire suffisants pour alimenter la biogenèse des centres Fe-S après l’arrêt des flux de NO. En effet, nous observons une restauration efficace de l’activité de l’aconitase mitochondriale dans les macrophages de souris sauvage alors qu’elle est bloquée dans les macrophages de souris Irp1-/-. De plus, l’IRP1 activée par NO, permet également de diminuer les taux de L- et H-Ft, anormalement élevée dans les macrophages de souris Irp2-/-. Nous montrons que le NO endogène active l’IRP1 sous sa forme trans-régulatrice alors qu’il tend à diminuer l’activité de l’IRP2. Néanmoins, l’IRP1 reste le régulateur principal des ferritines en conditions de normoxie. En condition hypoxique, les deux IRPs semble coopérer pour inhiber la traduction des ferritines car dans les macrophages Irp1-/-exposés à NO, l’IRP2 stabilisée est suffisante pour inhiber la traduction de la L- et H-Ft et ceci malgré l’activation transcriptionnelle des gènes de la L- et H-Ft. Concernant la régulation du TfR1 par NO et en hypoxie, TfR1 est principalement régulé par une voie transcriptionnelle dominant largement la voie post-transcriptionnelle impliquant l’IRP1. Le facteur de transcription HIF-1 alpha pourrait être le régulateur critique dans cette régulation. En conclusion, nous montrons dans cette étude, comment le regulon IRP participe à la régulation du métabolisme du fer intracellulaire en réponse à NO et son étroite connexion avec la concentration en oxygène. Nos résultats soulignent l’importance d’explorer davantage le rôle de l’IRP1 dans des situations inflammatoires in vivo, où les tissus peuvent être exposé à un microenvironnement non hypoxiqueIron Regulatory Protein 1 (IRP1) and 2 (IRP2) are two cytosolic regulators of mammalian cellular iron homeostasis. IRPs post-transcriptionally modulate expression of iron-related genes by binding to specific sequences, called Iron Regulatory Elements (IREs), located in the untranslated regions (UTR) of mRNAs. Either of the two IRPs inhibits translation when bound to the single 5’UTR IRE in the mRNA encoding proteins of iron export (ferroportin - Fpn) and storage (ferritin - Ft) or prevents mRNA degradationwhen bound to the multiple IREs within the 3’UTR of the mRNA encoding the transferrinreceptor 1 (TfR1) - iron uptake molecule. The IRE-binding activity of both IRPs respondsto cellular iron levels, albeit via distinct mechanisms. IRP1 is a bifunctional protein, whichmostly exists in its non IRE-binding, [4Fe-4S] aconitase form and can be regulated by apost-translational incorporation or removal of the Fe-S cluster. In contrast to IRP1, IRP2 isnot able to ligate an Fe-S cluster, and its IRE-binding activity is determined by the rate ofits proteasomal degradation. Although both IRP1 and IRP2 can regulate cellular ironhomeostasis, only mice lacking IRP2 were shown to display iron mismanagement in mosttissues. This could be explained by the fact that IRP1 exists mostly in its non IRE−binding,aconitase form under physiological oxygen conditions (3-6%). Interestingly, nitric oxide(NO), an important signalling molecule involved in immune defence, targets the Fe-Scluster of IRP1 in both normoxia and hypoxia, and converts IRP1 from aconitase to anIRE-binding form. It has also been reported that IRP2 could sense NO, but the intrinsicfunction of IRP1 and IRP2 in NO−mediated regulation of cellular iron metabolism hasremained a matter of controversy. In this study, we took advantage of mouse models ofIRP deficiency to define the respective role of IRP1 and IRP2 in the regulation of cellulariron metabolism by NO and assess the contribution of oxygen tension on the regulation.Therefore, we exposed bone marrow-derived macrophages (BMMs) from Irp1-/-, Irp2-/- andmacrophage specific double knockout mosaic mice (Irp1/2-/-) to exogenous andendogenous NO under different oxygen conditions (21% O2 for normoxia and 3-5% forhypoxia experiments) and measured IRPs activities, iron-related genes expression andactivity of Fe-S cluster protein – mitochondrial aconitase. We showed that in normoxia, thegenerated apo-form of IRP1 by NO was entirely responsible for the post-transcriptionalregulation of TfR1, H-Ft, L-Ft and Fpn. Moreover, by increasing iron uptake and reducingiron sequestration and export, NO−dependent IRP1 activation served to maintainadequate levels of intracellular iron in order to fuel the Fe−S biosynthetic pathway, asdemonstrated by the efficient restoration of the mitochondrial Fe−S aconitase, which wasprevented under IRP1 deficiency. Furthermore, activated IRP1 was potent enough todown-regulate the abnormally increased L-Ft and H-Ft protein levels in Irp2-/-macrophages. Endogenous NO activated IRP1 IRE-binding activity and tended todecrease IRP2 IRE-binding activity. Nevertheless, IRP1 was the predominant regulator offerritin in those conditions. In hypoxia, in Irp1+/+ and Irp2+/+ macrophages exposed to NO,both stabilized IRP2 and NO-activated IRP1 seemed to cooperate to inhibit ferritinsynthesis. However, in Irp1-/- cells, IRP2 stabilized in hypoxia was sufficient to inhibit LandH-Ft synthesis despite the concomitant increase of corresponding mRNAs.Interestingly, TfR1 was shown to be predominantly regulated at the transcriptional level byNO in hypoxia, in which HIF-1 alpha may be the critical regulator. In conclusion, we revealin this study how the IRP regulon participates in the regulation of cellular iron metabolismin response to NO and its intimate interplay with the oxygen pathway. The findingsunderlie the importance to further explore the role of IRP1 in inflammation in vivo, in nonhypoxictissue microenvironments
31
Quisumbing, Teresita Lambo. "Studies of iron metabolism and metabolic rate in iron-deficient and cold-acclimatized rats". Hong Kong : University of Hong Kong, 1985. http://sunzi.lib.hku.hk/hkuto/record.jsp?B1231545X.
Testo completo
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SIGHINOLFI, SILVIA. "INTRACELLULAR IRON OVERLOAD AFFECTS HSC METABOLISM BY IMPAIRING MITOCHONDRIAL FITNESS IN β-THALASSEMIA". Doctoral thesis, Università Vita-Salute San Raffaele, 2023. https://hdl.handle.net/20.500.11768/137019.
Testo completoAbstract (sommario):
Mitochondrial activity and metabolism significantly control hematopoietic stem cell (HSC) function and fate. HSCs change the metabolic state in response to stress signals, such as reactive oxygen species (ROS), which drive HSC entry into cell cycle accompanied by increased mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis. However, excessive accumulation of ROS results in oxidative damage of cellular organelles, including mitochondria. Iron is one of the sources of ROS and HSCs can uptake iron but little is known about the effects of iron on HSC metabolism.
Recently, we demonstrated an impaired function of HSCs in β-Thalassemia (BThal), a condition of systemic iron overload (IO). We also observed that IO reduces the hematopoietic supportive capacity of BThal BM mesenchymal stromal cells. However, there is no evidence of the direct effect of IO on HSCs in BThal. We hypothesized that IO and the resulting oxidative stress could alter HSC metabolism and function.
We found a positive enrichment of iron homeostasis genes in HSCs from thalassemic th3 mice, suggesting increased iron uptake and storage. Consistently, we detected high levels of free reactive iron in the cytoplasm and in mitochondria of th3 HSCs, correlating with high ROS levels. As a result, mitochondria are impaired, with low mass and activity. Interestingly, th3 multipotent progenitors inherited dysfunctional mitochondria since the rescue of mitochondrial activity occurred in the transition to more committed progenitors. In line with mitochondrial dysfunction, th3 HSCs had reduced OXPHOS-derived ATP and relied on glycolysis. In vivo reduction of mitochondrial ROS rescued mitochondrial activity and metabolism, and increased th3 HSC frequency and quiescence, thus indicating that oxidative stress is the cause of mitochondrial dysfunction and potentially HSC defects. Importantly, in vivo administration of iron dextran to wt mice generated intracellular IO and mitochondrial oxidative stress and decreased mitochondrial activity in HSCs, indicating that IO alone is sufficient to impair mitochondria.
Our study unveils that IO directly impacts on HSC metabolism by inducing oxidative stress and mitochondrial dysfunction. Alterations in mitochondrial activity and metabolic profile, in response to IO, are expected to alter HSC function. This research will add novel insight about the role of iron in regulating HSC metabolism and provide clues for improving clinical conditions associated to IO, such as BThal.L'attività e il metabolismo mitocondriali controllano in modo significativo la funzione e il destino delle cellule staminali ematopoietiche (HSC). Le HSC modificano lo stato metabolico in risposta a segnali di stress, come le specie reattive dell'ossigeno (ROS), che guidano l'ingresso delle HSC nel ciclo cellulare accompagnato da un aumento della fosforilazione ossidativa mitocondriale (OXPHOS) e della glicolisi. Tuttavia, l'eccessivo accumulo di ROS provoca il danno ossidativo degli organelli cellulari, compresi i mitocondri. Il ferro è una delle fonti di ROS e le HSC possono assorbire il ferro, ma si sa poco sugli effetti del ferro sul metabolismo delle HSC. Recentemente, abbiamo dimostrato una funzione alterata delle HSC nella β-talassemia (BThal), una condizione di sovraccarico sistemico di ferro (IO). Abbiamo anche osservato che l'eccesso di ferro riduce la capacità di supporto ematopoietica delle cellule stromali mesenchimali talassemiche. Tuttavia, non ci sono prove dell'effetto diretto del sovraccarico di ferro sulle HSC in BThal. Abbiamo ipotizzato che il sovraccarico di ferro e il conseguente stress ossidativo alterino il metabolismo e la funzione delle HSC. Abbiamo trovato un arricchimento positivo dei geni dell'omeostasi del ferro nelle HSC dei topi talassemici th3, suggerendo un aumento dell'assorbimento e dell'immagazzinamento del ferro. Coerentemente, abbiamo rilevato alti livelli di ferro reattivo libero nel citoplasma e nei mitocondri di th3 HSC, che correlano con alti livelli di ROS. Di conseguenza, i mitocondri sono alterati, con ridotta massa e attività. I progenitori multipotenti th3 hanno ereditato mitocondri disfunzionali poiché la correzione dell'attività mitocondriale si è verificata nella transizione verso progenitori più differenziati. In linea con la disfunzione mitocondriale, le HSC th3 hanno una ridotta produzione di ATP mediante OXPHOS e dipendono dalla glicolisi. La riduzione in vivo dei ROS mitocondriali ha ripristinato l'attività e il metabolismo mitocondriali e ha aumentato la frequenza e la quiescenza delle HSC th3, dimostrando così che lo stress ossidativo è la causa della disfunzione mitocondriale e dei potenziali difetti delle HSC. È importante sottolineare che la somministrazione in vivo di ferro destrano a topi wt ha generato eccesso di ferro intracellulare e stress ossidativo mitocondriale e una ridotta attività mitocondriale nelle HSC, indicando che il sovraccarico di ferro da solo è sufficiente per compromettere i mitocondri. Il nostro studio rivela che il sovraccarico di ferro ha un impatto diretto sul metabolismo delle HSC inducendo stress ossidativo e disfunzione mitocondriale. Le alterazioni dell'attività mitocondriale e del profilo metabolico, in risposta al sovraccarico di ferro, potrebbero alterare la funzione delle HSC. Questa ricerca aggiungerà nuove informazioni sul ruolo del ferro nella regolazione del metabolismo delle HSC e fornirà nuove conoscenze utili per migliorare le condizioni cliniche caratterizzate da sovraccarico di ferro, come BThal.
33
Fosset, Cedric. "Iron and copper interactions in humans : models and mechanisms". Thesis, Robert Gordon University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268863.
Testo completo
34
Morris, Patricia Ann. "EXAFS of non-heme iron containing proteins". Diss., Georgia Institute of Technology, 1986. http://hdl.handle.net/1853/27402.
Testo completo
35
Peers, Graham Stewart. "Increased metabolic requirements for manganese and copper in iron-limited marine diatoms". Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85950.
Testo completoAbstract (sommario):
Productivity in large areas of the world's oceans is limited by low concentrations of dissolved iron in surface waters. Phytoplankton have adapted to persist in these environments by reducing their requirements for iron (Fe) in key metabolic pathways, in some cases by replacing Fe-containing catalysts with their iron-free functional equivalents. This thesis examines the requirements and biochemical roles for copper (Cu) and manganese (Mn) in Fe-limited centric marine diatoms. A major finding of my research is that diatoms have elevated requirements for Mn and Cu when grown in Fe-deficient seawater. Iron deficiency induces oxidative stress and increases the cellular concentrations of toxic oxygen radicals and damage products in Thalassiosira pseudonana. The increased Mn-requirement is used, in part, to activate Mn-containing isoforms of the antioxidant enzyme superoxide dismutase. Cultures co-limited by Fe and Mn exhibit high levels of oxidative stress and an inefficient detoxification pathway that further reduces cell growth. Diatoms isolated from the metal poor open ocean require more Cu to divide than related species from metal-rich coastal waters. This pattern is in stark contrast to all other known nutritive trace metals. One part of the diatom Cu requirement that is independent of provenance is for efficient Fe transport. The additional Cu requirement of oceanic species appears to be due to the constitutive expression of a Cu-containing electron transport protein, possibly plastocyanin. Coastal species, which have higher Fe-requirements for growth, retain the Fe-containing functional homologue cytochrome c6. By employing metals other than Fe within photosynthesis and antioxidant pathways, marine diatoms are able to increase their fitness in Fe-deficient environments. However, Mn and Cu also occur in low concentrations in the open ocean and thus may co-limit growth of natural populations of phytoplankton. Metal enrichment experiments i
36
Constante, Pereira Marco. "Development of synthetic biology devices for iron metabolism research". Doctoral thesis, Universitat Pompeu Fabra, 2011. http://hdl.handle.net/10803/53579.
Testo completoAbstract (sommario):
Synthetic biology is a fairly recent field that aims to engineer novel functions in biological systems. In a broad sense synthetic biology encompasses the development of tools that makes the engineering of biology easier. In this thesis I develop a collection of standard DNA parts (Biobricks) that consists of a tool to build custom eukaryotic plasmids. This is not just intended for biology researchers in the field of synthetic biology, but also for more general use. Besides the development of molecular biology tools that facilitate the engineering of biology, synthetic biology researchers have implemented devices that are electronics-like in behavior and have demonstrated the potential of the field for the production of biofuels, pharmaceutics and biosensors. Here I present a sensor of iron regulatory protein activity, based on Biobricks. To demonstrate its use I apply it to the study of a novel reconstituted two cell-type co-culture (BNL CL.2 and RAW 264.7), surrogate for hepatocyte-macrophage communicationLa biología sintética es un campo recientemente desarrollado con el objectivo de implementar nuevas funciones en sistemas biológicos. De forma global, la biología sintética incluye el desarrollo de herramientas para facilitar la ingeniería de sistemas biológicos. En diversas publicaciones, investigadores en el campo de la biología sintética han implementado dispositivos que funcionan de forma similar a circuitos electrónicos y han demonstrado el potencial del campo para la producción de biocarburantes, farmaceuticos y biosensores. Para la presente tesis he creado una colección de plasmidos estandarizados (Biobricks) que pueden ser de interés para biólogos fuera del campo da la biología sintética. Además, utilizando estos Biobricks, he creado un sensor de la actividad de las proteínas reguladas por el hierro. Para demonstrar su aplicación, he utilizado el sensor para estudiar un nuevo sistema de co-cultura de dos tipos celulares (BNL CL.2 y RAW 264.7), substituto para la comunicación entre hepatocitos y macrófagos
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Metzendorf, Christoph. "Mitochondrial Iron Metabolism : Study of mitoferrin in Drosophila melanogaster". Doctoral thesis, Uppsala universitet, Jämförande fysiologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-114201.
Testo completoAbstract (sommario):
Iron has a dualistic character. On the one hand it is essential for the life of most organisms, on the other hand it is involved in the generation of reactive oxygen species that are implicated in diseases and aging. During evolution efficient mechanisms for uptake, handling and storage of iron in a safe way have developed to keep the balance between iron availability and minimizing the hazards. In eukaryotes, mitochondria are the central organelle for “metabolizing” iron and consequently play an important role in cellular iron homeostasis. Mitoferrins are mitochondrial carrier proteins, which are involved in iron transport into mitochondria. In vertebrates two mitoferrins exist, one (mitoferrin1) of which is essential for heme synthesis during erythropoiesis, while the function of the other (mitoferrin2) is not well defined. In the fruit fly we found only one mitoferrin gene (dmfrn), which codes most likely for a functional homologueof vertebrate mitoferrin2. In Drosophila cell culture, dmfrn overexpression resulted in an overestimation of cell sensed iron levels. The signal responsible for this, is most likely a yet unidentified compound of ISC synthesis. In the cell culture system we also showed that iron chelation blocks the progression of the cell cycle in a reversible and therefore most likely controlled way. Study of different dmfrn mutants indicates a role of dmfrn during spermatogenesis and development to adulthood. As dmfrn deletion mutants are not lethal, it is likely that other lower affinity iron transporters exist. A similar conclusion has been drawn by others from the study of yeast mitoferrin homologuemutants. Rim2p/Mrs12p has recently been implicated in mitochondrial iron transport, and might be an alternative metal carrier. We identified a putative homologuein the fruit fly and found a possible link between mutants in this gene and iron. Our results emphasize the importance of the mitochondrial iron metabolism in cellular iron homeostasis. We also show for the first time, a direct connection between the mitochondrial iron metabolism and spermatogenesis. Mutants characterized and developed by us will help to study these processes in further detail and reveal the underlying mechanisms.
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Procter, Catherine M. "The roles of the FRO genes in iron metabolism". Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313219.
Testo completo
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Schiffhauer, Samuel Peter. "Crosstalk Signaling Between Circadian Clock Components and Iron Metabolism". Diss., Virginia Tech, 2017. http://hdl.handle.net/10919/85398.
Testo completoAbstract (sommario):
Circadian rhythms are daily molecular oscillations within cells ranging from prokaryotes to humans. This rhythm is self sustaining, and receives external cues in order to synchronize an organism's behavior and physiology with the environment. Many metabolites utilized in metabolic processes seem to follow a pattern of circadian oscillation. Iron, an essential component in cellular processes such as respiration and DNA synthesis, is obtained almost exclusively through diet, yet little is known about how the clock governs iron metabolism. The regulation of iron within the cell is very tightly controlled, as iron is highly reactive in the generation of oxidative stress and the excretion of excess iron is very limited. There are limited findings indicating that there are molecular ties between the circadian clock and the regulation of iron metabolism.
The first half of my dissertation focuses on the role of the circadian clock in modulating expression of iron metabolic components. We found that key components of iron import, in TFRC, and export, in SLC40A1, show altered expression in response to changes in the expression of clock transcription components. Furthermore, in circadian synchronized HepG2 hepatocytes TFRC and SLC40A1 showed rhythms in their mRNA expression, although expression of these genes was highly altered in conditions of high iron availability. We also examined IREB2, which expresses a master regulator of iron concentration in IRP2. IRP2 showed rhythms in phase with circadian component PER2, and IRP2's rhythmicity was lost under iron overload conditions. We observed that the ability of these three critical iron metabolic components to respond to sudden increases in available iron was mitigated in cells with clock impairment. Whole cistrome and transcriptome analysis was used to determine that rhythmicity in TFRC and SLC40A1 are not equal in their recruitment of circadian protein binding or in the stage of transcription in which circadian rhythms are generated. The cumulative effect of all of this regulation is that rhythmic variation in intracellular hepatic ferrous iron is clock controlled.
The second half of my dissertation focuses on understanding how iron uptake influences clock resetting. Initially, iron was added to the cells in the form of ferrous sulfate, or chelated out of the cells using 2-2'-dipyridyl and clock gene expression was monitored. Altered rhythmicity of these components was seen at both the mRNA and protein level in cells with disrupted iron homeostasis. Then, we measured changes in period, phase, and amplitude of these rhythms, ultimately using a luciferase reporter cell line to demonstrate that even slight changes in cellular iron produce an effect on rhythmic period. We find that the circadian clock and iron metabolism pathway are intimately related, and that the intracellular iron concentration plays a role in circadian clock behavior.
Overall, our research illustrates the importance of the circadian clock in liver metabolism and physiology. Improper iron metabolism due to genetic or dietary shortcomings is common in humans, and our work builds on the importance of chronotherapy in treatment of these conditions. Conversely, our research into the effect intracellular iron has on the clock contributes to the growing body of research into how circadian clocks, especially the peripheral clock of the liver, receive input from a range of metabolites in conjunction with signals from the master oscillator of the suprachiasmatic nucleus.Ph. D.
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Rhodes, Christopher James. "Iron metabolism and biomarkers in idiopathic pulmonary arterial hypertension". Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/6915.
Testo completoAbstract (sommario):
Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterised by increased vascular resistance and remodelling of the pulmonary vasculature. This causes strain on the right ventricle, leading eventually to failure and death. Iron status is thought to influence pulmonary vascular tone, particularly in hypoxia, and may be important in IPAH. Proteomic studies of lung tissues from IPAH patients versus control lobectomy samples revealed downregulated levels of the haemoglobin- and haem-scavenging proteins haptoglobin (Hp) and haemopexin. Plasma levels of Hp were also reduced in IPAH and related to the Hp genotype. Consistently low Hp levels were associated with dysregulated iron homeostasis in IPAH patients. Iron deficiency, as defined by raised plasma soluble transferrin receptor (sTfR) levels, was prevalent in IPAH patients and related to increased levels of the master iron regulator hepcidin. Iron deficiency was also associated with poor exercise capacity, disease progression and mortality. Circulating sTfR levels were compared against other iron-related and established prognostic biomarkers in IPAH, including N-terminal brain natriuretic peptide (NT-proBNP), red cell distribution width (RDW), growth differentiation factor-15 and interleukin-6. All predicted survival and related to disease severity in IPAH, but RDW and NT-proBNP provided the most information when clinical and haemodynamic indices were considered. Dysfunctional bone morphogenetic protein (BMP) receptor type II (BMPR2) signalling contributes to idiopathic as well as heritable PAH. Downregulation of BMPR2, but not the other type II BMP receptors ActRIIA and ActRIIB, led to increased hepcidin expression and secretion in response to BMP-6 stimulation in hepatocellular carcinoma HepG2 cells. Hepcidin expression was also enhanced in rat lung tissue following 1 or 2 weeks exposure to hypoxia. In conclusion, dysregulation of iron homeostasis is common in IPAH and appears to be important clinically. Increased hepcidin levels may contribute to this phenomenon and reflect the dysfunctional BMPR2 signalling associated with the disease.
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Müller, Katrin [Verfasser]. "Regulation of iron metabolism during liver injury / Katrin Müller". Ulm : Universität Ulm. Fakultät für Naturwissenschaften, 2013. http://d-nb.info/1038734851/34.
Testo completo
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Ricard, Michelle. "Iron acquisition from porcine proteins by Actinobacillus pleuropneumoniae biotype 1". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0034/MQ64438.pdf.
Testo completo
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Hawula, Zachary John. "Identification and analysis of genetic and chemical modulators of iron metabolism". Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/225904/1/Zachary_Hawula_Thesis.pdf.
Testo completoAbstract (sommario):
This dissertation focused on identifying novel chemical and genetic modulators of iron homeostasis. Iron is an essential element for human health. Disorders such as anaemia and haemochromatosis can develop when iron levels are not maintained within a normal physiological range. The findings of this program included the identification of a new iron chelating compound, demonstration of iron chelation in a haemochromatosis mouse model by a flavonol, identification of iron metabolism-related genes and variants which may assist in distinguishing suitable blood donors, and the identification of novel genes which may contribute to modulating iron homeostasis by regulating the iron exporter ferroportin.
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Salmon, Timothy Peter Civil & Environmental Engineering Faculty of Engineering UNSW. "Physiological and genetic characterisation of iron acquisition by the coastal cyanobacterium Lyngbya majuscula (Oscillatoriales)". Publisher:University of New South Wales. Civil & Environmental Engineering, 2007. http://handle.unsw.edu.au/1959.4/40725.
Testo completoAbstract (sommario):
Large summertime proliferations (or blooms) of the noxious filamentous cyanobacterium Lyngbya majuscula have been observed in the coastal marine waters of Moreton Bay, Queensland. This photosynthetic organism is believed to have a high iron requirement and preliminary studies have shown that the presence of organically complexed iron stimulates growth. Since there is no evidence that Lyngbya produces siderophores to aid iron acquisition, it has been hypothesized that this organism may acquire iron via reduction of ferric complexes to the typically more labile, ferrous form. Both the phylogenetic diversity of the genus Lyngbya and the iron metabolism of L. majuscula are examined in this thesis. Software was developed to assist in the design of peR primers that targeted l6S rRNA, rpoB and Highly Iterated Palindrome (HIP) genetic structures and the subsequent phylogenetic analysis. The mechanism of iron acquisition by L. majuscula and the influence of organic complexation of iron were investigated using radioisotope and chemiluminescence-based techniques. Molecular techniques were also used to investigate the genetics of iron metabolism of L. majuscula. Results of the l6S rRNA analysis indicate that the morpho-genus Lyngbya encompasses a large genetic diversity within the cyanobacteria that is consistent with its reported metabolic and ecological diversity. Five discrete lineages comprised of organisms that fit the morophological definition of Lyngbya were discovered in this analysis. L. majuscula utilises endogenously-produced superoxide as a reductant of ferric complexes to produce the more labile ferrous forms. The nature of the organic complexes has been shown to determine the efficacy of this mechanism. A model of iron acquisition by these reductive processes was developed and was shown to generally describe all known methods of reduction-mediated iron acqUIsItIOn. Finally, the genetics of iron metabolism of L. majuscula was found to be consistent with the mechanism we propose, including the discovery of a component of a ferrous iron uptake mechanism.
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D'Silva, Colin Gerard. "Iron acquisition by Actinobacillus pleuropneumoniae". Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28720.
Testo completoAbstract (sommario):
Four strains of the swine pathogen Actinobacillus pleuropneumoniae, namely, the type strain (ATCC 27088), the "reference" strain of biotype 2 (Bertschinger 2008/76) and two additional biotype 1 strains, strain BC181, which is less virulent than the type strain, and strain K17 (reference strain of serotype 5A), which was isolated from a lamb, were investigated with respect to iron acquisition. All four strains produced iron-repressible outer membrane proteins. However, only strains ATCC 27088 and Bertschinger 2008/76 could acquire iron from porcine transferrin. No organism could utilize human, bovine or ovine transferrin, or ovine or porcine lactoferrin. Haemoglobin supported good growth of all strains except K17 (which also failed to acquire iron from haemin). In all cases, iron acquisition from transferrin or haemoglobin required direct contact between the organisms and the proteins. Total membranes derived from iron-restricted organisms were subjected to an affinity isolation technique based on biotinylated porcine transferrin and streptavidin-agarose, and the following polypeptides were isolated: 99 kDa and 64 kDa from strain ATCC 27088; 93 kDa from strain Bertschinger 2008/76; 95 kDa (trace amounts) and 60 kDa from strain BC181; none from strain K17. These polypeptides appear to be transferrin receptor components. The 99 kDa polypeptide (TBPl) from the type strain was purified by SDS-PAGE and transferred electrophoretically onto polyvinylidene difluoride membrane. The N-terminal amino acid sequence of the polypeptide was determined commercially. A commercially-synthesized oligonucleotide probe was used to clone the gene encoding the TBPl of the type strain in competent Escherichia coli DH5$ alpha$ cells.
46
Mettrick, Karla Adelle, e n/a. "Iron signalling pathways of Pseudomonas aeruginosa". University of Otago. Department of Biochemistry, 2008. http://adt.otago.ac.nz./public/adt-NZDU20081128.143145.
Testo completoAbstract (sommario):
The pathogenic bacterium Pseudomonas aeruginosa uses a variety of highly efficient chelating compounds (siderophores) to acquire sufficient iron for growth and virulence. These siderophores can either be endogenous or acquired from exogenous sources such as other bacteria or fungi. The transport of the endogenous siderophore pyoverdine activates a signal-transduction pathway that increases the synthesis of both the ferripyoverdine receptor protein (FpvA) and pyoverdine itself. Signal-transduction systems similar to this have three specific proteins involved: a receptor protein specific for one siderophore in the outer membrane, an anti-sigma factor in the cytoplasmic membrane and a sigma factor that activates gene expression in the cytoplasm.
The aim of the research presented in this thesis was to study the roles of the proteins in three different iron uptake and signalling pathways of P. aeruginosa. The substrates for each receptor protein were confirmed and the roles of each protein in the pathways were compared to the P. aeruginosa pyoverdine signalling pathway. The pyoverdine, desferrioxamine and ferrichrome transport pathways were studied to find whether interactions occur between them and if so, the mechanism(s) for that interaction. Furthermore, a technique for analysing gene expression of P. aeruginosa in sputum from the cystic fibrosis (CF) lung was developed. This technique was subsequently used to study the levels of iron responsive gene expression.
The receptor, sigma factor and anti-sigma factors were all found to have a role in the siderophore-induced expression of their own signalling pathway. The experimental data provide evidence of similarities in the roles of the sigma and receptor proteins within each pathway but different roles for the anti-sigma factors. In the absence of the cognate sigma factor or anti-sigma factor the expression of the desferrioxamine and ferrichrome receptors could not be upregulated. Without its cognate sigma factor fpvA could no longer be upregulated in the presence of pyoverdine. However, unlike the other systems, in the absence of the cognate anti-sigma factor, expression of fpvA was always observed. This is consistent with the anti-sigma factors being required for the activity of the cognate sigma factor in the ferrichrome and desferrioxamine signalling pathways but not the pyoverdine signalling pathway.
The siderophore signalling pathways were found to be upregulated in the presence of multiple siderophores, but generally to a lesser extent than if only one siderophore was available. This suggests that in the presence of multiple siderophores, P. aeruginosa uses all available iron chelators. The study of the role of the receptor, sigma factor and anti-sigma factor into these effects indicate sigma factor competition for RNA polymerase has a major role in the effects of multiple siderophores on pathways upregulation.
The gene expression studies of P. aeruginosa in sputum from the lungs of CF patients provided support for the hypothesis that the bacteria were growing in an environment where iron levels were sufficient for bacterial growth, but not storage of iron. The expression of the sigma factor gene pvdS that is required for pyoverdine synthesis was studied because expression of this gene is a sensitive reporter of intracellular iron levels. It was found to be downregulated in bacteria in sputum compared to laboratory grown bacteria. This result suggests the bacteria are inhabiting a more iron-replete environment within the lung. This finding advances our understanding of the CF lung environment and the impact it has on P. aeruginosa infection. This knowledge has medical implications for the development of novel therapies to combat P. aeruginosa infection.
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Park, Thomas. "The Role of NfuA Protein in Acinetobacter baumannii Iron Metabolism". Miami University Honors Theses / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=muhonors1303498264.
Testo completo
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Strickland, Natalie Judith. "In silico and functional analyses of the iron metabolism pathway". Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/79871.
Testo completoAbstract (sommario):
Thesis (PhD)--Stellenbosch University, 2013.ENGLISH ABSTRACT: Iron is an essential micronutrient that is an absolute requirement for correct cellular function in all eukaryotic organisms. However, ferrous iron has the ability to catalyze the formation of potentially toxic reactive oxygen species and regulation of iron metabolism is therefore of critical importance. Currently, there is little known about the co-ordinated regulation of the plethora of genes coding for proteins involved in this biochemical pathway, with the exception of the well characterized post-transcriptional IRE/IRP system. Regulation of gene expression in eukaryotic organisms is a highly intricate process. Transcriptional regulation is the first step and is controlled by the presence of specific cis-regulatory regions (cis-motifs), residing within the promoter region of genes, and the functional interactions between the products of specific regulatory genes (transcription factors) and these cismotifs. A combinatorial bioinformatic and functional approach was designed and utilized in this study for the analysis of the promoter architecture of genes of the iron metabolic pathway. The upstream non-coding region (~2 kb) of 18 genes (ACO1, CP, CYBRD1, FTH1, FTL, HAMP, HEPH, HFE, HFE2, HMOX1, IREB2, LTF, SLC11A2, SLC40A1, STEAP3, TF, TFRC, TFR2), known to be involved in the iron metabolism pathway, was subjected to computational analyses to identify regions of conserved nucleotide identity utilizing specific software tools. A subset of nine (CYBRD1, FTH1, HAMP, HFE, HFE2, HMOX1, IREB2, LTF, TFRC) of the genes were found to contain a genomic region that demonstrated over 75% sequence identity between the genes of interest. This conserved region (CR) is approximately 140 bp in size and was identified in each of the promoters of the nine genes. The CR was subjected to further detailed examination with comparative algorithms from different software for motif detection. Four specific cis-motifs were discovered within the CR, which were found to be in the same genomic position and orientation in each of the CR-containing genes. In silico prediction of putative transcription factor binding sites revealed the presence of numerous binding motifs of interest that could credibly be associated with a biological function in this pathway, including a novel MTF-1 binding site in five of the genes of interest. Validation of the bioinformatic predictions was performed in order to fully assess the relevance of the results in an in vitro setting. Luciferase reporter constructs for the nine CRcontaining genes were designed containing: 1) the 2 kb promoter, 2) a 1.86 kb promoter with the CR removed and 3) the 140 bp CR element. The expression levels of these three reporter gene constructs were monitored with a dual-luciferase reporter assay under standard culture conditions and simulated iron overload conditions in two different mammalian cell lines. Results of the luciferase assays indicate that the CR promoter constructs displayed statistically significant variation in expression values when compared to the untreated control constructs. Further, the CR appears to mediate transcriptional regulatory effects via an iron-independent mechanism. It is therefore apparent that the bioinformatic predictions were shown to be functionally relevant in this study and warrant further investigation. Results of these experiments represent a unique and comprehensive overview of novel transcriptional control elements of the iron metabolic pathway. The findings of this study strengthen the hypothesis that genes with similar promoter architecture, and involved in a common pathway, may be co-regulated. In addition, the combinatorial strategy employed in this study has applications in alternate pathways, and could serve as a refined approach for the prediction and study of regulatory targets in non-coding genomic DNA.
AFRIKAANSE OPSOMMING: Yster is ‘n noodsaaklike mikrovoedingstof wat ‘n vereiste is vir korrekte sellulêre funksie in alle eukariotiese organismes. Yster (II) of Fe2+ het egter die vermoë om die vorming van potensiële toksies reaktiewe suurstof spesies te kataliseer en dus is die regulasie van die yster metaboliese padweg van kardinale belang. Tans is daar beperkte inligting oor koördineerde regulasie van die gene, en dus proteïene waarvoor dit kodeer, in hierdie padweg. ‘n Uitsondering is die goed gekarakteriseerde na-transkripsionele “IRE/IRP” sisteem. Regulasie van geenuitdrukking in eukariotiese organismes is ‘n ingewikkelde proses. Transkripsionele regulasie is die eerste stap en word beheer deur die teenwoordigheid van spesefieke cis-regulatoriese elemente (cis-motiewe), geleë in die promotor area van gene, en die funksionele interaksies wat plaasvind tussen die produkte van spesifieke regulatoriese faktore (of transkripsie faktore) en hierdie cis-motiewe. ‘n Gekombineerde bioinformatiese en funksionele benadering was ontwerp en daarna gebruik in dié studie vir die analise van die promotor argitektuur van gene wat ‘n rol speel in die yster metaboliese padweg. Die stroomop nie-koderende streek (~2 kb) van 18 gene (ACO1, CP, CYBRD1, FTH1, FTL, HAMP, HEPH, HFE, HFE2, HMOX1, IREB2, LTF, SCL11A2, SLC40A1, STEAP3, TF, TFRC, TFR2), bekend vir hul betrokkenheid in die yster metabolisme padweg, was bloodgestel aan bioinformatiese analises om die streke van konservering te identifiseer met die hulp van spesifieke sagteware. Slegs nege (CYBRD1, FTH1, HAMP, HFE, HFE2, HMOX1, IREB2, LTF, TFRC) van die geanaliseerde gene het ‘n genomiese area bevat wat meer as 75% konservering getoon het. Hierdie gekonserveerde area (GA) is 140 bp in lengte en is geïdentifiseer in elk van die promotors van die nege gene. Die GA was verder bloodgestel aan analises, met die hulp van spesifieke sgateware, wat gebruik maak van vergelykende algoritmes vir motief karakterisering. Vier cis-motiewe is identifiseer en kom voor in dieselfde volgorde en oriëntasie in elk van die gene. In silico voorspelling van moontlike transkripsie faktor bindingsplekke het getoon dat daar talle bindingsmotiewe van belang teenwoordig is en dié motiewe kan gekoppel word aan biologiese funksies in hierdie padweg, insluitend ‘n nuwe MTF-1 bindingsplek in vyf van die gene van belang. Die bioinformatiese analises is verder gevalideer om die relevansie van die resultate in ‘n in vitro sisteem ten volle te assesseer. Luciferase rapporteerder konstrukte is vir die nege gene ontwerp wat die volgende bevat: 1) die 2 kb promotor, 2) ‘n 1.86 kb promotor met die GA verwyder en 3) die 140 bp GA element. Die vlakke van uitdrukking van hierdie drie rapporteerder konstrukte was genormaliseer met ‘n dubbele-luciferase rapporteerder assay onder standaard kultuur kondisies en gesimuleerde ysteroorlading kondisies in twee verskillende soogdier sellyne. Resultate van die luciferase assays dui aan dat die GA promotor konstrukte statisties betekenisvolle variasie toon in vergelyking met die onbehandelde kontrole konstrukte. Verder, die GA blyk om transkipsionele regulatoriese effekte te medieer via ‘n yster-onafhanklike meganisme. Dit blyk duidelik dat die bioinformatiese voorspellings ook funksioneel getoon kon word en was dus relevant in dié studie en regverdig verdere ondersoek. Hierdie eksperimentele ontwerp verteenwoordig ‘n unieke en omvattende oorsig van nuwe transkripsionele beheer elemente wat voorkom in die yster metaboliese padweg. Die resultate van dié studie versterk die hipotese dat gene met soortgelyke promotor argitektuur en wat betrokke is in ‘n gemene padweg saam gereguleer kan word. Daarbenewens, die gekombineerde strategie wat in hierdie studie gebruik is het toepassings in alternatiewe metaboliese paaie, en kan dien as ‘n verfynde benadering vir die voorspelling en studie van die regulerende teikens in nie-koderende genomiese DNS.
National Research Foundation (Thuthuka)
Stellenbosch University
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Vazzola, V. "Frataxin, a protein involved in iron metabolism, in Arabidopsis thaliana". Doctoral thesis, Università degli Studi di Milano, 2009. http://hdl.handle.net/2434/61969.
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Tilley, Gareth John. "Electrochemical investigations into iron-sulfur cluster containing proteins". Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365300.
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