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1
Duck, Kari A., and James R. Connor. "Iron uptake and transport across physiological barriers." BioMetals 29, no. 4 (July 25, 2016): 573–91. http://dx.doi.org/10.1007/s10534-016-9952-2.
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Li, Shuang, Yihu Yang, and Weikai Li. "Human ferroportin mediates proton-coupled active transport of iron." Blood Advances 4, no. 19 (October 2, 2020): 4758–68. http://dx.doi.org/10.1182/bloodadvances.2020001864.
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Abstract As the sole iron exporter in humans, ferroportin controls systemic iron homeostasis through exporting iron into the blood plasma. The molecular mechanism of how ferroportin exports iron under various physiological settings remains unclear. Here we found that purified ferroportin incorporated into liposomes preferentially transports Fe2+ and exhibits lower affinities of transporting other divalent metal ions. The iron transport by ferroportin is facilitated by downhill proton gradients at the same direction. Human ferroportin is also capable of transporting protons, and this activity is tightly coupled to the iron transport. Remarkably, ferroportin can conduct active transport uphill against the iron gradient, with favorable charge potential providing the driving force. Targeted mutagenesis suggests that the iron translocation site is located at the pore region of human ferroportin. Together, our studies enhance the mechanistic understanding by which human ferroportin transports iron and suggest that a combination of electrochemical gradients regulates iron export.
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Venkidusamy, Krishnaveni, Mallavarapu Megharaj, Uwe Schröder, Fouad Karouta, S. Venkata Mohan, and Ravi Naidu. "Electron transport through electrically conductive nanofilaments in Rhodopseudomonas palustris strain RP2." RSC Advances 5, no. 122 (2015): 100790–98. http://dx.doi.org/10.1039/c5ra08742b.
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The study demonstrates the physiological induction of electrically conductive nanofilaments from a metabolically versatile, iron(iii) respiring, photosynthetic bacteriumRhodopseudomonas palustrisstrain RP2.
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Li, Jingwei, and J. A. Cowan. "Glutathione-coordinated [2Fe–2S] cluster: a viable physiological substrate for mitochondrial ABCB7 transport." Chemical Communications 51, no. 12 (2015): 2253–55. http://dx.doi.org/10.1039/c4cc09175b.
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Zhang, Xinxin, Di Zhang, Wei Sun, and Tianzuo Wang. "The Adaptive Mechanism of Plants to Iron Deficiency via Iron Uptake, Transport, and Homeostasis." International Journal of Molecular Sciences 20, no. 10 (May 16, 2019): 2424. http://dx.doi.org/10.3390/ijms20102424.
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Iron is an essential element for plant growth and development. While abundant in soil, the available Fe in soil is limited. In this regard, plants have evolved a series of mechanisms for efficient iron uptake, allowing plants to better adapt to iron deficient conditions. These mechanisms include iron acquisition from soil, iron transport from roots to shoots, and iron storage in cells. The mobilization of Fe in plants often occurs via chelating with phytosiderophores, citrate, nicotianamine, mugineic acid, or in the form of free iron ions. Recent work further elucidates that these genes’ response to iron deficiency are tightly controlled at transcriptional and posttranscriptional levels to maintain iron homeostasis. Moreover, increasing evidences shed light on certain factors that are identified to be interconnected and integrated to adjust iron deficiency. In this review, we highlight the molecular and physiological bases of iron acquisition from soil to plants and transport mechanisms for tolerating iron deficiency in dicotyledonous plants and rice.
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Hunt, Janet R. "Dietary and Physiological Factors That Affect the Absorption and Bioavailability of Iron." International Journal for Vitamin and Nutrition Research 75, no. 6 (November 1, 2005): 375–84. http://dx.doi.org/10.1024/0300-9831.75.6.375.
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Iron deficiency, a global health problem, impairs reproductive performance, cognitive development, and work capacity. One proposed strategy to address this problem is the improvement of dietary iron bioavailability. Knowledge of the molecular mechanisms of iron absorption is growing rapidly, with identification of mucosal iron transport and regulatory proteins. Both body iron status and dietary characteristics substantially influence iron absorption, with minimal interaction between these two factors. Iron availability can be regarded mainly as a characteristic of the diet, but comparisons between human studies of iron availability for absorption require normalization for the iron status of the subjects. The dietary characteristics that enhance or inhibit iron absorption from foods have been sensitively and quantitatively determined in human studies employing iron isotopes. People with low iron status can substantially increase their iron absorption from diets with moderate to high availability. But while iron supplementation and fortification trials can effectively increase blood indices of iron status, improvements in dietary availability alone have had minimal influence on such indices within several weeks or months. Plentiful, varied diets are the ultimate resolution to iron deficiency. Without these, more modest food-based approaches to human iron deficiency likely will need to be augmented by dietary iron fortification.
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Gulec, Sukru, Gregory J. Anderson, and James F. Collins. "Mechanistic and regulatory aspects of intestinal iron absorption." American Journal of Physiology-Gastrointestinal and Liver Physiology 307, no. 4 (August 15, 2014): G397—G409. http://dx.doi.org/10.1152/ajpgi.00348.2013.
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Iron is an essential trace mineral that plays a number of important physiological roles in humans, including oxygen transport, energy metabolism, and neurotransmitter synthesis. Iron absorption by the proximal small bowel is a critical checkpoint in the maintenance of whole-body iron levels since, unlike most other essential nutrients, no regulated excretory systems exist for iron in humans. Maintaining proper iron levels is critical to avoid the adverse physiological consequences of either low or high tissue iron concentrations, as commonly occurs in iron-deficiency anemia and hereditary hemochromatosis, respectively. Exquisite regulatory mechanisms have thus evolved to modulate how much iron is acquired from the diet. Systemic sensing of iron levels is accomplished by a network of molecules that regulate transcription of the HAMP gene in hepatocytes, thus modulating levels of the serum-borne, iron-regulatory hormone hepcidin. Hepcidin decreases intestinal iron absorption by binding to the iron exporter ferroportin 1 on the basolateral surface of duodenal enterocytes, causing its internalization and degradation. Mucosal regulation of iron transport also occurs during low-iron states, via transcriptional (by hypoxia-inducible factor 2α) and posttranscriptional (by the iron-sensing iron-regulatory protein/iron-responsive element system) mechanisms. Recent studies demonstrated that these regulatory loops function in tandem to control expression or activity of key modulators of iron homeostasis. In health, body iron levels are maintained at appropriate levels; however, in several inherited disorders and in other pathophysiological states, iron sensing is perturbed and intestinal iron absorption is dysregulated. The iron-related phenotypes of these diseases exemplify the necessity of precisely regulating iron absorption to meet body demands.
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Kitphati, Worawan, Patchara Ngok-ngam, Sukanya Suwanmaneerat, Rojana Sukchawalit, and Skorn Mongkolsuk. "Agrobacterium tumefaciens fur Has Important Physiological Roles in Iron and Manganese Homeostasis, the Oxidative Stress Response, and Full Virulence." Applied and Environmental Microbiology 73, no. 15 (June 1, 2007): 4760–68. http://dx.doi.org/10.1128/aem.00531-07.
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ABSTRACT In Agrobacterium tumefaciens, the balance between acquiring enough iron and avoiding iron-induced toxicity is regulated in part by Fur (ferric uptake regulator). A fur mutant was constructed to address the physiological role of the regulator. Atypically, the mutant did not show alterations in the levels of siderophore biosynthesis and the expression of iron transport genes. However, the fur mutant was more sensitive than the wild type to an iron chelator, 2,2′-dipyridyl, and was also more resistant to an iron-activated antibiotic, streptonigrin, suggesting that Fur has a role in regulating iron concentrations. A. tumefaciens sitA, the periplasmic binding protein of a putative ABC-type iron and manganese transport system (sitABCD), was strongly repressed by Mn2+ and, to a lesser extent, by Fe2+, and this regulation was Fur dependent. Moreover, the fur mutant was more sensitive to manganese than the wild type. This was consistent with the fact that the fur mutant showed constitutive up-expression of the manganese uptake sit operon. FurAt showed a regulatory role under iron-limiting conditions. Furthermore, Fur has a role in determining oxidative resistance levels. The fur mutant was hypersensitive to hydrogen peroxide and had reduced catalase activity. The virulence assay showed that the fur mutant had a reduced ability to cause tumors on tobacco leaves compared to wild-type NTL4.
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Froschauer, Elisabeth M., Nicole Rietzschel, Melanie R. Hassler, Markus Binder, Rudolf J. Schweyen, Roland Lill, Ulrich Mühlenhoff, and Gerlinde Wiesenberger. "The mitochondrial carrier Rim2 co-imports pyrimidine nucleotides and iron." Biochemical Journal 455, no. 1 (September 13, 2013): 57–65. http://dx.doi.org/10.1042/bj20130144.
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Mitochondrial iron uptake is of key importance both for organelle function and cellular iron homoeostasis. The mitochondrial carrier family members Mrs3 and Mrs4 (homologues of vertebrate mitoferrin) function in organellar iron supply, yet other low efficiency transporters may exist. In Saccharomyces cerevisiae, overexpression of RIM2 (MRS12) encoding a mitochondrial pyrimidine nucleotide transporter can overcome the iron-related phenotypes of strains lacking both MRS3 and MRS4. In the present study we show by in vitro transport studies that Rim2 mediates the transport of iron and other divalent metal ions across the mitochondrial inner membrane in a pyrimidine nucleotide-dependent fashion. Mutations in the proposed substrate-binding site of Rim2 prevent both pyrimidine nucleotide and divalent ion transport. These results document that Rim2 catalyses the co-import of pyrimidine nucleotides and divalent metal ions including ferrous iron. The deletion of RIM2 alone has no significant effect on mitochondrial iron supply, Fe–S protein maturation and haem synthesis. However, RIM2 deletion in mrs3/4Δ cells aggravates their Fe–S protein maturation defect. We conclude that under normal physiological conditions Rim2 does not play a significant role in mitochondrial iron acquisition, yet, in the absence of the main iron transporters Mrs3 and Mrs4, this carrier can supply the mitochondrial matrix with iron in a pyrimidine-nucleotide-dependent fashion.
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Meynard, Delphine, Jodie L. Babitt, and Herbert Y. Lin. "The liver: conductor of systemic iron balance." Blood 123, no. 2 (January 9, 2014): 168–76. http://dx.doi.org/10.1182/blood-2013-06-427757.
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Abstract Iron is a micronutrient essential for almost all organisms: bacteria, plants, and animals. It is a metal that exists in multiple redox states, including the divalent ferrous (Fe2+) and the trivalent ferric (Fe3+) species. The multiple oxidation states of iron make it excellent for electron transfer, allowing iron to be selected during evolution as a cofactor for many proteins involved in central cellular processes including oxygen transport, mitochondrial respiration, and DNA synthesis. However, the redox cycling of ferrous and ferric iron in the presence of H2O2, which is physiologically present in the cells, also leads to the production of free radicals (Fenton reaction) that can attack and damage lipids, proteins, DNA, and other cellular components. To meet the physiological needs of the body, but to prevent cellular damage by iron, the amount of iron in the body must be tightly regulated. Here we review how the liver is the central conductor of systemic iron balance and show that this central role is related to the secretion of a peptide hormone hepcidin by hepatocytes. We then review how the liver receives and integrates the many signals that report the body’s iron needs to orchestrate hepcidin production and maintain systemic iron homeostasis.
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Vigani, Gianpiero, �d�m Solti, S�bastien Thomine, and Katrin Philippar. "Essential and Detrimental — an Update on Intracellular Iron Trafficking and Homeostasis." Plant and Cell Physiology 60, no. 7 (May 15, 2019): 1420–39. http://dx.doi.org/10.1093/pcp/pcz091.
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Abstract Chloroplasts, mitochondria and vacuoles represent characteristic organelles of the plant cell, with a predominant function in cellular metabolism. Chloroplasts are the site of photosynthesis and therefore basic and essential for photoautotrophic growth of plants. Mitochondria produce energy during respiration and vacuoles act as internal waste and storage compartments. Moreover, chloroplasts and mitochondria are sites for the biosynthesis of various compounds of primary and secondary metabolism. For photosynthesis and energy generation, the internal membranes of chloroplasts and mitochondria are equipped with electron transport chains. To perform proper electron transfer and several biosynthetic functions, both organelles contain transition metals and here iron is by far the most abundant. Although iron is thus essential for plant growth and development, it becomes toxic when present in excess and/or in its free, ionic form. The harmful effect of the latter is caused by the generation of oxidative stress. As a consequence, iron transport and homeostasis have to be tightly controlled during plant growth and development. In addition to the corresponding transport and homeostasis proteins, the vacuole plays an important role as an intracellular iron storage and release compartment at certain developmental stages. In this review, we will summarize current knowledge on iron transport and homeostasis in chloroplasts, mitochondria and vacuoles. In addition, we aim to integrate the physiological impact of intracellular iron homeostasis on cellular and developmental processes.
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Zeller, Tanja, Oleg V. Moskvin, Kuanyu Li, Gabriele Klug, and Mark Gomelsky. "Transcriptome and Physiological Responses to Hydrogen Peroxide of the Facultatively Phototrophic Bacterium Rhodobacter sphaeroides." Journal of Bacteriology 187, no. 21 (November 1, 2005): 7232–42. http://dx.doi.org/10.1128/jb.187.21.7232-7242.2005.
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ABSTRACT The transcriptome responses to hydrogen peroxide, H2O2, of the facultatively phototrophic bacterium Rhodobacter sphaeroides grown under semiaerobic conditions were investigated. At 7 min after the addition of 1 mM H2O2, the expression of approximately 9% of all genes (total, 394) was changed reliably by at least twofold. At 30 min, the number of genes (total, 88) and the magnitude of expression changes were much lower, indicating rapid recovery from stress. Two types of responses were observed: (i) an H2O2 stress response per se and (ii) a shift to high-oxygen metabolism. The former response involved the upregulation of genes for H2O2 detoxification, protein folding and proteolysis, DNA damage repair, iron transport and storage, iron-sulfur cluster repair, and the downregulation of genes for protein translation, motility, and cell wall and lipopolysaccharide synthesis. The shift to high-oxygen metabolism was evident from the differential regulation of genes for aerobic electron transport chain components and the downregulation of tetrapyrrole biosynthesis and photosystem genes. The abundance of photosynthetic complexes was decreased upon prolonged exposure of R. sphaeroides to H2O2, thus confirming the physiological significance of the transcriptome data. The regulatory pathways mediating the shift to high-oxygen metabolism were investigated. They involved the anaerobic activator FnrL and the antirepressor-repressor AppA-PpsR system. The transcription of FnrL-dependent genes was down at 7 min, apparently due to the transient inactivation by H2O2 of the iron-sulfur cluster of FnrL. The transcription of the AppA-PpsR-dependent genes was down at 30 min, apparently due to the significant decrease in appA mRNA.
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Ollinger, Juliane, Kyung-Bok Song, Haike Antelmann, Michael Hecker, and John D. Helmann. "Role of the Fur Regulon in Iron Transport in Bacillus subtilis." Journal of Bacteriology 188, no. 10 (May 15, 2006): 3664–73. http://dx.doi.org/10.1128/jb.188.10.3664-3673.2006.
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ABSTRACT The Bacillus subtilis ferric uptake regulator (Fur) protein mediates the iron-dependent repression of at least 20 operons encoding ∼40 genes. We investigated the physiological roles of Fur-regulated genes by the construction of null mutations in 14 transcription units known or predicted to function in siderophore biosynthesis or iron uptake. We demonstrate that ywbLMN, encoding an elemental iron uptake system orthologous to the copper oxidase-dependent Fe(III) uptake system of Saccharomyces cerevisiae, is essential for growth in low iron minimal medium lacking citric acid. 2,3-Dihydroxybenzoyl-glycine (Itoic acid), the siderophore precursor produced by laboratory strains of B. subtilis, is of secondary importance. In the presence of citrate, the YfmCDEF ABC transporter is required for optimal growth. B. subtilis is unable to grow in minimal medium containing the iron chelator EDDHA unless the ability to synthesize the intact bacillibactin siderophore is restored (by the introduction of a functional sfp gene) or exogenous siderophores are provided. Utilization of the catecholate siderophores bacillibactin and enterobactin requires the FeuABC importer and the YusV ATPase. Utilization of hydroxamate siderophores requires the FhuBGC ABC transporter together with the FhuD (ferrichrome) or YxeB (ferrioxamine) substrate-binding proteins. Growth with schizokinen or arthrobactin is at least partially dependent on the YfhA YfiYZ importer and the YusV ATPase. We have also investigated the effects of a fur mutation on the proteome and documented the derepression of 11 Fur-regulated proteins, including a newly identified thioredoxin reductase homolog, YcgT.
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Rafii, Bijan, Chris Coutinho, Gail Otulakowski, and Hugh O'Brodovich. "Oxygen induction of epithelial Na+ transport requires heme proteins." American Journal of Physiology-Lung Cellular and Molecular Physiology 278, no. 2 (February 1, 2000): L399—L406. http://dx.doi.org/10.1152/ajplung.2000.278.2.l399.
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Fetal distal lung epithelial (FDLE) cells exposed to a postnatal O2 concentration of 21% have higher epithelial Na+ channel (ENaC) mRNA levels and Na+ transport relative to FDLE cells grown in a fetal O2 concentration of 3%. To investigate the mechanism of this process, FDLE monolayers were initially cultured in 3% O2, and then some were switched to a 21% O2environment. Incubation of FDLE cells with the iron chelator deferoxamine, CoCl2, NiCl2, or an inhibitor of heme synthesis prevented or diminished the O2induction of amiloride-sensitive short-circuit current in FDLE cells. Similarly, defer- oxamine and cobalt prevented O2-induced ENaC mRNA expression. Exposure of FDLE cells grown under hypoxic conditions to carbon monoxide increased both ENaC mRNA expression and amiloride-sensitive short-circuit current. We therefore concluded that induction of ENaC mRNA expression and amiloride-sensitive Na+ transport in FDLE cells by a physiological increase in O2 concentration seen at birth requires iron and heme proteins.
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Schaedler, Theresia A., Belinda Faust, Chitra A. Shintre, Elisabeth P. Carpenter, Vasundara Srinivasan, Hendrik W. van Veen, and Janneke Balk. "Structures and functions of mitochondrial ABC transporters." Biochemical Society Transactions 43, no. 5 (October 1, 2015): 943–51. http://dx.doi.org/10.1042/bst20150118.
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A small number of physiologically important ATP-binding cassette (ABC) transporters are found in mitochondria. Most are half transporters of the B group forming homodimers and their topology suggests they function as exporters. The results of mutant studies point towards involvement in iron cofactor biosynthesis. In particular, ABC subfamily B member 7 (ABCB7) and its homologues in yeast and plants are required for iron-sulfur (Fe-S) cluster biosynthesis outside of the mitochondria, whereas ABCB10 is involved in haem biosynthesis. They also play a role in preventing oxidative stress. Mutations in ABCB6 and ABCB7 have been linked to human disease. Recent crystal structures of yeast Atm1 and human ABCB10 have been key to identifying substrate-binding sites and transport mechanisms. Combined with in vitro and in vivo studies, progress is being made to find the physiological substrates of the different mitochondrial ABC transporters.
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Станіслав Видиборець and Дмитро Борисенко. "ГЕПСИДИН, ТРАНСФЕРИН, ФЕРИТИН: ФІЗІОЛОГІЧНА РОЛЬ ЯК ЦЕНТРАЛЬНИХ РЕГУЛЯТОРІВ ОБМІНУ ЗАЛІЗА В ОРГАНІЗМІ." Science Review, no. 10(27) (December 30, 2019): 8–16. http://dx.doi.org/10.31435/rsglobal_sr/30122019/6862.
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The knowledge about mammalian iron metabolism has advanced dramatically over the past decades. Studies of genetics, biochemistry and molecular biology allowed us the identification and characterization of many of the molecules involved in regulation of iron homeostasis. Important progresses were made after the discovery in 2000 of a small peptide – hepsidin – that has been proved to play a central role in orchestration on iron metabolism also providing a link between iron metabolism and inflammation and innate immunity. Hepsidin directly interacts with ferroportin, the only known mammalian iron exporter, which is expressed by enterocytes, macrophages and hepatocytes. The direct hepsidin- ferroportin interaction allows an adaptative response from the body in situations that alter normal iron homeostasis (hypoxia, anemia, iron deficiency, iron overload, and inflammation). In clause the items of information on transport protein of iron - transferrin are stated. Its physiological role and clinical importance is shown. Dynamics of the contents of the hepsidin, transferrin, ferritin in persons with latent deficiency of iron. The conclusion about importance of the given parameter for laboratory diagnostics of iron deficiency condition is made. In the article the items of information about the ferritin - protein - depot of iron in body are given. Its physiological role and clinical importance is displayed. Dynamics of changes of the contents ferritin during treatment of the patients with iron deficiency anemia and persons with latent deficiency of iron is shown. The conclusion about the level of the ferritin in serum of blood is the important dynamic parameter for laboratory diagnostics iron deficiency of condition is made.
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Lee, Jennifer K., Jung-Heun Ha, and James F. Collins. "Dietary Iron Intake in Excess of Requirements Impairs Intestinal Copper Absorption in Sprague Dawley Rat Dams, Causing Copper Deficiency in Suckling Pups." Biomedicines 9, no. 4 (March 27, 2021): 338. http://dx.doi.org/10.3390/biomedicines9040338.
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Physiologically relevant iron-copper interactions have been frequently documented. For example, excess enteral iron inhibits copper absorption in laboratory rodents and humans. Whether this also occurs during pregnancy and lactation, when iron supplementation is frequently recommended, is, however, unknown. Here, the hypothesis that high dietary iron will perturb copper homeostasis in pregnant and lactating dams and their pups was tested. We utilized a rat model of iron-deficiency/iron supplementation during pregnancy and lactation to assess this possibility. Rat dams were fed low-iron diets early in pregnancy, and then switched to one of 5 diets with normal (1×) to high iron (20×) until pups were 14 days old. Subsequently, copper and iron homeostasis, and intestinal copper absorption (by oral, intragastric gavage with 64Cu), were assessed. Copper depletion/deficiency occurred in the dams and pups as dietary iron increased, as evidenced by decrements in plasma ceruloplasmin (Cp) and superoxide dismutase 1 (SOD1) activity, depletion of hepatic copper, and liver iron loading. Intestinal copper transport and tissue 64Cu accumulation were lower in dams consuming excess iron, and tissue 64Cu was also low in suckling pups. In some cases, physiological disturbances were noted when dietary iron was only ~3-fold in excess, while for others, effects were observed when dietary iron was 10–20-fold in excess. Excess enteral iron thus antagonizes the absorption of dietary copper, causing copper depletion in dams and their suckling pups. Low milk copper is a likely explanation for copper depletion in the pups, but experimental proof of this awaits future experimentation.
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Khan, Ali G., Stephen R. Shouldice, Shane D. Kirby, Rong-hua Yu, Leslie W. Tari, and Anthony B. Schryvers. "High-affinity binding by the periplasmic iron-binding protein from Haemophilus influenzae is required for acquiring iron from transferrin." Biochemical Journal 404, no. 2 (May 14, 2007): 217–25. http://dx.doi.org/10.1042/bj20070110.
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The periplasmic iron-binding protein, FbpA (ferric-ion-binding protein A), performs an essential role in iron acquisition from transferrin in Haemophilus influenzae. A series of site-directed mutants in the metal-binding amino acids of FbpA were prepared to determine their relative contribution to iron binding and transport. Structural studies demonstrated that the mutant proteins crystallized in an open conformation with the iron atom associated with the C-terminal domain. The iron-binding properties of the mutant proteins were assessed by several assays, including a novel competitive iron-binding assay. The relative ability of the proteins to compete for iron was pH dependent, with a rank order at pH 6.5 of wild-type, Q58L, H9Q>H9A, E57A>Y195A, Y196A. The genes encoding the mutant FbpA were introduced into H. influenzae and the resulting strains varied in the level of ferric citrate required to support growth on iron-limited medium, suggesting a rank order for metal-binding affinities under physiological conditions comparable with the competitive binding assay at pH 6.5 (wild-type=Q58L>H9Q>H9A, E57A>Y195A, Y196A). Growth dependence on human transferrin was only obtained with cells expressing wild-type, Q58L or H9Q FbpAs, proteins with stability constants derived from the competition assay >2.0×1018 M−1. These results suggest that a relatively high affinity of iron binding by FbpA is required for removal of iron from transferrin and its transport across the outer membrane.
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Kariuki, Stijlemans, and Magez. "The Trypanosomal Transferrin Receptor of Trypanosoma Brucei—A Review." Tropical Medicine and Infectious Disease 4, no. 4 (October 1, 2019): 126. http://dx.doi.org/10.3390/tropicalmed4040126.
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Iron is an essential element for life. Its uptake and utility requires a careful balancing with its toxic capacity, with mammals evolving a safe and bio-viable means of its transport and storage. This transport and storage is also utilized as part of the iron-sequestration arsenal employed by the mammalian hosts’ ‘nutritional immunity’ against parasites. Interestingly, a key element of iron transport, i.e., serum transferrin (Tf), is an essential growth factor for parasitic haemo-protozoans of the genus Trypanosoma. These are major mammalian parasites causing the diseases human African trypanosomosis (HAT) and animal trypanosomosis (AT). Using components of their well-characterized immune evasion system, bloodstream Trypanosoma brucei parasites adapt and scavenge for the mammalian host serum transferrin within their broad host range. The expression site associated genes (ESAG6 and 7) are utilized to construct a heterodimeric serum Tf binding complex which, within its niche in the flagellar pocket, and coupled to the trypanosomes’ fast endocytic rate, allows receptor-mediated acquisition of essential iron from their environment. This review summarizes current knowledge of the trypanosomal transferrin receptor (TfR), with emphasis on the structure and function of the receptor, both in physiological conditions as well as in conditions where the iron supply to parasites is being limited. Potential applications using current knowledge of the parasite receptor are also briefly discussed, primarily focused on potential therapeutic interventions.
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Potashnik, R., N. Kozlovsky, S. Ben-Ezra, A. Rudich, and N. Bashan. "Regulation of glucose transport and GLUT-1 expression by iron chelators in muscle cells in culture." American Journal of Physiology-Endocrinology and Metabolism 269, no. 6 (December 1, 1995): E1052—E1058. http://dx.doi.org/10.1152/ajpendo.1995.269.6.e1052.
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Possible association between the degree of iron load and glucose metabolism has been postulated by both in vivo and in vitro studies. Because skeletal muscle plays a major role in whole body glucose utilization, we evaluated the effect of iron chelators deferoxamine (DFO) and bipyridyl (Bip) on glucose metabolism and transport in cultured L6 muscle cells. Bip (0.1 mM) or DFO (0.5 mM) added for 24 h to the culture medium increased glucose consumption, lactate production, and [14C]glucose incorporation into glycogen by approximately twofold. 2-Deoxy-glucose uptake by L6 myotubes increased time dependently, reaching a 5-fold and 2.5-fold increase after 12 h for Bip and DFO, respectively. Insulin induced a 2.5-fold increase in glucose uptake in untreated cells, which was additive to the chelator's effect. Iron chelator-induced glucose transport stimulation was inhibited by cycloheximide (2.5 micrograms/ml), indicating dependence on de novo protein synthesis. Increases in GLUT-1 protein and mRNA concentration, without changes in GLUT-4, were found to be responsible for iron chelator effects. We conclude that L6 cells adapt to reduction in iron availability by increasing glucose utilization through an enhanced expression of GLUT-1, without losing their physiological response to insulin.
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Bozzi, Aaron T., Lukas B. Bane, Wilhelm A. Weihofen, Anne L. McCabe, Abhishek Singharoy, Christophe J. Chipot, Klaus Schulten, and Rachelle Gaudet. "Conserved methionine dictates substrate preference in Nramp-family divalent metal transporters." Proceedings of the National Academy of Sciences 113, no. 37 (August 29, 2016): 10310–15. http://dx.doi.org/10.1073/pnas.1607734113.
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Natural resistance-associated macrophage protein (Nramp) family transporters catalyze uptake of essential divalent transition metals like iron and manganese. To discriminate against abundant competitors, the Nramp metal-binding site should favor softer transition metals, which interact either covalently or ionically with coordinating molecules, over hard calcium and magnesium, which interact mainly ionically. The metal-binding site contains an unusual, but conserved, methionine, and its sulfur coordinates transition metal substrates, suggesting a vital role in their transport. Using a bacterial Nramp model system, we show that, surprisingly, this conserved methionine is dispensable for transport of the physiological manganese substrate and similar divalents iron and cobalt, with several small amino acid replacements still enabling robust uptake. Moreover, the methionine sulfur’s presence makes the toxic metal cadmium a preferred substrate. However, a methionine-to-alanine substitution enables transport of calcium and magnesium. Thus, the putative evolutionary pressure to maintain the Nramp metal-binding methionine likely exists because it—more effectively than any other amino acid—increases selectivity for low-abundance transition metal transport in the presence of high-abundance divalents like calcium and magnesium.
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Станіслав Видиборець and Дмитро Борисенко. "ДІАГНОСТИЧНА ЦІННІСТЬ ДОСЛІДЖЕННЯ ТРАНСФЕРИНУ НА РІЗНИХ СТАДІЯХ РОЗВИТКУ АНЕМІЇ ЗЛОЯКІСНОГО НОВОУТВОРЕННЯ У ПАЦІЄНТІВ ІЗ УРОТЕЛІАЛЬНИМ РАКОМ СЕЧОВОГО МІХУРА." World Science 1, no. 12(52) (December 30, 2019): 25–31. http://dx.doi.org/10.31435/rsglobal_ws/30122019/6827.
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In clause the items of information on transport protein of iron - transferrin are stated. Its physiological role and clinical importance is shown.The content of iron in the blood whey (SZH) and index of general iron- binding ability of the whey (OZHSS) were determined by batofenantrolin method. The index of the unsaturated iron-binding ability of the whey (NZHSS) was calculated as a difference between OZHSS and SZH. The coefficient of saturation of transferrin by iron (KNTZH) was determined as correlation of maintenance of SZH to OZHSS. The contents of transferrin (TF) was determined on the index of OZHSS, ferritin (FN) by a radiometric method. Dynamics of the contents of the transferrin of the patients with anemia of malignant growth in patients with urothelial cancer of the urinary bladder. The conclusion about importance of the given parameter for laboratory diagnostics of iron deficiency condition and anemia of malignant growth is made.
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Mahender, Anumalla, B. Swamy, Annamalai Anandan, and Jauhar Ali. "Tolerance of Iron-Deficient and -Toxic Soil Conditions in Rice." Plants 8, no. 2 (January 28, 2019): 31. http://dx.doi.org/10.3390/plants8020031.
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Iron (Fe) deficiency and toxicity are the most widely prevalent soil-related micronutrient disorders in rice (Oryza sativa L.). Progress in rice cultivars with improved tolerance has been hampered by a poor understanding of Fe availability in the soil, the transportation mechanism, and associated genetic factors for the tolerance of Fe toxicity soil (FTS) or Fe deficiency soil (FDS) conditions. In the past, through conventional breeding approaches, rice varieties were developed especially suitable for low- and high-pH soils, which indirectly helped the varieties to tolerate FTS and FDS conditions. Rice-Fe interactions in the external environment of soil, internal homeostasis, and transportation have been studied extensively in the past few decades. However, the molecular and physiological mechanisms of Fe uptake and transport need to be characterized in response to the tolerance of morpho-physiological traits under Fe-toxic and -deficient soil conditions, and these traits need to be well integrated into breeding programs. A deeper understanding of the several factors that influence Fe absorption, uptake, and transport from soil to root and above-ground organs under FDS and FTS is needed to develop tolerant rice cultivars with improved grain yield. Therefore, the objective of this review paper is to congregate the different phenotypic screening methodologies for prospecting tolerant rice varieties and their responsible genetic traits, and Fe homeostasis related to all the known quantitative trait loci (QTLs), genes, and transporters, which could offer enormous information to rice breeders and biotechnologists to develop rice cultivars tolerant of Fe toxicity or deficiency. The mechanism of Fe regulation and transport from soil to grain needs to be understood in a systematic manner along with the cascade of metabolomics steps that are involved in the development of rice varieties tolerant of FTS and FDS. Therefore, the integration of breeding with advanced genome sequencing and omics technologies allows for the fine-tuning of tolerant genotypes on the basis of molecular genetics, and the further identification of novel genes and transporters that are related to Fe regulation from FTS and FDS conditions is incredibly important to achieve further success in this aspect.
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Ravia, Jennifer J., Renu M. Stephen, Fayez K. Ghishan, and James F. Collins. "Menkes Copper ATPase (Atp7a) Is a Novel Metal-responsive Gene in Rat Duodenum, and Immunoreactive Protein Is Present on Brush-border and Basolateral Membrane Domains." Journal of Biological Chemistry 280, no. 43 (August 4, 2005): 36221–27. http://dx.doi.org/10.1074/jbc.m506727200.
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We previously noted strong induction of genes related to intestinal copper homeostasis (Menkes Copper ATPase (Atp7a) and metallothionein) in the duodenal epithelium of iron-deficient rats across several stages of postnatal development (Collins, J. F., Franck, C. A., Kowdley, K. V., and Ghishan, F. K. (2005) Am. J. Physiol., 288, G964–G971). We now report significant copper loading in the livers and intestines of iron-deficient rats. These findings are consistent with the hypothesis that there is increased intestinal copper transport during iron deficiency. We additionally found that hepatic Atp7b gene expression does not change with iron deficiency, suggesting that liver copper excretion is not altered. We have developed polyclonal antibodies against rat ATP7A, and we demonstrate the specificity of the immunogenic reaction. We show that the ATP7A protein is present on apical domains of duodenal enterocytes in control rats and on brush-border and basolateral membrane domains in iron-deprived rats. This localization is surprising, as previous in vitro studies have suggested that ATP7A traffics between the trans-Golgi network and the basolateral membrane. We further demonstrate that ATP7A protein levels are dramatically increased in brush-border and basolateral membrane vesicles isolated from iron-deficient rats. Other experiments show that iron refeeding partially corrects the hematological abnormalities seen in iron-deficient rats but that it does not ameliorate ATP7A protein induction, suggesting that Atp7a does not respond to intracellular iron levels. We conclude that ATP7A is involved in copper loading observed during iron deficiency and that increased intestinal copper transport is of physiological relevance, as copper plays important roles in overall body iron homeostasis.
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Beauchene, Nicole A., Erin L. Mettert, Laura J. Moore, Sündüz Keleş, Emily R. Willey, and Patricia J. Kiley. "O2availability impacts iron homeostasis inEscherichia coli." Proceedings of the National Academy of Sciences 114, no. 46 (October 30, 2017): 12261–66. http://dx.doi.org/10.1073/pnas.1707189114.
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The ferric-uptake regulator (Fur) is an Fe2+-responsive transcription factor that coordinates iron homeostasis in many bacteria. Recently, we reported that expression of theEscherichia coliFur regulon is also impacted by O2tension. Here, we show that for most of the Fur regulon, Fur binding and transcriptional repression increase under anaerobic conditions, suggesting that Fur is controlled by O2availability. We found that the intracellular, labile Fe2+pool was higher under anaerobic conditions compared with aerobic conditions, suggesting that higher Fe2+availability drove the formation of more Fe2+-Fur and, accordingly, more DNA binding. O2regulation of Fur activity required the anaerobically induced FeoABC Fe2+uptake system, linking increased Fur activity to ferrous import under iron-sufficient conditions. The increased activity of Fur under anaerobic conditions led to a decrease in expression of ferric import systems. However, the combined positive regulation of thefeoABCoperon by ArcA and FNR partially antagonized Fur-mediated repression offeoABCunder anaerobic conditions, allowing ferrous transport to increase even though Fur is more active. This design feature promotes a switch from ferric import to the more physiological relevant ferrous iron under anaerobic conditions. Taken together, we propose that the influence of O2availability on the levels of active Fur adds a previously undescribed layer of regulation in maintaining cellular iron homeostasis.
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Griffiths, William J. H., and Timothy M. Cox. "Co-localization of the Mammalian Hemochromatosis Gene Product (HFE) and a Newly Identified Transferrin Receptor (TfR2) in Intestinal Tissue and Cells." Journal of Histochemistry & Cytochemistry 51, no. 5 (May 2003): 613–23. http://dx.doi.org/10.1177/002215540305100507.
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Mutations in the HFE gene and a newly identified second transferrin receptor gene, TfR2, cause hemochromatosis. The cognate proteins, HFE and TfR2, are therefore of key importance in human iron homeostasis. HFE is expressed in small intestinal crypt cells where transferrin-iron entry may determine subsequent iron absorption by mature enterocytes, but the physiological function of TfR2 is unknown. Using specific peptide antisera, we examined the duodenal localization of HFE and TfR2 in humans and mice, with and without HFE deficiency, by confocal microscopy. We also investigated potential interactions of these proteins in human intestinal cells in situ. Duodenal expression of HFE and TfR2 (but not TfR1) in wild-type mice and humans was restricted to crypt cells, in which they co-localized. HFE deficiency disrupted this interaction, altering the cellular distribution of TfR2 in human crypts. In human Caco-2 cells, HFE and TfR2 co-localized to a distinct CD63-negative vesicular compartment showing marked signal enhancement on exposure to iron-saturated transferrin ligand, indicating that HFE preferentially interacts with TfR2 in a specialized early endosomal transport pathway for transferrin-iron. This interaction occurs specifically in small intestinal crypt cells that differentiate to become iron-absorbing enterocytes. Our immunohistochemical findings provide evidence for a novel mechanism for the regulation of iron balance in mammals.
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Hernandez, Monica N., and Steven E. Lindow. "Contact-dependent traits in Pseudomonas syringae B728a." PLOS ONE 16, no. 2 (February 11, 2021): e0241655. http://dx.doi.org/10.1371/journal.pone.0241655.
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Production of the biosurfactant syringafactin by the plant pathogen Pseudomonas syringae B728a is a surface contact-dependent trait. Expression of syfA, as measured using a gfp reporter gene fusion was low in planktonic cells in liquid cultures but over 4-fold higher in cells immobilized on surfaces as varied as glass, plastic, paper, parafilm, agar, membrane filters, and leaves. Induction of syfA as measured by GFP fluorescence was rapid, occurring within two hours after immobilization of cells on surfaces. Comparison of the global transcriptome by RNA sequencing of planktonic cells in a nutrient medium with that of cells immobilized for 2 hours on filters placed on this solidified medium revealed that, in addition to syfA, 3156 other genes were differentially expressed. Genes repressed in immobilized cells included those involved in quaternary ammonium compound (QAC) metabolism and transport, compatible solute production, carbohydrate metabolism and transport, organic acid metabolism and transport, phytotoxin synthesis and transport, amino acid metabolism and transport, and secondary metabolism. Genes induced in immobilized cells included syfA plus those involved in translation, siderophore synthesis and transport, nucleotide metabolism and transport, flagellar synthesis and motility, lipopolysaccharide (LPS) synthesis and transport, energy generation, transcription, chemosensing and chemotaxis, replication and DNA repair, iron-sulfur proteins, peptidoglycan/cell wall polymers, terpenoid backbone synthesis, iron metabolism and transport, and cell division. That many genes are rapidly differentially expressed upon transfer of cells from a planktonic to an immobilized state suggests that cells experience the two environments differently. It seems possible that surface contact initiates anticipatory changes in P. syringae gene expression, which enables rapid and appropriate physiological responses to the different environmental conditions such as might occur in a biofilm. Such responses could help cells survive transitions from aquatic habitats fostering planktonic traits to attachment on surfaces, conditions that alternatively occur on leaves.
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Dinarieva, Tatiana Y., Anna E. Zhuravleva, Oksana A. Pavlenko, Iraida A. Tsaplina, and Alexander I. Netrusov. "Ferrous iron oxidation in moderately thermophilic acidophile Sulfobacillus sibiricus N1T." Canadian Journal of Microbiology 56, no. 10 (October 2010): 803–8. http://dx.doi.org/10.1139/w10-063.
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The iron-oxidizing system of a moderately thermophilic, extremely acidophilic, gram-positive mixotroph, Sulfobacillus sibiricus N1T, was studied by spectroscopic, high-performance liquid chromatography and inhibitory analyses. Hemes B, A, and O were detected in membranes of S. sibiricus N1T. It is proposed that the electron transport chain from Fe2+ to O2 is terminated by 2 physiological oxidases: aa3-type cytochrome, which dominates in the early-exponential phase of growth, and bo3-type cytochrome, whose role in iron oxidation becomes more prominent upon growth of the culture. Both oxidases were sensitive to cyanide and azide. Cytochrome aa3 was more sensitive to cyanide and azide, with Ki values of 4.1 and 2.5 µmol·L–1, respectively, compared with Ki values for cytochrome bo3, which were 9.5 µmol·L–1 for cyanide and 7.0 µmol·L–1 for azide. This is the first evidence for the participation of a bo3-type oxidase in ferrous iron oxidation. The respiratory chain of the mixotroph contains, in addition to the 2 terminal oxidases, a membrane-bound cytochrome b573.
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Wincup, C., G. Robinson, T. Mcdonnell, A. Radziszewska, F. Farinha, and A. Rahman. "OP0006 ABNORMAL IRON METABOLISM AND MITOCHONDRIAL DYSFUNCTION: INVESTIGATING A NOVEL PATHOLOGICAL MECHANISM IN SYSTEMIC LUPUS ERYTHEMATOSUS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 5.2–5. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2487.
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Background:Iron is vital for numerous essential physiological processes including erythropoiesis and energy metabolism (as iron is found in the mitochondrial electron transport chain, the central site of ATP production). Iron homeostasis is tightly controlled by a number of regulators including; 1. Hepcidin, which prevents iron release from stores (under the influence of IL6 and IL1β); 2. Ferritin, an iron storage protein; 3. Lipocalin-2 (LCN2), which is released upon innate immune activation that induces iron sequestration; 4. Transferrin, which binds circulating iron and enables its transport to effector cell targets; 5. Haptoglobin, which binds free haemoglobin and assisting iron recycling; 6. Erythropoietin (EPO), which stimulates erythropoiesis as a result of hypoxia.Chronic inflammation may result in dysregulation of iron metabolism and in turn impair mitochondrial function yet little is known regarding how these processes change in systemic lupus erythematosus (SLE).Objectives:In this study, we investigated how dysregulation of iron metabolism may occur in SLE and subsequently sought to identify how a lack of iron may ultimately induce abnormal mitochondrial function.Methods:1. Investigating abnormal iron metabolism in SLE.Serum samples from patients with SLE (n=39) and healthy controls (HC, n=17) were assessed hepcidin, IL-1ß, IL-6, ferritin, LCN2, EPO, haptoglobin and transferrin levels by ELISA. Hierarchical cluster analysis of normalised data (converted to Z-scores) was performed using MeV software in order to characterise patient groups based upon iron metabolism profile. Anti-dsDNA antibody titres, complement C3 levels and SLEDAI-2K were excluded to limit the influence of these variables on cluster analysis. Results were presented as a heatmap.2. Studying mitochondrial function in iron deficiency and SLE. Peripheral blood mononuclear cells (PBMCs) from HCs and patients with SLE were analysed using Seahorse Respirometry, which measures mitochondrial oxygen consumption rate (a measure of energy metabolism dependent upon oxidative phosphorylation). To assess differences between health, iron deficiency and SLE 3 groups were assessed; 1. PBMCs derived from HCs; 2. PBMCs from patients with SLE; 3. Healthy PBMCs cultured in iron deficient condition, in which cells were treated with the potent iron chelator, Deferiprone.Results:Figure 1a demonstrates that four groups were identified following cluster analysis. In spite of excluding markers of disease activity, these groups showed significant differences in SLEDAI-2K (shown in Figure 1b). In summary, patients with more active disease (Groups C and D) showed higher levels of hepcidin (which prevents the release of iron from stores, under the influence of IL-1ß and IL-6) and reduced transferrin thus suggesting that iron is inefficiently transported when compared with those with less active disease (in Groups A and B).Figure 2a demonstrates that basal mitochondrial respiration is significantly reduced in PBMCs derived from healthy controls when grown in iron deficiency conditions (following treatment with Deferiprone and is lower still in those with SLE. Figure 2b shows that PBMCs from patients with SLE have reduced maximal mitochondrial respiration capacity that is comparable to the levels seen in iron deficient healthy PBMCs.Conclusion:Patients with SLE demonstrate abnormalities in iron metabolism that results in cellular iron deficiency as iron is not released from stores, nor adequately transported at the rate required to meet physiological demands. Furthermore, PBMCs derived from patients with SLE who impaired basal and maximal respiration that is comparable with healthy PBMCs treated potent iron chelation. This suggests that abnormal iron metabolism may in turn limit mitochondrial energy metabolism in SLE and represents a potential future therapeutic target.References:NilAcknowledgments:Versus Arthritis (Grant No 594143) and LUPUS UKDisclosure of Interests:None declared
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Chan, Yee Kwan, Hye Kyoung Sung, and Gary Sweeney. "Iron metabolism and regulation by neutrophil gelatinase-associated lipocalin in cardiomyopathy." Clinical Science 129, no. 10 (August 28, 2015): 851–62. http://dx.doi.org/10.1042/cs20150075.
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Neutrophil gelatinase-associated lipocalin (NGAL) has recently become established as an important contributor to the pathophysiology of cardiovascular disease. Accordingly, it is now viewed as an attractive candidate as a biomarker for various disease states, and in particular has recently become regarded as one of the best diagnostic biomarkers available for acute kidney injury. Nevertheless, the precise physiological effects of NGAL on the heart and the significance of their alterations during the development of heart failure are only now beginning to be characterized. Furthermore, the mechanisms via which NGAL mediates its effects are unclear because there is no conventional receptor signalling pathway. Instead, previous work suggests that regulation of iron metabolism could represent an important mechanism of NGAL action, with wide-ranging consequences spanning metabolic and cardiovascular diseases to host defence against bacterial infection. In the present review, we summarize rapidly emerging evidence for the role of NGAL in regulating heart failure. In particular, we focus on iron transport as a mechanism of NGAL action and discuss this in the context of the existing strong associations between iron overload and iron deficiency with cardiomyopathy.
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Varga, Monica E. R., and Joel H. Weiner. "Physiological role of GlpB of anaerobic glycerol-3-phosphate dehydrogenase ofEscherichia coli." Biochemistry and Cell Biology 73, no. 3-4 (March 1, 1995): 147–53. http://dx.doi.org/10.1139/o95-018.
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Anaerobic sn-glycerol-3-phosphate dehydrogenase of Escherichia coli is encoded by an operon of three genes, glpACB. The promoter distal gene, glpB, encodes a 44-kilodalton polypeptide that is not part of the purified soluble dehydrogenase. By recombinant plasmid complementation, in a strain harboring a chromosomal deletion of glpACB, we found that all three genes were essential for anaerobic growth on glycerol-3-phosphate (G3P). By isolation of inner membrane preparations we confirmed the cytoplasmic membrane localization of GlpB. GlpB displayed an electron paramagnetic resonance spectrum that suggested the presence of iron–sulfur center(s) within GlpB. We used this spectrum to show that the center(s) were reduced by the artificial reductant dithionite and by the physiological substrate G3P but not by lactate or formate. The center(s) were oxidized by fumarate. These data indicated that GlpB mediates electron transfer from the soluble GlpAC dimer to the terminal electron acceptor fumarate via the membrane-bound menaquinone pool.Key words: glycerol-3-phosphate dehydrogenase, anaerobic electron transport, membrane proteins, ferredoxin, Escherichia coli.
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Ma, Xiaocui, Baolong Zhang, Rongli Miao, Xuan Deng, You Duan, Yingyin Cheng, Wanting Zhang, Mijuan Shi, Kaiyao Huang, and Xiao-Qin Xia. "Transcriptomic and Physiological Responses to Oxidative Stress in a Chlamydomonas reinhardtii Glutathione Peroxidase Mutant." Genes 11, no. 4 (April 24, 2020): 463. http://dx.doi.org/10.3390/genes11040463.
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Aerobic photosynthetic organisms such as algae produce reactive oxygen species (ROS) as by-products of metabolism. ROS damage biomolecules such as proteins and lipids in cells, but also act as signaling molecules. The mechanisms that maintain the metabolic balance in aerobic photosynthetic organisms and how the cells specifically respond to different levels of ROS are unclear. Glutathione peroxidase (GPX) enzymes detoxify hydrogen peroxide or organic hydroperoxides, and thus are important components of the antioxidant system. In this study, we employed a Chlamydomonas reinhardtii glutathione peroxidase knockout (gpx5) mutant to identify the genetic response to singlet oxygen (1O2) generated by the photosensitizer rose bengal (RB). To this end, we compared the transcriptomes of the parental strain CC4348 and the gpx5 mutant sampled before, and 1 h after, the addition of RB. Functional annotation of differentially expressed genes showed that genes encoding proteins related to ROS detoxification, stress-response-related molecular chaperones, and ubiquitin–proteasome pathway genes were upregulated in CC4338. When GPX5 was mutated, higher oxidative stress specifically induced the TCA cycle and enhanced mitochondrial electron transport. Transcription of selenoproteins and flagellar-associated proteins was depressed in CC4348 and the gpx5 mutant. In addition, we found iron homeostasis played an important role in maintaining redox homeostasis, and we uncovered the relationship between 1O2 stress and iron assimilation, as well as selenoproteins. Based on the observed expression profiles in response to different levels of oxidative stress, we propose a model for dose-dependent responses to different ROS levels in Chlamydomonas.
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Rishi, Gautam, Eriza S. Secondes, Daniel F. Wallace, and V. Nathan Subramaniam. "Normal systemic iron homeostasis in mice with macrophage-specific deletion of transferrin receptor 2." American Journal of Physiology-Gastrointestinal and Liver Physiology 310, no. 3 (February 1, 2016): G171—G180. http://dx.doi.org/10.1152/ajpgi.00291.2015.
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Iron is an essential element, since it is a component of many macromolecules involved in diverse physiological and cellular functions, including oxygen transport, cellular growth, and metabolism. Systemic iron homeostasis is predominantly regulated by the liver through the iron regulatory hormone hepcidin. Hepcidin expression is itself regulated by a number of proteins, including transferrin receptor 2 (TFR2). TFR2 has been shown to be expressed in the liver, bone marrow, macrophages, and peripheral blood mononuclear cells. Studies from our laboratory have shown that mice with a hepatocyte-specific deletion of Tfr2 recapitulate the hemochromatosis phenotype of the global Tfr2 knockout mice, suggesting that the hepatic expression of TFR2 is important in systemic iron homeostasis. It is unclear how TFR2 in macrophages contributes to the regulation of iron metabolism. We examined the role of TFR2 in macrophages by analysis of transgenic mice lacking Tfr2 in macrophages by crossing Tfr2 f/f mice with LysM-Cre mice. Mice were fed an iron-rich diet or injected with lipopolysaccharide to examine the role of macrophage Tfr2 in iron- or inflammation-mediated regulation of hepcidin. Body iron homeostasis was unaffected in the knockout mice, suggesting that macrophage TFR2 is not required for the regulation of systemic iron metabolism. However, peritoneal macrophages of knockout mice had significantly lower levels of ferroportin mRNA and protein, suggesting that TFR2 may be involved in regulating ferroportin levels in macrophages. These studies further elucidate the role of TFR2 in the regulation of iron homeostasis and its role in regulation of ferroportin and thus macrophage iron homeostasis.
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Hawkins, P. T., D. R. Poyner, T. R. Jackson, A. J. Letcher, D. A. Lander, and R. F. Irvine. "Inhibition of iron-catalysed hydroxyl radical formation by inositol polyphosphates: a possible physiological function for myo-inositol hexakisphosphate." Biochemical Journal 294, no. 3 (September 15, 1993): 929–34. http://dx.doi.org/10.1042/bj2940929.
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1. The ability of myo-inositol polyphosphates to inhibit iron-catalysed hydroxyl radical formation was studied in a hypoxanthine/xanthine oxidase system [Graf, Empson and Eaton (1987) J. Biol. Chem. 262, 11647-11650]. Fe3+ present in the assay reagents supported some radical formation, and a standard assay, with 5 microM Fe3+ added, was used to investigate the specificity of compounds which could inhibit radical generation. 2. InsP6 (phytic acid) was able to inhibit radical formation in this assay completely. In this respect it was similar to the effects of the high affinity Fe3+ chelator Desferral, and dissimilar to the effects of EDTA which, even at high concentrations, still allowed detectable radical formation to take place. 3. The six isomers of InsP5 were purified from an alkaline hydrolysate of InsP6 (four of them as two enantiomeric mixtures), and they were compared with InsP6 in this assay. Ins(1,2,3,4,6)P5 and D/L-Ins(1,2,3,4,5)P5 were similar to InsP6 in that they caused a complete inhibition of iron-catalysed radical formation at > 30 microM. Ins(1,3,4,5,6)P5 and D/L-Ins(1,2,4,5,6)P5, however, were markedly less potent than InsP6, and did not inhibit radical formation completely; even when Ins(1,3,4,5,6)P5 was added up to 600 microM, significant radical formation was still detected. Thus InsP5s lacking 2 or 1/3 phosphates are in this respect qualitatively different from InsP6 and the other InsP5s. 4. scyllo-Inositol hexakisphosphate was also tested, and although it caused a greater inhibition than Ins(1,3,4,5,6)P5, it too still allowed detectable free radical formation even at 600 microM. 5. We conclude that the 1,2,3 (equatorial-axial-equatorial) phosphate grouping in InsP6 has a conformation that uniquely provides a specific interaction with iron to inhibit totally its ability to catalyse hydroxyl radical formation; we suggest that a physiological function of InsP6 might be to act as a ‘safe’ binding site for iron during its transport through the cytosol or cellular organelles.
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Markova, Veronika, Charlotte Holm, Anja Pinborg, Lars Thomsen, and Torben Moos. "Impairment of the Developing Human Brain in Iron Deficiency: Correlations to Findings in Experimental Animals and Prospects for Early Intervention Therapy." Pharmaceuticals 12, no. 3 (August 14, 2019): 120. http://dx.doi.org/10.3390/ph12030120.
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Due to the necessity of iron for a variety of cellular functions, the developing mammalian organism is vulnerable to iron deficiency, hence causing structural abnormalities and physiological malfunctioning in organs, which are particularly dependent on adequate iron stores, such as the brain. In early embryonic life, iron is already needed for proper development of the brain with the proliferation, migration, and differentiation of neuro-progenitor cells. This is underpinned by the widespread expression of transferrin receptors in the developing brain, which, in later life, is restricted to cells of the blood–brain and blood–cerebrospinal fluid barriers and neuronal cells, hence ensuring a sustained iron supply to the brain, even in the fully developed brain. In embryonic human life, iron deficiency is thought to result in a lower brain weight, with the impaired formation of myelin. Studies of fully developed infants that have experienced iron deficiency during development reveal the chronic and irreversible impairment of cognitive, memory, and motor skills, indicating widespread effects on the human brain. This review highlights the major findings of recent decades on the effects of gestational and lactational iron deficiency on the developing human brain. The findings are correlated to findings of experimental animals ranging from rodents to domestic pigs and non-human primates. The results point towards significant effects of iron deficiency on the developing brain. Evidence would be stronger with more studies addressing the human brain in real-time and the development of blood biomarkers of cerebral disturbance in iron deficiency. Cerebral iron deficiency is expected to be curable with iron substitution therapy, as the brain, privileged by the cerebral vascular transferrin receptor expression, is expected to facilitate iron extraction from the circulation and enable transport further into the brain.
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Wang, Bo, and Xiao-Ping Wang. "Does Ceruloplasmin Defend Against Neurodegenerative Diseases?" Current Neuropharmacology 17, no. 6 (May 9, 2019): 539–49. http://dx.doi.org/10.2174/1570159x16666180508113025.
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Ceruloplasmin (CP) is the major copper transport protein in plasma, mainly produced by the liver. Glycosylphosphatidylinositol-linked CP (GPI-CP) is the predominant form expressed in astrocytes of the brain. A growing body of evidence has demonstrated that CP is an essential protein in the body with multiple functions such as regulating the homeostasis of copper and iron ions, ferroxidase activity, oxidizing organic amines, and preventing the formation of free radicals. In addition, as an acute-phase protein, CP is induced during inflammation and infection. The fact that patients with genetic disorder aceruloplasminemia do not suffer from tissue copper deficiency, but rather from disruptions in iron metabolism shows essential roles of CP in iron metabolism rather than copper. Furthermore, abnormal metabolism of metal ions and oxidative stress are found in other neurodegenerative diseases, such as Wilson’s disease, Alzheimer’s disease and Parkinson’s disease. Brain iron accumulation and decreased activity of CP have been shown to be associated with neurodegeneration. We hypothesize that CP may play a protective role in neurodegenerative diseases. However, whether iron accumulation is a cause or a result of neurodegeneration remains unclear. Further research on molecular mechanisms is required before a consensus can be reached regarding a neuroprotective role for CP in neurodegeneration. This review article summarizes the main physiological functions of CP and the current knowledge of its role in neurodegenerative diseases.
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O'Hara, G. W. "Nutritional constraints on root nodule bacteria affecting symbiotic nitrogen fixation: a review." Australian Journal of Experimental Agriculture 41, no. 3 (2001): 417. http://dx.doi.org/10.1071/ea00087.
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Root nodule bacteria require access to adequate concentrations of mineral nutrients for metabolic processes to enable their survival and growth as free-living soil saprophytes, and in their symbiotic relationship with legumes. Essential nutrients, with a direct requirement in metabolism of rhizobia are carbon, hydrogen, oxygen, nitrogen, phosphorus, sulfur, potassium, calcium, magnesium, iron, manganese, copper, zinc, molybdenum, nickel, cobalt and selenium. Boron does not seem to be required by rhizobia, but is essential for the establishment of effective legume symbioses. Nutrient constraints can affect both free-living and symbiotic forms of root nodule bacteria, but whether they do is a function of a complex series of events and interactions. Important physiological characteristics of rhizobia involved in, or affected by, their mineral nutrition include nutrient uptake, growth rate, gene regulation, nutrient storage, survival, genetic exchange and the viable non-culturable state. There is considerable variation between genera, species and strains of rhizobia in their response to nutrient deficiency. The effects of nutrient deficiencies on free-living rhizobia in the soil are poorly understood. Competition between strains of rhizobia for limiting phosphorus and iron in the rhizosphere may affect their ability to nodulate legumes. Processes in the development of some legume symbioses specifically require calcium, cobalt, copper, iron, potassium, molybdenum, nickel, phosphorus, selenium, zinc and boron. Limitations of phosphorus, calcium, iron and molybdenum in particular, can reduce legume productivity by affecting nodule development and function. The effects of nutrient deficiencies on rhizobia–legume signalling are not understood. The supply of essential inorganic nutrients to bacteroids in relation to nutrient partitioning in nodule tissues and nutrient transport to the symbiosome may affect effectiveness of nitrogen fixation. An integration of molecular approaches with more traditional biochemical, physiological and field-based studies is needed to improve understanding of the agricultural importance of rhizobia response to nutrient stress.
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Yang, Zhantao, Raymond T. Doty, Marie H. Nguyen, Ann Smith, and Janis L. Abkowitz. "Evidence That Heme Export Via the Feline Leukemia Virus, Subgroup, C Receptor (FLVCR) Is Carrier Dependent and Its Physiological Implications." Blood 110, no. 11 (November 16, 2007): 2659. http://dx.doi.org/10.1182/blood.v110.11.2659.2659.
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Abstract FLVCR is a heme export protein that is required for proerythroblast survival (Cell18:757, 2004), macrophage heme-iron recycling, and systemic iron homeostasis (ASH abstract, 2007). However, the mechanism and regulation of export through this and related major facilitator superfamily (MFS) members (e.g., Glut4, GlpT) is unknown. To gain insights into the structure and function of FLVCR, we studied the export of zinc mesoporphyrin (ZnMP), a fluorescent heme analog that traffics like heme and blocks heme oxygenase (HO) activity. NRK cells engineered to express huFLVCR were loaded with ZnMP for 30 min, then incubated at 37°C × 90 min with no carrier protein, albumin, or hemopexin (HPXN). In the absence of carrier protein, no export was seen. Export was near complete in the presence of 152 μM (1%) albumin, but less extensive with 15.2 μM albumin and absent with 1.52 μM albumin. Interestingly, HPXN appeared 100 fold more efficacious in inducing ZnMP export, as the residual ZnMP fluorescence in the presence of 0.152 μM HPXN was equivalent to residual intensity in the presence of 15.2 μM albumin. Comparable results were obtained in studies of human blood macrophages. Heme trafficking was next quantitated using 55Fe-heme and a similar study design (ZnMP was added to block HO activity). In the presence of 1.52 μM albumin, 6% of the 55Fe-heme load was exported, while 52% was exported in the presence of 1.52 μM HPXN. When the albumin concentration was increased 100 fold to 152 μM, 67% was exported. As Kds are ∼10 nM and <1 pM, for albumin and HPXN, respectively, our data argue that the rate of heme export depends on the avidity of this binding. Carrier proteins coordinate the heme-iron through two histidines and stabilize this interaction with multiple aromatic amino acids lining the heme-binding pocket. Of note, there are three conserved histidine residues in FLVCR, two of which (aa 145 and 198) are on adjacent extracellular loops, and based upon known MFS family member structures (Protein Sci.13:1832, 2004), are potentially optimally located to coordinate the heme-iron exiting the channel. Adjacent transmembrane regions contain several aromatic residues capable of lining a heme pocket. These histidine residues are conserved in human, cat, and mouse FLVCR, but are not conserved in closely related paralogs (Gene286:203, 2002), which lack heme export function. We hypothesize they act as a temporary docking site for heme after it exits through the transport channel and prior to being picked up by HPXN in the circulation, and thus as a structural regulator of export efficiency. We anticipate that when heme binds to this site, the channel is held in the open-out position preventing additional heme from being transported. We are currently using site-directed mutagenesis to generate a mutant FLVCR lacking these two histidines and will test its export function. To our knowledge, comparable regulatory mechanisms have not been previously described for other MFS family members or for transport proteins more broadly. Since HPXN is present in a high concentration in human serum (17–25 μM, similar to transferrin, 22–31 μM), it may function physiologically to facilitate the recycling of heme-iron from macrophages after they ingest senescent red cells, in addition to its role as a scavenger protein for protection from internal bleeding or extravascular hemolysis. By extension, modulation of the serum HPXN concentration might ameliorate the anemia of chronic inflammation.
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Kent, Sarah A., Tara L. Spires-Jones, and Claire S. Durrant. "The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics." Acta Neuropathologica 140, no. 4 (July 29, 2020): 417–47. http://dx.doi.org/10.1007/s00401-020-02196-w.
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Abstract Tau and amyloid beta (Aβ) are the prime suspects for driving pathology in Alzheimer’s disease (AD) and, as such, have become the focus of therapeutic development. Recent research, however, shows that these proteins have been highly conserved throughout evolution and may have crucial, physiological roles. Such functions may be lost during AD progression or be unintentionally disrupted by tau- or Aβ-targeting therapies. Tau has been revealed to be more than a simple stabiliser of microtubules, reported to play a role in a range of biological processes including myelination, glucose metabolism, axonal transport, microtubule dynamics, iron homeostasis, neurogenesis, motor function, learning and memory, neuronal excitability, and DNA protection. Aβ is similarly multifunctional, and is proposed to regulate learning and memory, angiogenesis, neurogenesis, repair leaks in the blood–brain barrier, promote recovery from injury, and act as an antimicrobial peptide and tumour suppressor. This review will discuss potential physiological roles of tau and Aβ, highlighting how changes to these functions may contribute to pathology, as well as the implications for therapeutic development. We propose that a balanced consideration of both the physiological and pathological roles of tau and Aβ will be essential for the design of safe and effective therapeutics.
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Mazgaj, Rafał, Mateusz Szudzik, Paweł Lipiński, Aneta Jończy, Ewa Smuda, Marian Kamyczek, Beata Cieślak, Dorine Swinkels, Małgorzata Lenartowicz, and Rafał R. Starzyński. "Effect of Oral Supplementation of Healthy Pregnant Sows with Sucrosomial Ferric Pyrophosphate on Maternal Iron Status and Hepatic Iron Stores in Newborn Piglets." Animals 10, no. 7 (June 29, 2020): 1113. http://dx.doi.org/10.3390/ani10071113.
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Background: The similarities between swine and humans in physiological and genomic patterns, as well as significant correlation in size and anatomy, make pigs an useful animal model in nutritional studies during pregnancy. In humans and pigs iron needs exponentially increase during the last trimester of pregnancy, mainly due to increased red blood cell mass. Insufficient iron supply during gestation may be responsible for the occurrence of maternal iron deficiency anemia and decreased iron status in neonates. On the other hand, preventive iron supplementation of non-anemic mothers may be of potential risk due to iron toxicity. Several different regimens of iron supplementation have been applied during pregnancy. The majority of oral iron supplementations routinely applied to pregnant sows provide inorganic, non-heme iron compounds, which exhibit low bioavailability and intestinal side effects. The aim of this study was to check, using pig as an animal model, the effect of sucrosomial ferric pyrophosphate (SFP), a new non-heme iron formulation on maternal and neonate iron and hematological status, placental transport and pregnancy outcome; Methods: Fifteen non-anemic pregnant sows were recruited to the experiment at day 80 of pregnancy and randomized into the non-supplemented group (control; n = 5) and two groups receiving oral iron supplementation—sows given sucrosomial ferric pyrophosphate, 60 mg Fe/day (SFP; n = 5) (SiderAL®, Pisa, Italy) and sows given ferrous sulfate 60 mg Fe/day (Gambit, Kutno, Poland) (FeSO4; n = 5) up to delivery (around day 117). Biological samples were collected from maternal and piglet blood, placenta and piglet tissues. In addition, data on pregnancy outcome were recorded.; Results: Results of our study show that both iron supplements do not alter neither systemic iron homeostasis in pregnant sows nor their hematological status at the end of pregnancy. Moreover, we did not detect any changes of iron content in the milk and colostrum of iron supplemented sows in comparison to controls. Neonatal iron status of piglets from iron supplemented sows was not improved compared with the progeny of control females. No statistically significant differences were found in average piglets weight and number of piglets per litter between animals from experimental groups. The placental expression of iron transporters varied depending on the iron supplement.
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Sanikidze, Tamar V., Levan A. Cheishvili, Nana V. Kipiani, Eka R. Shekiladze, Nina V. Kipiani, Gubaz Z. Sharashenidze, and Eduard N. Chikvaidze. "Role of the Nitric Oxide (NO) in the Regulation of Steroidogenesis in Placenta During Physiological Pregnancy and Preeclampsia (Experimental Study)." Current Topics in Biophysics 42, no. 1 (December 1, 2019): 1–11. http://dx.doi.org/10.2478/ctb-2019-0003.
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AbstractThe aim of the study was to establish the role of nitric oxide (NO) in the regulation of steroidogenesis in the placenta during physiological pregnancy and experimental preeclampsia (PE) in rats. EPR centers of the placenta, free NO and its metabolites were determined by the Electron Paramagnetic Resonance (EPR) method. At the last stage of pregnancy in the EPR spectra of the rats’ placenta with PE alterations of the signals intensity of mitochondrial steroidogenic electron transport proteins were detected: the FeS-centers of adrenodoxin decreased, the ferricytochrome P-450 increased, the free NO content decreased, and the complexes of NO with heme (HbNO) and non-heme iron (FeSNO) were detected. These data indicate the violation of placental steroidogenesis, which is confirmed by a decrease in the level of progesterone in blood. Therefore, the nitrosylation of mitochondrial proteins is an important redox-dependent mechanism of regulation of the intensity of steroidogenesis.
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Rtibi, Kaïs, Slimen Selmi, Dhekra Grami, Hichem Sebai, and Lamjed Marzouki. "Methotrexate Produces Gastrointestinal Stress via Oxidative Stress-caused Acute Physiological Disruptions in Water and Electrolytes Transport in the Mucosal Intestine." Recent Advances in Biology and Medicine 04 (2018): 10. http://dx.doi.org/10.18639/rabm.2018.04.565816.
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Methotrexate (MTX), a chemotherapeutic agent, is used to treat various types of cancers. MTX was known for its toxic effects, particularly in the gastrointestinal (GI) tract. Consequently, the objective of this present research was to investigate the GI disorders during oxidative stress in rats subjected to oral dose of MTX (100 mg kg−1). Thirty male Wistar rats were equally divided at random into three groups (10 animals in each group): the unexposed group and two groups treated with a single dose of MTX. Acute diarrhea was assessed in rats using the defecation and enteropooling methods. Electrolyte levels in intraluminal fluid were analyzed by flame photometry. Oxidative stress indicators and intracellular mediators were determined in mucosal intestine by colorimetric methods. The MTX treatment of rats caused critical changes in the gastrointestinal functions. Mainly, intensification of the liquid stools and intestinal fluid accumulation as well as perturbation in the electrolyte transport was observed. In addition, MTX has a prooxidant effect, which was indicated by an augmentation of malondialdehyde (MDA) and H2O2 generation and a decrease of the enzymatic antioxidants such as SOD, CAT, and GPx. These effects were accompanied with hispathological injury and alteration of lipid metabolism and intracellular mediators such as free iron and calcium. In summary, we found a close association between the gastrointestinal disruptions and the oxidative stress intensity induced by MTX in rats.
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Epsztejn, Silvina, Hava Glickstein, Virginie Picard, Itzchak N. Slotki, William Breuer, Carole Beaumont, and Z. Ioav Cabantchik. "H-Ferritin Subunit Overexpression in Erythroid Cells Reduces the Oxidative Stress Response and Induces Multidrug Resistance Properties." Blood 94, no. 10 (November 15, 1999): 3593–603. http://dx.doi.org/10.1182/blood.v94.10.3593.422k26_3593_3603.
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The labile iron pool (LIP) of animal cells has been implicated in cell iron regulation and as a key component of the oxidative-stress response. A major mechanism commonly implied in the downregulation of LIP has been the induced expression of ferritin (FT), particularly the heavy subunits (H-FT) that display ferroxidase activity. The effects of H-FT on LIP and other physiological parameters were studied in murine erythroleukemia (MEL) cells stably transfected with H-FT subunits. Clones expressing different levels of H-FT displayed similar concentrations of total cell iron (0.3 ± 0.1 mmol/L) and of reduced/total glutathione. However, with increasing H-FT levels the cells expressed lower levels of LIP and reactive oxygen species (ROS) and ensuing cell death after iron loads and oxidative challenges. These results provide direct experimental support for the alleged roles of H-FT as a regulator of labile cell iron and as a possible attenuator of the oxidative cell response. H-FT overexpression was of no apparent consequence to the cellular proliferative capacity. However, concomitant with the acquisition of iron and redox regulatory capacities, the H-FT–transfectant cells commensurately acquired multidrug resistance (MDR) properties. These properties were identified as increased expression of MDR1 mRNA (by reverse transcription polymerase chain reaction [RT-PCR]), P-glycoprotein (Western immunoblotting), drug transport activity (verapamil-sensitive drug efflux), and drug cytotoxicity associated with increased MDR1 or PgP. Although enhanced MDR expression per se evoked no significant changes in either LIP levels or ROS production, it might be essential for the survival of H-FT transfectants, possibly by expediting the export of cell-generated metabolites.
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Longhini, Cybelle Menolli, Fabian Sá, and Renato Rodrigues Neto. "Review and synthesis: iron input, biogeochemistry, and ecological approaches in seawater." Environmental Reviews 27, no. 2 (June 2019): 125–37. http://dx.doi.org/10.1139/er-2018-0020.
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The processes involved in the biogeochemical cycle of Fe in the oceans have been intensely discussed in recent decades because this element is limiting to primary productivity in most oceanic regions. From biogeochemical and ecological perspectives, inputs from anthropogenic sources, especially mining activities, may be more representative than natural inputs in coastal areas affected by metal loads from tailings. Here we provide a review of all the stages related to Fe behaviour in marine ecosystems, including Fe input sources, which may be of natural and (or) anthropogenic origin; input rates; chemical speciation; bioavailability; and changes in the phytoplankton community structure. To allow conceptualization of the anthropogenic processes, the collapse of the Fundão tailings dam (southeast Brazil) was used as a case study of one of the worst environmental disasters of the mining industry. From this perspective, the interrelations among the chemical, biological, and ecological components were discussed. Regarding the chemical component, Fe speciation must be determined by the input of several other materials, mainly organic compounds that can be complexed to this element and increase its solubility. From a biological perspective, the biochemical and physiological processes used for the assimilation of this element, such as the reduction in cell membranes and the production of chelating substances (such as siderophores), will also determine the forms of this element present in the water column. On the other hand, the groups that obtain a competitive advantage due to these assimilation strategies must be dominant in the system. Synergistic effects are also expected with other materials such as the inorganic nutrients, organic compounds, and metals that are carried to the coastal region together with Fe. In the specific case of mine tailings, the accumulation of this material in the river banks and bed should cause an increase in Fe input from other sources, such as atmospheric transport and submarine groundwater discharge, as well as river discharge by erosion and transport under increased river flow conditions. The iron fluxes from mining areas to coastal oceans and the effects of these loads to phytoplankton ecological aspects should be investigated.
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Papassotiriou, Ioannis, Alexandra Margeli, Antonios Drakatos, Sophia Delikou, Korina Kassiou, Christos Kattamis, Vassilios Ladis, and Antonios Kattamis. "Neutrophil Gelatinase-Associated Lipocalin Levels in Patients with Thalassemia Intermedia: Lack of Association with Erythropoiesis, Iron Metabolism, Renal Dysfunction and Inflammation." Blood 110, no. 11 (November 16, 2007): 3814. http://dx.doi.org/10.1182/blood.v110.11.3814.3814.
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Abstract Neutrophil Gelatinase-Associated Lipocalin (NGAL, 24p3, SIP24, lipocalin-2 or siderocalin) is a novel iron-carrier protein exerting pleiotropic properties. The physiological role of NGAL is not fully elucidated though a few pivotal functions, such as regulation of apoptosis of leukocytes have been described recently. It has also been demonstrated that NGAL is abundantly expressed in erythroid progenitor cells inducing apoptosis and inhibiting their differentiation. NGAL is reduced in the erythroid cells of mice with acute anemia and injection of recombinant lipocalin-2 delayed the recovery of red blood cells suggesting a negative effect of NGAL in accelerating erythropoiesis. The recently reported functions of NGAL on erythroid progenitor cells and its relation to iron transport prompted us to study the pattern of NGAL levels in Thalassemia Intermedia (TI), which is characterized by erythroid progenitor cells hyperactivity and irregularities in iron metabolism (especially iron transport). To this end we measured NGAL levels in 30 patients with TI and in 20 apparently healthy controls matched for age. We also evaluated other parameters that could be possibly related to NGAL’s functions as: soluble transferrin receptor (sTfR) for eythroid marrow activity; NTBI concentration for non-transferrin-bound mediate iron delivery pathway; creatinine, cystatin C and β2-microglobulin for renal dysfunction and CRP and IL-6 for low grade inflammation. The main results of the showed that: a) NGAL levels were significantly higher in patients with TI compared to controls (139.1±86.1 vs 51.2±11.8 μg/L, p<0.0001), while 4 patients presented with NGAL levels within normal range, b) in patients with TI no correlation was found between NGAL and the erythropoiesis’ parameters Hb, Hb F and sTfR, (p>0.66, p>0.67 and p>0.81 respectively), the parameters of iron metabolism, ferritin and NTBI (p>0.90 and p>0.95 respectively) the markers of renal dysfunction and/or those of low-grade inflammation (p>0.50). The increased NGAL levels observed in TI patients in this study are in agreement with the elevated expression of NGAL observed in experimental models of thalassemia. We postulate that the induction of NGAL in these patients may represent either a response facilitating the survival of the less damaged thalassemic erythroid precursors, or a consequence due to the abnormal iron regulation in patients with TI.
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Celletti, Silvia, Youry Pii, Fabio Valentinuzzi, Raphael Tiziani, Maria Chiara Fontanella, Gian Maria Beone, Tanja Mimmo, Stefano Cesco, and Stefania Astolfi. "Physiological Responses to Fe Deficiency in Split-Root Tomato Plants: Possible Roles of Auxin and Ethylene?" Agronomy 10, no. 7 (July 11, 2020): 1000. http://dx.doi.org/10.3390/agronomy10071000.
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Iron (Fe) bioavailability in soils is often limited and can be further exacerbated by a non- homogeneous distribution in the soil profile, which has been demonstrated to vary both in space and time. Consequently, plants respond with morphological and physiological modifications at the root level involving a complex local and systemic signaling machinery. The present work unravels the role of two phytohormones (i.e., ethylene and auxin) and their integrated signaling in plant response to Fe deficiency. Inhibitors of auxin polar transport and of ethylene biosynthesis (N-1-naphthylphthalamic acid - NPA and aminoethoxyvinylglycine - AVG, respectively) were applied on tomato (Solanum lycopersicum L.) plants grown by the split-root technique, which allows to simulate condition of Fe heterogeneous distribution. Results showed that plants, exposed to an uneven Fe supply, triggered a complex auxin-ethylene signaling. A systemic action of auxin on FERRIC REDUCTASE OXIDASE 1 (SlFRO1) expression was revealed, while ethylene signaling was effective both locally and systemically. In addition, the investigation of Fe concentration in tissues showed that when leaves overcame Fe deficiency a Fe “steady state” was maintained. Therefore, physiological adaptation to this heterogeneous Fe supply could be mediated by the integration of the complex signaling pathways prompted by both auxin and ethylene activities.
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Prakash, Divya, Prashanti R. Iyer, Suharti Suharti, Karim A. Walters, Michel Geovanni Santiago-Martinez, John H. Golbeck, Katsuhiko S. Murakami, and James G. Ferry. "Structure and function of an unusual flavodoxin from the domainArchaea." Proceedings of the National Academy of Sciences 116, no. 51 (December 4, 2019): 25917–22. http://dx.doi.org/10.1073/pnas.1908578116.
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Flavodoxins, electron transfer proteins essential for diverse metabolisms in microbes from the domainBacteria, are extensively characterized. Remarkably, although genomic annotations of flavodoxins are widespread in microbes from the domainArchaea, none have been isolated and characterized. Herein is described the structural, biochemical, and physiological characterization of an unusual flavodoxin (FldA) fromMethanosarcina acetivorans, an acetate-utilizing methane-producing microbe of the domainArchaea. In contrast to all flavodoxins, FldA is homodimeric, markedly less acidic, and stabilizes an anionic semiquinone. The crystal structure reveals an flavin mononucleotide (FMN) binding site unique from all other flavodoxins that provides a rationale for stabilization of the anionic semiquinone and a remarkably low reduction potentials for both the oxidized/semiquinone (−301 mV) and semiquinone/hydroquinone couples (−464 mV). FldA is up-regulated in acetate-grown versus methanol-grown cells and shown here to substitute for ferredoxin in mediating the transfer of low potential electrons from the carbonyl of acetate to the membrane-bound electron transport chain that generates ion gradients driving ATP synthesis. FldA offers potential advantages over ferredoxin by (i) sparing iron for abundant iron-sulfur proteins essential for acetotrophic growth and (ii) resilience to oxidative damage.
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Schuback, Nina, Mirkko Flecken, Maria T. Maldonado, and Philippe D. Tortell. "Diurnal variation in the coupling of photosynthetic electron transport and carbon fixation in iron-limited phytoplankton in the NE subarctic Pacific." Biogeosciences 13, no. 4 (February 23, 2016): 1019–35. http://dx.doi.org/10.5194/bg-13-1019-2016.
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Abstract. Active chlorophyll a fluorescence approaches, including fast repetition rate fluorometry (FRRF), have the potential to provide estimates of phytoplankton primary productivity at an unprecedented spatial and temporal resolution. FRRF-derived productivity rates are based on estimates of charge separation in reaction center II (ETRRCII), which must be converted into ecologically relevant units of carbon fixation. Understanding sources of variability in the coupling of ETRRCII and carbon fixation provides physiological insight into phytoplankton photosynthesis and is critical for the application of FRRF as a primary productivity measurement tool. In the present study, we simultaneously measured phytoplankton carbon fixation and ETRRCII in the iron-limited NE subarctic Pacific over the course of a diurnal cycle. We show that rates of ETRRCII are closely tied to the diurnal cycle in light availability, whereas rates of carbon fixation appear to be influenced by endogenous changes in metabolic energy allocation under iron-limited conditions. Unsynchronized diurnal oscillations of the two rates led to 3.5-fold changes in the conversion factor between ETRRCII and carbon fixation (Kc / nPSII). Consequently, diurnal variability in phytoplankton carbon fixation cannot be adequately captured with FRRF approaches if a constant conversion factor is applied. Utilizing several auxiliary photophysiological measurements, we observed that a high conversion factor is associated with conditions of excess light and correlates with the increased expression of non-photochemical quenching (NPQ) in the pigment antenna, as derived from FRRF measurements. The observed correlation between NPQ and Kc / nPSII requires further validation but has the potential to improve estimates of phytoplankton carbon fixation rates from FRRF measurements alone.
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Schuback, N., M. Flecken, M. T. Maldonado, and P. D. Tortell. "Diurnal variation in the coupling of photosynthetic electron transport and carbon fixation in iron-limited phytoplankton in the NE subarctic Pacific." Biogeosciences Discussions 12, no. 20 (October 19, 2015): 16803–45. http://dx.doi.org/10.5194/bgd-12-16803-2015.
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Abstract. Active chlorophyll a fluorescence approaches, including fast repetition rate fluorometry (FRRF), have the potential to provide estimates of phytoplankton primary productivity at unprecedented spatial and temporal resolution. FRRF-derived productivity rates are based on estimates of charge separation at PSII (ETRRCII), which must be converted into ecologically relevant units of carbon fixation. Understanding sources of variability in the coupling of ETRRCII and carbon fixation provides physiological insight into phytoplankton photosynthesis, and is critical for the application of FRRF as a primary productivity measurement tool. In the present study, we simultaneously measured phytoplankton carbon fixation and ETRRCII in the iron-limited NE subarctic Pacific, over the course of a diurnal cycle. We show that rates of ETRRCII are closely tied to the diurnal cycle in light availability, whereas rates of carbon fixation appear to be influenced by endogenous changes in metabolic energy allocation under iron-limited conditions. Unsynchronized diurnal oscillations of the two rates led to 3.5 fold changes in the conversion factor coupling ETRRCII and carbon fixation (Φe:C / nPSII). Consequently, diurnal variability in phytoplankton carbon fixation cannot be adequately captured with FRRF approaches if a constant conversion factor is applied. Utilizing several auxiliary photophysiological measurements, we observed that a high conversion factor is associated with conditions of excess light, and correlates with the expression of non-photochemical quenching (NPQ) in the pigment antenna, as derived from FRRF measurements. The observed correlation between NPQ and the conversion factor Φe:C / nPSII has the potential to improve estimates of phytoplankton carbon fixation rates from FRRF measurements alone.
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Noetzli, Leila J., Ashok Panigrahy, Mehrdad Joukar, Aleya Hyderi, Steven D. Mittelman, Thomas Coates, and John C. Wood. "Pituitary Iron and Volume in Transfusional Iron Overload." Blood 114, no. 22 (November 20, 2009): 2017. http://dx.doi.org/10.1182/blood.v114.22.2017.2017.
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Abstract Abstract 2017 Poster Board I-1039 Introduction: Hypogonadotropic hypogonadism (HH) is the most common endocrine problem in chronically transfused patients. Unfortunately, gonadotrophe iron toxicity is not readily detectable until puberty and stimulation tests can be difficult to interpret in adolescents. MRI can image preclinical pituitary iron deposition, similar to its use in the heart, liver and pancreas. Increased pituitary R2, a surrogate for iron, and decreased pituitary volume have both been shown to predict clinical and biochemical HH in iron overloaded adults 1,2. However, data regarding pituitary iron deposition and toxicity is lacking in younger patients with iron overload. We present baseline results from a two year observational trial of changes in pituitary R2 and volume in response to deferasirox therapy in patients with transfusional siderosis. Methods: We studied 22 chronically-transfused patients with Thalassemia Major and 2 patients with Diamond Blackfan Anemia. The average age was 13.1 ± 5.2 years (range: 3.7-23.6 years). All studies were performed on a 1.5 T Philips Achieva. Anterior pituitary R2 was assessed in the sagittal and coronal planes using multiple spin echoes from 15 to 120 ms. Pituitary volume was assessed using a 3D spoiled gradient echo sequence with 1 mm3 isotropic voxels. Pituitary R2 was calculated by pixelwise monoexponential fit, with median values used to represent the overall gland R2; boundaries were confirmed by a board-certified neuroradiologist. Normative data for pituitary iron and volume was drawn from another study in 49 normal volunteers. MRI estimates of hepatic iron concentration (HIC), cardiac iron (T2*), and pancreatic iron (R2*) were obtained as clinical standard of care. All statistics were performed using JMP5.1 (SAS, Cary, NC). Results: Patients were mild to moderately iron loaded, with a HIC of 10.2 ± 12.0 mg/g dry wt (median 4.5 mg/g, nl < 1.5 mg/g), cardiac T2* of 29.4 ± 9.2 ms (median 31.5 ms, nl > 20ms), and pancreas R2* of 136 ± 156 Hz (median 73 Hz, nl < 27 Hz). Fourteen patients were below the 10th percentile for height including 7 below the 5th percentile. One patient had been diagnosed with delayed puberty and was on estrogen replacement. Pituitary R2 was elevated in 13/24 patients, beginning in the first decade of life and worsening in patients older than 13 years of age (Figure 1, left). Mean Z-score was 3.2 ± 3.7 (median 2.5, range -0.5 to12.8). Pituitary R2 was correlated with HIC (r2=0.68) and pancreatic R2* (r2=0.40), but not cardiac R2*. Area under the receiver operator characteristic curve was 0.76 for both HIC and pancreatic iron for the prediction of pituitary iron loading. Anterior pituitary volumes were low-normal in the first decade of life but were below the 1st percentile in 4/16 patients older than 13 years of age (Figure 1, right); all 4 patients with severe pituitary shrinkage had significant pituitary iron loading (Z-scores ranging from 2.8 to 12.8). The patient having documented HH had an iron Z-score of 12.8 and a volume Z-score of –5.0. Discussion: HH remains one of the most difficult endocrinopathies to recognize and prevent in transfusional siderosis. The present data demonstrate that iron accumulation occurs early in these patients and worsens dramatically in the second decade of life. Pituitary R2 was closely correlated with liver and pancreatic iron suggesting more rapid iron transport kinetics than for the heart. The low-normal pituitary volumes in childhood may reflect ethnic mismatches between the control and study populations, early iron toxicity, or hypothalamic dysfunction from increased erythropoiesis and metabolic demand. However, severe pituitary volume loss was limited to the second decade of life and associated with markedly increased pituitary iron (R2). Thus, there appears to be a broad, preclinical window to reduce pituitary toxicity. MRI screening of pituitary size and iron concentration needs to be expanded, clinically, to explore this hypothesis and hopefully prevent the significant physiological and psychological sequelae associated with hypogonadism. Disclosures: Coates: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Wood:Novartis: Research Funding.