Science.gov

Sample records for iron chelating agents

  1. Iron Chelation

    MedlinePlus

    ... iron overload and need treatment. What is iron overload? Iron chelation therapy is used when you have ... may want to perform: How quickly does iron overload happen? This is different for each person. It ...

  2. Using iron chelating agents to enhance dermatological PDT

    NASA Astrophysics Data System (ADS)

    Curnow, Alison; Dogra, Yuktee; Winyard, Paul; Campbell, Sandra

    2009-06-01

    Topical protoporphyrin IX (PPIX) induced photodynamic therapy (PDT) of basal cell carcinoma (BCC) produces good clinical outcomes with excellent cosmesis as long as the disease remains superficial. Efficacy for nodular BCC however appears inferior to standard treatment unless repeat treatments are performed. Enhancement is therefore required and is possible by employing iron chelating agents to temporarily increase PPIX accumulation above the levels normally obtained using aminolevulinic acid (ALA) or the methyl ester of ALA (MAL) alone. In vitro studies investigated the effect of the novel iron chelator, CP94 on necrotic or apoptotic cell death in cultured human skin fibroblasts and epidermal carcinoma cells incubated with MAL. Furthermore, following a dose escalating safety study conducted with ALA in patients, an additional twelve nodular BCCs were recruited for topical treatment with standard MAL-PDT +/- increasing doses of CP94. Six weeks later following clinical assessment, the whole treatment site was excised for histological analysis. CP94 produced greater cell death in vitro when administered in conjunction with MAL than this porphyrin precursor could produce when administered alone. Clinically, PDT treatment using Metvix + CP94 was a simple and safe modification associated with a trend of reduced tumor thickness with increasing CP94 dose.

  3. Potential of iron chelators as effective antiproliferative agents.

    PubMed

    Richardson, D R

    1997-01-01

    Initially the impetus to develop iron (Fe) chelators for clinical use was based upon the need for a drug to treat Fe-overload diseases such as beta-thalassemia. However, it has become clear that Fe chelators may be useful for the treatment of a wide variety of disease states, including cancer, malaria, and free radical mediated injury. In particular, over the last 10 years a number of studies have shown that Fe chelators may be of use in the treatment of a number of aggressive human cancers, including neuroblastoma and leukemia, and several clinical trials have substantiated their potential. In the current review the role of Fe in cellular proliferation will be discussed, followed by the possible sites and mechanism of action of some of the most effective ligands. Attention will then be turned to examine the Fe chelators shown to possess antiproliferative activity and the clinical trials performed to assess their efficacy.

  4. Comparison of various iron chelators and prochelators as protective agents against cardiomyocyte oxidative injury.

    PubMed

    Jansová, Hana; Macháček, Miloslav; Wang, Qin; Hašková, Pavlína; Jirkovská, Anna; Potůčková, Eliška; Kielar, Filip; Franz, Katherine J; Simůnek, Tomáš

    2014-09-01

    Oxidative stress is a common denominator of numerous cardiovascular disorders. Free cellular iron catalyzes the formation of highly toxic hydroxyl radicals, and iron chelation may thus be an effective therapeutic approach. However, using classical iron chelators in diseases without iron overload poses risks that necessitate more advanced approaches, such as prochelators that are activated to chelate iron only under disease-specific oxidative stress conditions. In this study, three cell-membrane-permeable iron chelators (clinically used deferasirox and experimental SIH and HAPI) and five boronate-masked prochelator analogs were evaluated for their ability to protect cardiac cells against oxidative injury induced by hydrogen peroxide. Whereas the deferasirox-derived agents TIP and TRA-IMM displayed negligible protection and even considerable toxicity, the aroylhydrazone prochelators BHAPI and BSIH-PD provided significant cytoprotection and displayed lower toxicity after prolonged cellular exposure compared to their parent chelators HAPI and SIH, respectively. Overall, the most favorable properties in terms of protective efficiency and low inherent cytotoxicity were observed with the aroylhydrazone prochelator BSIH. BSIH efficiently protected both H9c2 rat cardiomyoblast-derived cells and isolated primary rat cardiomyocytes against hydrogen peroxide-induced mitochondrial and lysosomal dysregulation and cell death. At the same time, BSIH was nontoxic at concentrations up to its solubility limit (600 μM) and in 72-h incubation. Hence, BSIH merits further investigation for prevention and/or treatment of cardiovascular disorders associated with a known (or presumed) component of oxidative stress.

  5. Comparison of various iron chelators and prochelators as protective agents against cardiomyocyte oxidative injury

    PubMed Central

    Jansová, Hana; Macháček, Miloslav; Wang, Qin; Hašková, Pavlína; Jirkovská, Anna; Potůčková, Eliška; Kielar, Filip; Franz, Katherine J.; Šimůnek, Tomáš

    2014-01-01

    Oxidative stress is a common denominator of numerous cardiovascular disorders. Free cellular iron catalyzes formation of highly toxic hydroxyl radicals and iron chelation may thus be an effective therapeutic approach. However, using classical iron chelators in diseases without iron overload poses risks that necessitate more advanced approaches, such as prochelators that are activated to chelate iron only under disease-specific oxidative stress conditions. In this study, three cell membrane-permeable iron chelators (clinically-used deferasirox and experimental SIH and HAPI) and five boronate-masked prochelator analogs were evaluated for their ability to protect cardiac cells against oxidative injury induced by hydrogen peroxide. Whereas the deferasirox-derived agents TIP and TRA-IMM displayed negligible protection and even considerable toxicity, aroylhydrazone prochelators BHAPI and BSIH-PD provided significant cytoprotection and displayed lower toxicity following prolonged cellular exposure compared to their parent chelators HAPI and SIH, respectively. Overall, the most favorable properties in terms of protective efficiency and low inherent cytotoxicity were observed with aroylhydrazone prochelator BSIH. BSIH efficiently protected both H9c2 rat cardiomyoblast-derived cells as well as isolated primary rat cardiomyocytes against hydrogen peroxide-induced mitochondrial and lysosomal dysregulation and cell death. At the same time, BSIH was non-toxic at concentrations up to its solubility limit (600 µM) and 72-hour incubation. Hence, BSIH merits further investigation for prevention and/or treatment of cardiovascular disorders associated with a known (or presumed) component of oxidative stress. PMID:24992833

  6. Evaluation of iron-chelating agents in cultured heart muscle cells. Identification of a potential drug for chelation therapy.

    PubMed

    Sciortino, C V; Byers, B R; Cox, P

    1980-12-01

    Primary cultures of neonatal rat cardiac muscle cells incorporated radioiron from both [55Fe]transferrin and 59FeCl3 (added simultaneously). To evaluate the effect of iron chelators on such uptake, deferri chelators were added 6 hr after addition of the radioiron sources. The microbial chelator agrobactin was significantly more effective than the drug defoxamine in reduction of 55Fe uptake from [55Fe]transferrin; both chelators halted 59Fe3+ uptake. Agrobactin may have potential in chelation therpay for iron-overload disease. Certain other microbial chelators lowered radioiron uptake from either [55Fe]transferrin of 59FeCl3. These chelators should be useful inhibitors for studies of animal cell iron uptake and intracellular iron flow.

  7. Hydroxypyridonate chelating agents

    DOEpatents

    Raymond, Kenneth N.; Scarrow, Robert C.; White, David L.

    1987-01-01

    Chelating agents having 1-hydroxy-2-pyridinone (HOPO) and related moieties incorporated within their structures, including polydentate HOPO-substituted polyamines such as spermidine and spermine, and HOPO-substituted desferrioxamine. The chelating agents are useful in selectively removing certain cations from solution, and are particularly useful as ferric ion and actinide chelators. Novel syntheses of the chelating agents are provided.

  8. Iron-chelating agent, deferasirox, inhibits neutrophil activation and extracellular trap formation.

    PubMed

    Kono, Mari; Saigo, Katsuyasu; Yamamoto, Shiori; Shirai, Kohei; Iwamoto, Shuta; Uematsu, Tomoko; Takahashi, Takayuki; Imoto, Shion; Hashimoto, Makoto; Minami, Yosuke; Wada, Atsushi; Takenokuchi, Mariko; Kawano, Seiji

    2016-10-01

    Iron-chelating agents, which are frequently prescribed to transfusion-dependent patients, have various useful biological effects in addition to chelation. Reactive oxygen species (ROS) produced by neutrophils can cause pulmonary endothelial cell damage, which can lead to acute lung injury (ALI). We previously reported that deferasirox (DFS), an iron-chelating agent, inhibits phorbol myristate acetate (PMA) or formyl-methionyl-leucyl-phenylalanine (fMLP)-induced ROS production in neutrophils, in vitro. Here, we investigate whether DFS inhibits vacuolization in neutrophils and neutrophil extracellular trap (NET) formation. Human neutrophils were incubated with DFS and stimulated with PMA or fMLP. Human neutrophils were separated from heparinized peripheral blood using density gradient centrifugation, and subsequently incubated with DFS. After 10 minutes, neutrophils were stimulated by PMA or fMLP. Vacuole formation was observed by electron microscopy. For observing NET formations using microscopes, immunohistological analyses using citrullinated histone H3 and myeloperoxidase antibodies, and SYTOX Green (an impermeable DNA detection dye) staining, were conducted. NET formation was measured as the quantity of double-stranded DNA (dsDNA), using the AccuBlue Broad Range dsDNA Quantitation Kit. DFS (50 μmol/L) inhibited vacuole formation in the cytoplasm and NET formation. Additionally, 5-100 μmol/L concentration of DFS inhibited the release of dsDNA in a dose-independent manner. We demonstrate that DFS inhibits not only ROS production but also vacuolization and NET formation in neutrophils. These results suggest the possibility of protective effects of DFS against NET-related adverse effects, including ALI and thrombosis. PMID:27333499

  9. Rigid bifunctional chelating agents

    DOEpatents

    Sweet, Mark P.; Mease, Ronnie C.; Srivastava, Suresh C.

    2000-02-08

    Bicyclo[2.2.2]octane-2,3 diamine-N,N,N',N'-tetraacetic acids (BODTA) and bicyclo[2.2.1]heptane-2,3 diamine-N,N,N',N'-tetraacetic acid (BHDTA) are chelating agents useful in forming detectably labeled bioconjugate compounds for diagnostic and therapeutic purposes. New compounds and processes of forming BODTA and BHDTA are disclosed. Radioimmunoconjugates of the present invention show high and prolonged tumor uptake with low normal tissue uptakes.

  10. Rigid bifunctional chelating agents

    DOEpatents

    Sweet, M.P.; Mease, R.C.; Srivastava, S.C.

    1998-07-21

    Bicyclo[2.2.2] octane-2,3 diamine-N,N,N`,N`-tetraacetic acids (BODTA) and bicyclo[2.2.1] heptane-2,3 diamine-N,N,N`,N`-tetraacetic acid (BHDTA) are chelating agents useful in forming detectably labeled bioconjugate compounds for diagnostic and therapeutic purposes. New compounds and processes of forming BODTA and BHDTA are disclosed. Radioimmunoconjugates of the present invention show high and prolonged tumor uptake with low normal tissue uptakes.

  11. Rigid bifunctional chelating agents

    DOEpatents

    Sweet, Mark P.; Mease, Ronnie C.; Srivastava, Suresh C.

    1998-07-21

    Bicyclo›2.2.2! octane-2,3 diamine-N,N,N',N'-tetraacetic acids (BODTA) and bicyclo›2.2.1! heptane-2,3 diamine-N,N,N',N'-tetraacetic acid (BHDTA) are chelating agents useful in forming detectably labeled bioconjugate compounds for diagnostic and therapeutic purposes. New compounds and processes of forming BODTA and BHDTA are disclosed. Radioimmunoconjugates of the present invention show high and prolonged tumor uptake with low normal tissue uptakes.

  12. Iron-chelation therapy: an update.

    PubMed

    Franchini, Massimo; Veneri, Dino

    2004-01-01

    Chronically transfused patients develop iron overload that leads to organ damage and ultimately to death. The introduction of the iron-chelating agent, desferrioxamine mesylate, dramatically improved the life expectancy of these patients. However, the very demanding nature of this treatment (subcutaneous continuous infusion via a battery-operated portable pump) has been the motivation for attempts to develop alternative forms of treatment that would facilitate the patients' compliance. In this review, we describe the most important advances in iron-chelating therapy. In particular, we analyze a new method of administering desferrioxamine mesylate (twice daily subcutaneous bolus injections) and a novel, orally active iron chelator (ICL670A). We also present a meta-analysis of the largest trials on the oral iron chelator deferiprone and the results of combined therapy (deferiprone and desferrioxamine).

  13. Macrocyclic bifunctional chelating agents

    DOEpatents

    Meares, Claude F.; DeNardo, Sally J.; Cole, William C.; Mol, Min K.

    1987-01-01

    A copper chelate conjugate which is stable in human serum. The conjugate includes the copper chelate of a cyclic tetraaza di-, tri-, or tetra-acetic acid, a linker attached at one linker end to a ring carbon of the chelate, and a biomolecule joined at the other end of the linker. The conjugate, or the linker-copper chelate compound used in forming the conjugate, are designed for use in diagnostic and therapeutic applications which involve Cu(II) localization via the systemic route.

  14. Hydroxypyridonate and hydroxypyrimidinone chelating agents

    DOEpatents

    Raymond, Kenneth N.; Doble, Daniel M.; Sunderland, Christopher J.; Thompson, Marlon

    2005-01-25

    The present invention provides hydroxypyridinone and hydroxypyrimidone chelating agents. Also provides are Gd(III) complexes of these agents, which are useful as contrast enhancing agents for magnetic resonance imaging. The invention also provides methods of preparing the compounds of the invention, as well as methods of using the compounds in magnetic resonance imaging applications.

  15. Iron chelation and multiple sclerosis

    PubMed Central

    Weigel, Kelsey J.; Lynch, Sharon G.; LeVine, Steven M.

    2014-01-01

    Histochemical and MRI studies have demonstrated that MS (multiple sclerosis) patients have abnormal deposition of iron in both gray and white matter structures. Data is emerging indicating that this iron could partake in pathogenesis by various mechanisms, e.g., promoting the production of reactive oxygen species and enhancing the production of proinflammatory cytokines. Iron chelation therapy could be a viable strategy to block iron-related pathological events or it can confer cellular protection by stabilizing hypoxia inducible factor 1α, a transcription factor that normally responds to hypoxic conditions. Iron chelation has been shown to protect against disease progression and/or limit iron accumulation in some neurological disorders or their experimental models. Data from studies that administered a chelator to animals with experimental autoimmune encephalomyelitis, a model of MS, support the rationale for examining this treatment approach in MS. Preliminary clinical studies have been performed in MS patients using deferoxamine. Although some side effects were observed, the large majority of patients were able to tolerate the arduous administration regimen, i.e., 6–8 h of subcutaneous infusion, and all side effects resolved upon discontinuation of treatment. Importantly, these preliminary studies did not identify a disqualifying event for this experimental approach. More recently developed chelators, deferasirox and deferiprone, are more desirable for possible use in MS given their oral administration, and importantly, deferiprone can cross the blood–brain barrier. However, experiences from other conditions indicate that the potential for adverse events during chelation therapy necessitates close patient monitoring and a carefully considered administration regimen. PMID:24397846

  16. Chelation and mobilization of cellular iron by different classes of chelators.

    PubMed

    Zanninelli, G; Glickstein, H; Breuer, W; Milgram, P; Brissot, P; Hider, R C; Konijn, A M; Libman, J; Shanzer, A; Cabantchik, Z I

    1997-05-01

    Iron chelators belonging to three distinct chemical families were assessed in terms of their physicochemical properties and the kinetics of iron chelation in solution and in two biological systems. Several hydroxypyridinones, reversed siderophores, and desferrioxamine derivatives were selected to cover agents with different iron-binding stoichiometry and geometry and a wide range of lipophilicity, as determined by the octanol-water partition coefficients. The selection also included highly lipophilic chelators with potentially cell-cleavable ester groups that can serve as precursors of hydrophilic and membrane-impermeant chelators. Iron binding was determined by the chelator capacity for restoring the fluorescence of iron-quenched calcein (CA), a dynamic fluorescent metallosensor. The iron-scavenging properties of the chelators were assessed under three different conditions: (a) in solution, by mixing iron salts with free CA; (b) in resealed red cell ghosts, by encapsulation of CA followed by loading with iron; and (c) in human erythroleukemia K562 cells, by loading with the permeant CA-acetomethoxy ester, in situ formation of free CA, and binding of cytosolic labile iron. The time-dependent recovery of fluorescence in the presence of a given chelator provided a continuous measure for the capacity of the chelator to access the iron/CA-containing compartment. The resulting rate constants of fluorescence recovery indicated that chelation in solution was comparable for the members of each family of chelators, whereas chelation in either biological system was largely dictated by the lipophilicity of the free chelator. For example, desferrioxamine was among the fastest and most efficient iron scavengers in solution but was essentially ineffective in either biological system when used at < or = 200 microM over a 2-hr period at 37 degrees. On the other hand, the highly lipophilic and potentially cell-cleavable hydroxypyridinones and reversed siderophores were highly

  17. Hydroxypyridonate chelating agents and synthesis thereof

    DOEpatents

    Raymond, K.N.; Scarrow, R.C.; White, D.L.

    1985-11-12

    Chelating agents having 1-hydroxy-2-pyridinone (HOPO) and related moieties incorporated within their structures, including polydentate HOPO-substituted polyamines such as spermidine and spermine, and HOPO-substituted desferrioxamine. The chelating agents are useful in selectively removing certain cations from solution, and are particularly useful as ferric ion and actinide chelators. Novel syntheses of the chelating agents are provided. 4 tabs.

  18. Iron speciation in natural waters by sequential injection analysis with a hexadentate 3-hydroxy-4-pyridinone chelator as chromogenic agent.

    PubMed

    Miranda, Joana L A; Mesquita, Raquel B R; Nunes, Ana; Rangel, Maria; Rangel, António O S S

    2016-02-01

    A sequential injection method for iron speciation in various types of natural waters was developed using a synthesised hexadentate 3-hydroxy-4-pyridinone chelator (CP256). The denticity of the ligand that allow formation of the corresponding iron(III) complex in a 1:1 stoichiometry proved to be highly advantageous, in comparison with parent bidentate, hydroxy-4-piridinone chelators, with a two fold increase of reaction sensitivity and over 65% decrease of the LOD. A solid phase extraction approach was employed to attain matrix elimination, facilitating iron(III) determination and application to high salinity waters. The combination with the total iron determination obtained by the direct reaction of the ligand resulted in iron speciation. Two detection spectrophotometric cells were tested, a conventional flow cell (CFC) and a liquid waveguide capillary cell (LWCC). The dynamic concentration ranges were 0.1-2 mg/L with the CFC detection and 0.005-0.1 mg/L with the LWCC, with limit of detection of 30 µg/L and 6 µg/L, respectively. The developed method was successfully applied to a variety of natural waters.

  19. Polycatecholamide chelating agents

    DOEpatents

    Weitl, Frederick L.; Raymond, Kenneth N.

    1984-01-01

    Novel polybenzamide compounds useful for in vitro or in vivo chelation are described. The compounds have the formula ##STR1## Polyamines are reacted with 2,3-dimethoxy benzoyl chloride unsubstituted or substituted with SO.sub.3 H, SO.sub.3 M, NO.sub.2, CO.sub.2 H or CO.sub.2 M as desired is reacted with a polyamine in an inert solvent then demethylated with BBr.sub.3 or BCl.sub.3 in an inert solvent. Where compounds symmetrically substituted on the terminal N's are desired, the polyamine is first reductively alkylated by reaction with an aldehyde or ketone and the resulting Schiff base is hydrogenated.

  20. Novel polycatecholamide chelating agents

    DOEpatents

    Weitl, F.L.; Raymond, K.N.

    1981-08-24

    Novel polybenzamide compounds useful for in vitro or in vivo chelation are described. Formulas of the compounds are given. To prepare them polyamines are reacted with 2,3-dimethoxy benzoyl chloride unsubstituted or substituted with SO/sub 3/H, SO/sub 3/M, NO/sub 2/, CO/sub 2/H or CO/sub 2/M as desired is reacted with a polyamine in an inert solvent then demethylated with BBr/sub 3/ or BCl/sub 3/ in an inert solvent. Where compounds symmetrically substituted on the terminal N's are desired, the polyamine is first reductively alkylated by reaction with an aldehyde or ketone and the resulting Schiff base is hydrogenated.

  1. Polycatecholamide chelating agents

    DOEpatents

    Weitl, F.L.; Raymond, K.N.

    1984-04-10

    Novel polybenzamide compounds useful for in vitro or in vivo chelation are described. The compounds have the formula given in patent. Polyamines are reacted with 2,3-dimethoxy benzoyl chloride unsubstituted or substituted with SO[sub 3]H, SO[sub 3]M, NO[sub 2], CO[sub 2]H or CO[sub 2]M as desired is reacted with a polyamine in an inert solvent then demethylated with BBr[sub 3] or BCl[sub 3] in an inert solvent. Where compounds symmetrically substituted on the terminal N's are desired, the polyamine is first reductively alkylated by reaction with an aldehyde or ketone and the resulting Schiff base is hydrogenated. No Drawings

  2. An Evaluation of the Chelating Agent EDDS for Marigold Production

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aminopolycarboxylic acid (APCA) ligands (chelating agents) like ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) are commonly used in soluble fertilizers to supply copper (Cu), iron (Fe), manganese (Mn), and/or zinc (Zn) to plants. The offsite runoff and contamina...

  3. Chelating agents and cadmium intoxication

    SciTech Connect

    Shinobu, L.A.

    1985-01-01

    A wide range of conventional chelating agents have been screened for (a) antidotal activity in acute cadmium poisoning and (b) ability to reduce aged liver and kidney deposits of cadmium. Chelating agents belonging to the dithiocarbamate class have been synthesized and tested in both the acute and chronic modes of cadmium intoxication. Several dithiocarbamates, not only provide antidotal rescue, but also substantially decrease the intracellular deposits of cadmium associated with chronic cadmium intoxication. Fractionating the cytosol from the livers and kidneys of control and treated animals by Sephadex G-25 gel filtration clearly demonstrates that the dithiocarbamates are reducing the level of metallothionein-bound cadmium. However, the results of cell culture (Ehrlich ascites) studies designed to investigate the removal of cadmium from metallothionein and subsequent transport of the resultant cadmium complex across the cell membrane were inconclusive. In other in vitro investigations, the interaction between isolated native Cd, Zn-metallothionein and several chelating agents was explored. Ultracentrifugation, equilibrium dialysis, and Sephadex G-25 gel filtration studies have been carried out in an attempt to determine the rate of removal of cadmium from metallothionein by these small molecules. Chemical shifts for the relevant cadmium-dithiocarbamate complexes have been determined using natural abundance Cd-NMR.

  4. Iron Chelation Therapy in Myelodysplastic Syndromes

    PubMed Central

    Messa, Emanuela; Cilloni, Daniela; Saglio, Giuseppe

    2010-01-01

    Myelodysplastic syndromes (MDS) are a heterogeneous disorder of the hematopoietic stem cells, frequently characterized by anemia and transfusion dependency. In low-risk patients, transfusion dependency can be long lasting, leading to iron overload. Iron chelation therapy may be a therapeutic option for these patients, especially since the approval of oral iron chelators, which are easier to use and better accepted by the patients. The usefulness of iron chelation in MDS patients is still under debate, mainly because of the lack of solid prospective clinical trials that should take place in the future. This review aims to summarize what is currently known about the incidence and clinical consequences of iron overload in MDS patients and the state-of the-art of iron chelation therapy in this setting. We also give an overview of clinical guidelines for chelation in MDS published to date and some perspectives for the future. PMID:20672005

  5. Antimalarial properties of orally active iron chelators.

    PubMed

    Heppner, D G; Hallaway, P E; Kontoghiorghes, G J; Eaton, J W

    1988-07-01

    The appearance of widespread multiple drug resistance in human malaria has intensified the search for new antimalarial compounds. Metal chelators, especially those with high affinity for iron, represent one presently unexploited class of antimalarials. Unfortunately the use of previously identified chelators as antimalarials has been precluded by their toxicity and, in the case of desferrioxamine, the necessity for parenteral administration. The investigators now report that a new class of orally active iron chelators, namely the derivatives of alpha-ketohydroxypyridines (KHPs), are potent antimalarials against cultured Plasmodium falciparum. The KHPs evidently exert this effect by sequestering iron because a preformed chelator:iron complex has no antimalarial action. The pool(s) of iron being sequestered by the chelators have not been identified but may not include serum transferrin. Preincubation of human serum with KHPs followed by removal of the drug results in the removal of greater than 97% of total serum iron. Nonetheless, this serum effectively supports the growth of P falciparum cultures. Therefore the KHPs may exert antimalarial effect through chelation of erythrocytic rather than serum iron pool(s). The investigators conclude that these powerful, orally active iron chelators may form the basis of a new class of antimalarial drugs. PMID:3291984

  6. Natural chelating agents for radionuclide decorporation

    DOEpatents

    Premuzic, Eugene T.

    1988-01-01

    This invention relates to the preparation of new, naturally produced chelating agents as well as to the method and resulting chelates of desorbing cultures in a bioavailable form involving Pseudomonas species or other microorganisms. A preferred microorganism is Pseudomonas aeruginosa which forms multiple chelates with thorium in the range of molecular weight 100-1,000 and also forms chelates with uranium of molecular weight in the area of 100-1,000 and 1,000-2,000.

  7. Current approach to iron chelation in children.

    PubMed

    Aydinok, Yesim; Kattamis, Antonis; Viprakasit, Vip

    2014-06-01

    Transfusion-dependent children, mostly with thalassaemia major, but also and occasionally to a more significant degree, with inherited bone marrow failures, can develop severe iron overload in early life. Moreover, chronic conditions associated with ineffective erythropoiesis, such as non-transfusion-dependent thalassaemia (NTDT), may lead to iron overload through increased gut absorption of iron starting in childhood. Currently, the goal of iron chelation has shifted from treating iron overload to preventing iron accumulation and iron-induced end-organ complications, in order to achieve a normal pattern of complication-free survival and of quality of life. New chelation options increase the likelihood of achieving these goals. Timely initiation, close monitoring and continuous adjustment are the cornerstones of optimal chelation therapy in children, who have a higher transfusional requirements compared to adults in order to reach haemoglobin levels adequate for normal growth and development. Despite increased knowledge, there are still uncertainties about the level of body iron at which iron chelation therapy should be started and about the appropriate degree of iron stores' depletion.

  8. Natural chelating agents for radionuclide decorporation

    DOEpatents

    Premuzic, E.T.

    1985-06-11

    This invention relates to the production of metal-binding compounds useful for the therapy of heavy metal poisoning, for biological mining and for decorporation of radionuclides. The present invention deals with an orderly and effective method of producing new therapeutically effective chelating agents. This method uses challenge biosynthesis for the production of chelating agents that are specific for a particular metal. In this approach, the desired chelating agents are prepared from microorganisms challenged by the metal that the chelating agent is designed to detoxify. This challenge induces the formation of specific or highly selective chelating agents. The present invention involves the use of the challenge biosynthetic method to produce new complexing/chelating agents that are therapeutically useful to detoxify uranium, plutonium, thorium and other toxic metals. The Pseudomonas aeruginosa family of organisms is the referred family of microorganisms to be used in the present invention to produce the new chelating agent because this family is known to elaborate strains resistant to toxic metals.

  9. Toward resolving the unsettled role of iron chelation therapy in myelodysplastic syndromes.

    PubMed

    Merkel, Drorit G; Nagler, Arnon

    2014-07-01

    Transfusion dependent low risk myelodysplastic syndromes (MDS) patients, eventually develop iron overload. Iron toxicity, via oxidative stress, can damage cellular components and impact organ function. In thalassemia major patients, iron chelation therapy lowered iron levels with recovery of cardiac and liver functions and significant improvement in survival. Several noncontrolled studies show inferior survival in MDS patients with iron overload, including an increase in transplant-related mortality and infection risk while iron chelation appears to improve survival in both lower risk MDS patients and in stem cell transplant settings. Collated data are presented on the pathophysiological impact of iron overload; measuring techniques and chelating agents' therapy positive impact on hematological status and overall survival are discussed. Although suggested by retrospective analyses, the lack of clear prospective data of the beneficial effects of iron chelation on morbidity and survival, the role of iron chelation therapy in MDS patients remains controversial.

  10. Acute iron poisoning. Rescue with macromolecular chelators.

    PubMed Central

    Mahoney, J R; Hallaway, P E; Hedlund, B E; Eaton, J W

    1989-01-01

    Acute iron intoxication is a frequent, sometimes life-threatening, form of poisoning. Present therapy, in severe cases, includes oral and intravenous administration of the potent iron chelator, deferoxamine. Unfortunately, high dose intravenous deferoxamine causes acute hypotension additive with that engendered by the iron poisoning itself. To obviate this problem, we have covalently attached deferoxamine to high molecular weight carbohydrates such as dextran and hydroxyethyl starch. These macromolecular forms of deferoxamine do not cause detectable decreases in blood pressure of experimental animals, even when administered intravenously in very large doses, and persist in circulation much longer than the free drug. These novel iron-chelating substances, but not deferoxamine itself, will prevent mortality from otherwise lethal doses of iron administered to mice either orally or intraperitoneally. Further reflecting this enhanced therapeutic efficacy, the high molecular weight iron chelators also abrogate iron-mediated hepatotoxicity, suppressing the release of alanine aminotransferase. We conclude that high molecular weight derivatives of deferoxamine hold promise for the effective therapy of acute iron intoxication and may also be useful in other clinical circumstances in which control of free, reactive iron is therapeutically desirable. PMID:2794068

  11. Performance of Nonmigratory Iron Chelating Active Packaging Materials in Viscous Model Food Systems.

    PubMed

    Roman, Maxine J; Decker, Eric A; Goddard, Julie M

    2015-09-01

    Many packaged food products undergo quality deterioration due to iron promoted oxidative reactions. Recently, we have developed a nonmigratory iron chelating active packaging material that represents a novel approach to inhibit oxidation of foods while addressing consumer demands for "cleanˮ labels. A challenge to the field of nonmigratory active packaging is ensuring that surface-immobilized active agents retain activity in a true food system despite diffusional limitations. Yet, the relationship between food viscosity and nonmigratory active packaging activity retention has never been characterized. The objective of this study was to investigate the influence of food viscosity on iron chelation by a nonmigratory iron chelating active packaging material. Methyl cellulose was added to aqueous buffered iron solutions to yield model systems with viscosities ranging from ∼1 to ∼10(5)  mPa·s, representing viscosities ranging from beverage to mayonnaise. Iron chelation was quantified by material-bound iron content using colorimetry and inductively coupled plasma-optical emission spectrometry (ICP-OES).  Maximum iron chelation was reached in solutions up to viscosity ∼10(2)  mPa·s. In more viscous solutions (up to ∼10(4)  mPa·s), there was a significant decrease in iron chelating capacity (P < 0.05). However, materials still retained at least 76% iron chelating capacity. Additionally, the influence of different food hydrocolloids on the performance of nonmigratory iron chelating active packaging was characterized. Methyl cellulose and carrageenan did not compete with the material for specific iron chelation (P > 0.05). Materials retained 32% to 45% chelating capacity when in contact with competitively chelating hydrocolloids guar gum, locust bean gum, and xanthan gum. This work demonstrates the potential application of nonmigratory iron chelating active packaging in liquid and semi-liquid foods to allow for the removal of synthetic chelators, while

  12. Performance of Nonmigratory Iron Chelating Active Packaging Materials in Viscous Model Food Systems.

    PubMed

    Roman, Maxine J; Decker, Eric A; Goddard, Julie M

    2015-09-01

    Many packaged food products undergo quality deterioration due to iron promoted oxidative reactions. Recently, we have developed a nonmigratory iron chelating active packaging material that represents a novel approach to inhibit oxidation of foods while addressing consumer demands for "cleanˮ labels. A challenge to the field of nonmigratory active packaging is ensuring that surface-immobilized active agents retain activity in a true food system despite diffusional limitations. Yet, the relationship between food viscosity and nonmigratory active packaging activity retention has never been characterized. The objective of this study was to investigate the influence of food viscosity on iron chelation by a nonmigratory iron chelating active packaging material. Methyl cellulose was added to aqueous buffered iron solutions to yield model systems with viscosities ranging from ∼1 to ∼10(5)  mPa·s, representing viscosities ranging from beverage to mayonnaise. Iron chelation was quantified by material-bound iron content using colorimetry and inductively coupled plasma-optical emission spectrometry (ICP-OES).  Maximum iron chelation was reached in solutions up to viscosity ∼10(2)  mPa·s. In more viscous solutions (up to ∼10(4)  mPa·s), there was a significant decrease in iron chelating capacity (P < 0.05). However, materials still retained at least 76% iron chelating capacity. Additionally, the influence of different food hydrocolloids on the performance of nonmigratory iron chelating active packaging was characterized. Methyl cellulose and carrageenan did not compete with the material for specific iron chelation (P > 0.05). Materials retained 32% to 45% chelating capacity when in contact with competitively chelating hydrocolloids guar gum, locust bean gum, and xanthan gum. This work demonstrates the potential application of nonmigratory iron chelating active packaging in liquid and semi-liquid foods to allow for the removal of synthetic chelators, while

  13. Fluid extraction using carbon dioxide and organophosphorus chelating agents

    DOEpatents

    Smart, N.G.; Wai, C.M.; Lin, Y.; Kwang, Y.H.

    1998-11-24

    Methods for extracting metalloid and metal species from a solid or liquid material by exposing the material to a fluid solvent, particularly supercritical CO{sub 2}, and a chelating agent are described. The chelating agent forms a chelate with the species, the chelate being soluble in the fluid to allow removal of the species from the material. In preferred embodiments the extraction solvent is supercritical CO{sub 2} and the chelating agent comprises an organophosphorous chelating agent, particularly sulfur-containing organophosphorous chelating agents, including mixtures of chelating agents. Examples of chelating agents include monothiophosphinic acid, di-thiophosphinic acid, phosphine sulfite, phosphorothioic acid, and mixtures thereof. The method provides an environmentally benign process for removing metal and metalloids from industrial waste solutions, particularly acidic solutions. Both the chelate and the supercritical fluid can be regenerated and the contaminant species recovered to provide an economic, efficient process. 1 fig.

  14. Fluid extraction using carbon dioxide and organophosphorus chelating agents

    DOEpatents

    Smart, Neil G.; Wai, Chien M.; Lin, Yuehe; Kwang, Yak Hwa

    1998-01-01

    Methods for extracting metalloid and metal species from a solid or liquid material by exposing the material to a fluid solvent, particularly supercritical CO.sub.2, and a chelating agent are described. The chelating agent forms a chelate with the species, the chelate being soluble in the fluid to allow removal of the species from the material. In preferred embodiments the extraction solvent is supercritical CO.sub.2 and the chelating agent comprises an organophosphorous chelating agent, particularly sulfur-containing organophosphorous chelating agents, including mixtures of chelating agents. Examples of chelating agents include monothiophosphinic acid, di-thiophosphinic acid, phosphine sulfite, phosphorothioic acid, and mixtures thereof. The method provides an environmentally benign process for removing metal and metalloids from industrial waste solutions, particularly acidic solutions. Both the chelate and the supercritical fluid can be regenerated and the contaminant species recovered to provide an economic, efficient process.

  15. Method of encapsulating polyaminopolycarboxylic acid chelating agents in liposomes

    DOEpatents

    Rahman, Yueh Erh

    1977-11-10

    A method is provided for transferring a polyaminopolycarboxylic acid chelating agent across a cellular membrane by encapsulating the charged chelating agent within liposomes, which liposomes will be taken up by the cells, thereby transferring the chelating agent across the cellular membrane. The chelating agent is encapsulated within liposomes by drying a lipid mixture to form a thin film and wetting the lipid film with a solution containing the chelating agent. Mixing then results in the formation of a suspension of liposomes encapsulating the chelating agent, which liposomes can then be separated.

  16. Antibacterial and antibiofilm effects of iron chelators against Prevotella intermedia.

    PubMed

    Moon, Ji-Hoi; Kim, Cheul; Lee, Hee-Su; Kim, Sung-Woon; Lee, Jin-Yong

    2013-09-01

    Prevotella intermedia, a major periodontopathogen, has been shown to be resistant to many antibiotics. In the present study, we examined the effect of the FDA-approved iron chelators deferoxamine (DFO) and deferasirox (DFRA) against planktonic and biofilm cells of P. intermedia in order to evaluate the possibility of using these iron chelators as alternative control agents against P. intermedia. DFRA showed strong antimicrobial activity (MIC and MBC values of 0.16 mg ml(-1)) against planktonic P. intermedia. At subMICs, DFRA partially inhibited the bacterial growth and considerably prolonged the bacterial doubling time. DFO was unable to completely inhibit the bacterial growth in the concentration range tested and was not bactericidal. Crystal violet binding assay for the assessment of biofilm formation by P. intermedia showed that DFRA significantly decreased the biofilm-forming activity as well as the biofilm formation, while DFO was less effective. DFRA was chosen for further study. In the ATP-bioluminescent assay, which reflects viable cell counts, subMICs of DFRA significantly decreased the bioactivity of biofilms in a concentration-dependent manner. Under the scanning electron microscope, P. intermedia cells in DFRA-treated biofilm were significantly elongated compared to those in untreated biofilm. Further experiments are necessary to show that iron chelators may be used as a therapeutic agent for periodontal disease. PMID:23329319

  17. A Speciation Study on the Perturbing Effects of Iron Chelators on the Homeostasis of Essential Metal Ions.

    PubMed

    Crisponi, Guido; Nurchi, Valeria Marina; Crespo-Alonso, Miriam; Sanna, Gavino; Zoroddu, Maria Antonietta; Alberti, Giancarla; Biesuz, Raffaela

    2015-01-01

    A number of reports have appeared in literature calling attention to the depletion of essential metal ions during chelation therapy on β-thalassaemia patients. We present a speciation study to determine how the iron chelators used in therapy interfere with the homeostatic equilibria of essential metal ions. This work includes a thorough analysis of the pharmacokinetic properties of the chelating agents currently in clinical use, of the amounts of iron, copper and zinc available in plasma for chelation, and of all the implied complex formation constants. The results of the study show that a significant amount of essential metal ions is complexed whenever the chelating agent concentration exceeds the amount necessary to coordinate all disposable iron--a frequently occurring situation during chelation therapy. On the contrary, copper and zinc do not interfere with iron chelation, except for a possible influence of copper on iron speciation during deferiprone treatment.

  18. Iron chelators can protect against oxidative stress through ferryl heme reduction.

    PubMed

    Reeder, Brandon J; Hider, Robert C; Wilson, Michael T

    2008-02-01

    Iron chelators such as desferrioxamine have been shown to ameliorate oxidative damage in vivo. The mechanism of this therapeutic action under non-iron-overload conditions is, however, complex, as desferrioxamine has properties that can impact on oxidative damage independent of its capacity to act as an iron chelator. Desferrioxamine can act as a reducing agent to remove cytotoxic ferryl myoglobin and hemoglobin and has recently been shown to prevent the formation of a highly cytotoxic heme-to-protein cross-linked derivative of myoglobin. In this study we have examined the effects of a wide range of iron chelators, including the clinically used hydroxypyridinone CP20 (deferriprone), on the stability of ferryl myoglobin and on the formation of heme-to-protein cross-linking. We show that all hydroxypyridinones, as well as many other iron chelators, are efficient reducing agents of ferryl myoglobin. These compounds are also effective at preventing the formation of cytotoxic derivatives of myoglobin such as heme-to-protein cross-linking. These results show that the use of iron chelators in vivo may ameliorate oxidative damage under conditions of non-iron overload by at least two mechanisms. The antioxidant effects of chelators in vivo cannot, therefore, be attributed solely to iron chelation. PMID:18215735

  19. Differential ferrioxamine test for measuring chelatable body iron

    PubMed Central

    Fielding, J.

    1965-01-01

    The differential ferrioxamine test is a simple method for the measurement of chelation of body iron by desferrioxamine. A single six-hour specimen of urine is obtained after intravenous Desferal, accompanied by 59Fe-ferrioxamine. Two values are measured: Fd, the excretion of ferrioxamine derived from body iron by chelation, and Fex, the proportion of ferrioxamine excreted from a known intravenous dose. The data enables Fv, chelation of iron in vivo, to be calculated by simple proportion. Desferrioxamine chelation proceeds for about half an hour after injection. The results in normal subjects, in cases with known high iron stores, and in cases of iron-deficiency anaemia are described. High, normal, and low body iron states have been differentiated. Fv values in the higher ranges obtained in iron-storage diseases and in haemolytic states are differentiated by the pattern of excretion, high Fd values and low Fex values respectively. It is suggested that there are two main sources of chelatable body iron: as ferritin-haemosiderin and as iron newly released from haem in a more readily chelatable form. The significance of variable chelation susceptibility in iron metabolism is briefly discussed. It is suggested that variable chelatability of different sources of body iron may explain the preferential utilization of iron released from red cells or absorbed from the intestine, rather than storage iron, in the biosynthesis of haem. PMID:14247711

  20. Iron chelators in medicinal applications - chemical equilibrium considerations in pharmaceutical activity.

    PubMed

    Manning, Thomas; Kean, Greg; Thomas, Jessica; Thomas, Khaleh; Corbitt, Michael; Gosnell, Donna; Ware, Ronald; Fulp, Sonya; Jarrard, Joey; Phillips, Dennis

    2009-01-01

    Iron chelators are being examined as a potential class of pharmaceutical agents to battle different types of cancer as well as iron overload diseases. In recent studies, iron binding species such as desferrioxamine, triapine, tachpyridine, Dp44Mt, and PIH have been tested in cell line tests and clinical trials. Using published chemical equilibrium values (stability constants, equilibrium constants), it is argued that an iron chelator cannot competitively remove iron from a heme-containing biomolecule (i.e. hemoglobin (Hb), myoglobin) causing a cancerous cell to die. This type of reaction (DFO(aq) + [Fe(2+,3+)-Hb] --> [Fe(2+,3+)-DFO] + Hb) has been proposed in a number of published studies using circumstantial evidence. It is argued that iron chelators can potentially interact with iron from ferritin or iron that has precipitated or flocculated as oxyhydroxide under physiological pH's. It is argued that chelators can interfere with various physiological processes by binding cations such as Ca(2+), Zn(2+) or K(+). A number of siderophores and natural products that have the ability to bind Fe(3+)/Fe(2+) as well as other cations are discussed in terms of their potential pharmaceutical activity as chelators. Chemical equilibria between cations and pharmaceutical agents, which are rarely quantitated in explaining medicinal mechanisms, are used to show that chelators can bind and remove iron and other cations from physiologically important systems required for cell survival and propagation.

  1. Metal regeneration of iron chelates in nitric oxide scrubbing

    DOEpatents

    Chang, Shih-Ger; Littlejohn, David; Shi, Yao

    1997-08-19

    The present invention relates to a process of using metal particles to reduce NO to NH.sub.3. More specifically, the invention concerns an improved process to regenerate iron (II) (CHELATE) by reduction of iron (II) (CHELATE) (NO) complex, which process comprises: a) contacting an aqueous solution containing iron (II) (CHELATE) (NO) with metal particles at between about 20.degree. and 90.degree. C. to reduce NO present, produce ammonia or an ammonium ion, and produce free iron (II) (CHELATE) at a pH of between about 3 and 8. The process is useful to remove NO from flue gas and reduce pollution.

  2. Metal regeneration of iron chelates in nitric oxide scrubbing

    DOEpatents

    Chang, S.G.; Littlejohn, D.; Shi, Y.

    1997-08-19

    The present invention relates to a process of using metal particles to reduce NO to NH{sub 3}. More specifically, the invention concerns an improved process to regenerate iron (II) (CHELATE) by reduction of iron (II) (CHELATE) (NO) complex, which process comprises: (a) contacting an aqueous solution containing iron (II) (CHELATE) (NO) with metal particles at between about 20 and 90 C to reduce NO present, produce ammonia or an ammonium ion, and produce free iron (II) (CHELATE) at a pH of between about 3 and 8. The process is useful to remove NO from flue gas and reduce pollution. 34 figs.

  3. Synthetic and natural iron chelators: therapeutic potential and clinical use

    PubMed Central

    Hatcher, Heather C; Singh, Ravi N; Torti, Frank M; Torti, Suzy V

    2013-01-01

    Iron-chelation therapy has its origins in the treatment of iron-overload syndromes. For many years, the standard for this purpose has been deferoxamine. Recently, considerable progress has been made in identifying synthetic chelators with improved pharmacologic properties relative to deferoxamine. Most notable are deferasirox (Exjade®) and deferiprone (Ferriprox®), which are now available clinically. In addition to treatment of iron overload, there is an emerging role for iron chelators in the treatment of diseases characterized by oxidative stress, including cardiovascular disease, atherosclerosis, neurodegenerative diseases and cancer. While iron is not regarded as the underlying cause of these diseases, it does play an important role in disease progression, either through promotion of cellular growth and proliferation or through participation in redox reactions that catalyze the formation of reactive oxygen species and increase oxidative stress. Thus, iron chelators may be of therapeutic benefit in many of these conditions. Phytochemicals, many of which bind iron, may also owe some of their beneficial properties to iron chelation. This review will focus on the advances in iron-chelation therapy for the treatment of iron-overload disease and cancer, as well as neurodegenerative and chronic inflammatory diseases. Established and novel iron chelators will be discussed, as well as the emerging role of dietary plant polyphenols that effectively modulate iron biochemistry. PMID:21425984

  4. Translational downregulation of HSP90 expression by iron chelators in neuroblastoma cells.

    PubMed

    Sidarovich, Viktoryia; Adami, Valentina; Gatto, Pamela; Greco, Valentina; Tebaldi, Toma; Tonini, Gian Paolo; Quattrone, Alessandro

    2015-01-01

    Iron is an essential cellular nutrient, being a critical cofactor of several proteins involved in cell growth and replication. Compared with normal cells, neoplastic cells have been shown to require a greater amount of iron, thus laying the basis for the promising anticancer activity of iron chelators. In this work, we evaluated the effects of molecules with iron chelation activity on neuroblastoma (NB) cell lines. Of the 17 iron chelators tested, six reduced cell viability of two NB cell lines with an inhibition of growth of 50% below 10 µM; four of the six molecules-ciclopirox olamine (CPX), piroctone, 8-hydroxyquinoline, and deferasirox-were also shown to efficiently chelate intracellular iron within minutes after addition. Effects on cell viability of one of the compounds, CPX, were indeed dependent on chelation of intracellular iron and mediated by both G0/G1 cell cycle block and induction of apoptosis. By combined transcriptome and translatome profiling we identified early translational downregulation of several members of the heat shock protein group as a specific effect of CPX treatment. We functionally confirmed iron-dependent depletion of HSP90 and its client proteins at pharmacologically achievable concentrations of CPX, and we extended this effect to piroctone, 8-hydroxyquinoline, and deferasirox. Given the documented sensitivity of NB cells to HSP90 inhibition, we propose CPX and other iron chelators as investigational antitumor agents in NB therapy. PMID:25564462

  5. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents II: the mechanism of action of ligands derived from salicylaldehyde benzoyl hydrazone and 2-hydroxy-1-naphthylaldehyde benzoyl hydrazone.

    PubMed

    Richardson, D R; Milnes, K

    1997-04-15

    We have recently screened 36 analogues of the lipophilic iron (Fe) chelator, pyridoxal isonicotinoyl hydrazone (PIH), for their antiproliferative effect (Richardson et al, Blood 86:4295, 1995). Of these compounds, 1 chelator derived from salicylaldehyde benzoyl hydrazone (206) and 4 ligands derived from 2-hydroxy-1-naphthylaldehyde benzoyl hydrazone (308, 309, 311, and 315) showed pronounced antiproliferative activity, being far more effective than desferrioxamine (DFO). The present study was designed to investigate in detail the mechanism of action of these PIH analogues in a variety of neoplastic cell lines. This investigation showed that the analogues were far more active than DFO at inhibiting cellular proliferation and 3H-thymidine, 3H-leucine, and 3H-uridine incorporation. Additional experiments showed that, in contrast to DFO, the 5 analogues were potent at preventing 59Fe uptake from transferrin (Tf) and increasing 59Fe release from cells at concentrations as low as 10 micromol/L. Examination of the distribution of 59Fe in neoplastic cells using native polyacrylamide gel electrophoresis (PAGE)/59Fe-autoradiography showed that most of the 59Fe taken up from Tf was incorporated into ferritin, although 3 other previously unrecognized components (bands A, B, and C) were also identified. Band C comigrated with 59Fe-citrate and was chelated on incubation of neuroblastoma cells with DFO, PIH, or the PIH analogues, with this compartment being the main intracellular target of these ligands. Further work showed that the effects of the chelators at inducing characteristics consistent with apoptosis or necrosis were cell line-specific, and while DFO increased the percentage of cells in the G0/G1 phases in all cell types, the effect of analogue 311 on the cell cycle was variable depending on the cell line. This study provides further evidence for the potential use of these Fe chelators as anticancer agents.

  6. Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

    PubMed Central

    2013-01-01

    Abstract Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents. Recent Advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2α). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2α inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome. Critical Issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review. Future Directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed. Antioxid. Redox Signal. 00, 000–000. PMID:22900902

  7. Synergy and antagonism between iron chelators and antifungal drugs in Cryptococcus.

    PubMed

    Lai, Yu-Wen; Campbell, Leona T; Wilkins, Marc R; Pang, Chi Nam Ignatius; Chen, Sharon; Carter, Dee A

    2016-10-01

    Fungal infections remain very difficult to treat, and developing new antifungal drugs is difficult and expensive. Recent approaches therefore seek to augment existing antifungals with synergistic agents that can lower the therapeutic dose, increase efficacy and prevent resistance from developing. Iron limitation can inhibit microbial growth, and iron chelators have been employed to treat fungal infections. In this study, chequerboard testing was used to explore combinations of iron chelators with antifungal agents against pathogenic Cryptococcus spp. with the aim of determining how disruption to iron homeostasis affects antifungal susceptibility. The iron chelators ethylenediaminetetraacetic acid (EDTA), deferoxamine (DFO), deferiprone (DFP), deferasirox (DSX), ciclopirox olamine and lactoferrin (LF) were paired with the antifungal agents amphotericin B (AmB), fluconazole, itraconazole, voriconazole and caspofungin. All chelators except for DFO increased the efficacy of AmB, and significant synergy was seen between AmB and LF for all Cryptococcus strains. Addition of exogenous iron rescued cells from the antifungal effect of LF alone but could not prevent inhibition by AmB + LF, indicating that synergy was not due primarily to iron chelation but to other properties of LF that were potentiated in the presence of AmB. Significant synergy was not seen consistently for other antifungal-chelator combinations, and EDTA, DSX and DFP antagonised the activity of azole drugs in strains of Cryptococcus neoformans var. grubii. This study highlights the range of interactions that can be induced by chelators and indicates that most antifungal drugs are not enhanced by iron limitation in Cryptococcus. PMID:27474467

  8. Iron chelation therapy in transfusion-dependent thalassemia patients: current strategies and future directions

    PubMed Central

    Saliba, Antoine N; Harb, Afif R; Taher, Ali T

    2015-01-01

    Transfusional iron overload is a major target in the care of patients with transfusion-dependent thalassemia (TDT) and other refractory anemias. Iron accumulates in the liver, heart, and endocrine organs leading to a wide array of complications. In this review, we summarize the characteristics of the approved iron chelators, deferoxamine, deferiprone, and deferasirox, and the evidence behind the use of each, as monotherapy or as part of combination therapy. We also review the different guidelines on iron chelation in TDT. This review also discusses future prospects and directions in the treatment of transfusional iron overload in TDT whether through innovation in chelation or other therapies, such as novel agents that improve transfusion dependence. PMID:26124688

  9. Iron chelation therapy in transfusion-dependent thalassemia patients: current strategies and future directions.

    PubMed

    Saliba, Antoine N; Harb, Afif R; Taher, Ali T

    2015-01-01

    Transfusional iron overload is a major target in the care of patients with transfusion-dependent thalassemia (TDT) and other refractory anemias. Iron accumulates in the liver, heart, and endocrine organs leading to a wide array of complications. In this review, we summarize the characteristics of the approved iron chelators, deferoxamine, deferiprone, and deferasirox, and the evidence behind the use of each, as monotherapy or as part of combination therapy. We also review the different guidelines on iron chelation in TDT. This review also discusses future prospects and directions in the treatment of transfusional iron overload in TDT whether through innovation in chelation or other therapies, such as novel agents that improve transfusion dependence.

  10. The Management of Iron Chelation Therapy: Preliminary Data from a National Registry of Thalassaemic Patients

    PubMed Central

    Ceci, Adriana; Mangiarini, Laura; Felisi, Mariagrazia; Bartoloni, Franco; Ciancio, Angela; Capra, Marcello; D'Ascola, Domenico; Cianciulli, Paolo; Filosa, Aldo

    2011-01-01

    Thalassaemia and other haemoglobinopathies constitute an important health problem in Mediterranean countries, placing a tremendous emotional, psychological, and economic burden on their National Health systems. The development of new chelators in the most recent years had a major impact on the treatment of thalassaemia and on the quality of life of thalassaemic patients. A new initiative was promoted by the Italian Ministry of Health, establishing a Registry for thalassaemic patients to serve as a tool for the development of cost-effective diagnostic and therapeutic approaches and for the definition of guidelines supporting the most appropriate management of the iron-chelating therapy and a correct use of the available iron-chelating agents. This study represents the analysis of the preliminary data collected for the evaluation of current status of the iron chelation practice in the Italian thalassaemic population and describes how therapeutic interventions can widely differ in the different patients' age groups. PMID:21738864

  11. Orally active iron chelators in the treatment of iron overload.

    PubMed

    Olivieri, N F

    1996-03-01

    Data from several trials have provided evidence for the efficacy of deferiprone in the treatment of iron overload in thalassemia major. Deferiprone has now been shown to induce sustained decreases in tissue iron to concentrations that are associated with survival free of the complications of iron overload in deferoxamine-treated patients. Despite this evidence of efficacy, the risk of agranulocytosis mandates a careful evaluation of the risk of this drug in patients willing and able to use deferoxamine. The incidence of agranulocytosis associated with deferiprone is under study in a prospective multicenter trial in Canada, Italy, and the United States, under corporate sponsorship by Apotex Research in Canada. The results of this study should determine the risk associated with the use of this agent and may provide the data required for a US Food and Drug Administration decision regarding licensing of this agent for the treatment of iron overload, a goal supported by investigators worldwide.

  12. Iron chelation inhibits the development of pulmonary vascular remodeling.

    PubMed

    Wong, Chi-Ming; Preston, Ioana R; Hill, Nicholas S; Suzuki, Yuichiro J

    2012-11-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. Because iron is an important regulator of ROS biology, this study examined the effects of iron chelation on the development of pulmonary vascular remodeling. The administration of an iron chelator, deferoxamine, to rats prevented chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. Various iron chelators inhibited the growth of cultured pulmonary artery smooth muscle cells. Protein carbonylation, an important iron-dependent biological event, was promoted in association with pulmonary vascular remodeling and cell growth. A proteomic approach identified that Rho GDP-dissociation inhibitor (a negative regulator of RhoA) is carbonylated. In human plasma, the protein carbonyl content was significantly higher in patients with idiopathic pulmonary arterial hypertension than in healthy controls. These results suggest that iron plays an important role in the ROS-dependent mechanism underlying the development of pulmonary hypertension.

  13. Iron chelation inhibits the development of pulmonary vascular remodeling

    PubMed Central

    Wong, Chi-Ming; Preston, Ioana R.; Hill, Nicholas S.; Suzuki, Yuichiro J.

    2012-01-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. Since iron is an important regulator of ROS biology, the present study examined the effect of iron chelation on the development of pulmonary vascular remodeling. The administration of an iron chelator, deferoxamine, to rats prevented chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. Various iron chelators inhibited growth of cultured pulmonary artery smooth muscle cells. Protein carbonylation, an important iron-dependent biological event, was promoted in association with pulmonary vascular remodeling and cell growth. A proteomic approach identified that Rho GDP-dissociation inhibitor (a negative regulator of RhoA) is carbonylated. In human plasma, the protein carbonyl content was significantly higher in patients with idiopathic pulmonary arterial hypertension than in healthy controls. These results suggest that iron plays an important role in the ROS-dependent mechanism underlying the development of pulmonary hypertension. PMID:22974762

  14. A pro-chelator triggered by hydrogen peroxide inhibits iron-promoted hydroxyl radical formation.

    PubMed

    Charkoudian, Louise K; Pham, David M; Franz, Katherine J

    2006-09-27

    The synthesis and structural characterization of a new pro-chelating agent, isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide (BSIH), are presented. BSIH only weakly interacts with iron unless hydrogen peroxide (H2O2) is present to remove the boronic ester protecting group to reveal a phenol that is a key metal-binding group of tridentate salicylaldehyde isonicotinoyl hydrazone (SIH). BSIH prevents deoxyribose degradation caused by hydroxyl radicals that are generated from H2O2 and redox-active iron by sequestering Fe3+ and preventing iron-promoted hydroxyl radical formation. The rate-determining step for iron sequestration is conversion of BSIH to SIH, followed by rapid Fe3+ complexation. The pro-chelate approach of BSIH represents a promising strategy for chelating a specific pool of detrimental metal ions without disturbing healthy metal ion distribution.

  15. A pro-chelator triggered by hydrogen peroxide inhibits iron-promoted hydroxyl radical formation.

    PubMed

    Charkoudian, Louise K; Pham, David M; Franz, Katherine J

    2006-09-27

    The synthesis and structural characterization of a new pro-chelating agent, isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide (BSIH), are presented. BSIH only weakly interacts with iron unless hydrogen peroxide (H2O2) is present to remove the boronic ester protecting group to reveal a phenol that is a key metal-binding group of tridentate salicylaldehyde isonicotinoyl hydrazone (SIH). BSIH prevents deoxyribose degradation caused by hydroxyl radicals that are generated from H2O2 and redox-active iron by sequestering Fe3+ and preventing iron-promoted hydroxyl radical formation. The rate-determining step for iron sequestration is conversion of BSIH to SIH, followed by rapid Fe3+ complexation. The pro-chelate approach of BSIH represents a promising strategy for chelating a specific pool of detrimental metal ions without disturbing healthy metal ion distribution. PMID:16984186

  16. Iron chelators ICL670 and 311 inhibit HIV-1 transcription

    SciTech Connect

    Debebe, Zufan; Ammosova, Tatyana; Jerebtsova, Marina; Kurantsin-Mills, Joseph; Niu, Xiaomei; Charles, Sharroya; Richardson, Des R.; Ray, Patricio E.; Gordeuk, Victor R.; Nekhai, Sergei

    2007-10-25

    HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here we evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, our findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. Further consideration should be given to the development of iron chelators for future anti-retroviral therapeutics.

  17. Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization.

    PubMed

    Vlachodimitropoulou Koumoutsea, Evangelia; Garbowski, Maciej; Porter, John

    2015-09-01

    Iron chelators are increasingly combined clinically but the optimal conditions for cellular iron mobilization and mechanisms of interaction are unclear. Speciation plots for iron(III) binding of paired combinations of the licensed iron chelators desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) suggest conditions under which chelators can combine as 'shuttle' and 'sink' molecules but this approach does not consider their relative access and interaction with cellular iron pools. To address this issue, a sensitive ferrozine-based detection system for intracellular iron removal from the human hepatocyte cell line (HuH-7) was developed. Antagonism, synergism or additivity with paired chelator combinations was distinguished using mathematical isobologram analysis over clinically relevant chelator concentrations. All combinations showed synergistic iron mobilization at 8 h with clinically achievable concentrations of sink and shuttle chelators. Greatest synergism was achieved by combining DFP with DFX, where about 60% of mobilized iron was attributable to synergistic interaction. These findings predict that the DFX dose required for a half-maximum effect can be reduced by 3·8-fold when only 1 μmol/l DFP is added. Mechanisms for the synergy are suggested by consideration of the iron-chelate speciation plots together with the size, charge and lipid solubilities for each chelator. Hydroxypyridinones with low lipid solubilities but otherwise similar properties to DFP were used to interrogate the mechanistic interactions of chelator pairs. These studies confirm that synergistic cellular iron mobilization requires one chelator to have the physicochemical properties to enter cells, chelate intracellular iron and subsequently donate iron to a second 'sink' chelator.

  18. Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization.

    PubMed

    Vlachodimitropoulou Koumoutsea, Evangelia; Garbowski, Maciej; Porter, John

    2015-09-01

    Iron chelators are increasingly combined clinically but the optimal conditions for cellular iron mobilization and mechanisms of interaction are unclear. Speciation plots for iron(III) binding of paired combinations of the licensed iron chelators desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) suggest conditions under which chelators can combine as 'shuttle' and 'sink' molecules but this approach does not consider their relative access and interaction with cellular iron pools. To address this issue, a sensitive ferrozine-based detection system for intracellular iron removal from the human hepatocyte cell line (HuH-7) was developed. Antagonism, synergism or additivity with paired chelator combinations was distinguished using mathematical isobologram analysis over clinically relevant chelator concentrations. All combinations showed synergistic iron mobilization at 8 h with clinically achievable concentrations of sink and shuttle chelators. Greatest synergism was achieved by combining DFP with DFX, where about 60% of mobilized iron was attributable to synergistic interaction. These findings predict that the DFX dose required for a half-maximum effect can be reduced by 3·8-fold when only 1 μmol/l DFP is added. Mechanisms for the synergy are suggested by consideration of the iron-chelate speciation plots together with the size, charge and lipid solubilities for each chelator. Hydroxypyridinones with low lipid solubilities but otherwise similar properties to DFP were used to interrogate the mechanistic interactions of chelator pairs. These studies confirm that synergistic cellular iron mobilization requires one chelator to have the physicochemical properties to enter cells, chelate intracellular iron and subsequently donate iron to a second 'sink' chelator. PMID:26033030

  19. A novel antimycobacterial compound acts as an intracellular iron chelator.

    PubMed

    Dragset, Marte S; Poce, Giovanna; Alfonso, Salvatore; Padilla-Benavides, Teresita; Ioerger, Thomas R; Kaneko, Takushi; Sacchettini, James C; Biava, Mariangela; Parish, Tanya; Argüello, José M; Steigedal, Magnus; Rubin, Eric J

    2015-04-01

    Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound.

  20. A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

    PubMed Central

    Dragset, Marte S.; Poce, Giovanna; Alfonso, Salvatore; Padilla-Benavides, Teresita; Ioerger, Thomas R.; Kaneko, Takushi; Sacchettini, James C.; Biava, Mariangela; Parish, Tanya; Argüello, José M.

    2015-01-01

    Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound. PMID:25645825

  1. Effect of iron chelators on placental uptake and transfer of iron in rat

    SciTech Connect

    Wong, C.T.; McArdle, H.J.; Morgan, E.H.

    1987-05-01

    The uptake of radiolabeled transferrin and iron by the rat placenta has been studied using two approaches. The first involved injection of a ferrous or ferric iron chelator followed by injection of label. Neither chelator decreased the amount of labelled transferrin in the placenta after 2-h incubation and only bipyridine, a ferrous iron chelator, inhibited iron transport to the fetus. Deferoxamine (DFO), a ferric iron chelator, had no effect on iron transport to the fetus but reduced iron uptake by the liver. Both bipyridine and DFO increased iron excretion into the gut and by the urinary tract to the same degree into the gut, but there was a 10-fold greater urinary excretion with bipyridine than with DFO. Injection of iron attached to the chelators showed that neither bipyridine nor DFO could donate iron to the fetus as efficiently as transferrin. The mechanism involved was further investigated by studying the effect of the chelators on uptake of transferrin-bound iron by placental cells in culture. DFO inhibited iron accumulation more effectively than bipyridine in the cultured cells. The effect was not due to a decrease in the cycling time of the receptor. The results can be explained if the iron is released from the transferrin in intracellular vesicles in the ferrous form, where it may be chelated by bipyridine and prevented from passing to the fetus or converted to the ferric form once it is inside the cell matrix.

  2. Desferrithiocin: A Search for Clinically Effective Iron Chelators

    PubMed Central

    2015-01-01

    The successful search for orally active iron chelators to treat transfusional iron-overload diseases, e.g., thalassemia, is overviewed. The critical role of iron in nature as a redox engine is first described, as well as how primitive life forms and humans manage the metal. The problems that derive when iron homeostasis in humans is disrupted and the mechanism of the ensuing damage, uncontrolled Fenton chemistry, are discussed. The solution to the problem, chelator-mediated iron removal, is clear. Design options for the assembly of ligands that sequester and decorporate iron are reviewed, along with the shortcomings of the currently available therapeutics. The rationale for choosing desferrithiocin, a natural product iron chelator (a siderophore), as a platform for structure–activity relationship studies in the search for an orally active iron chelator is thoroughly developed. The study provides an excellent example of how to systematically reengineer a pharmacophore in order to overcome toxicological problems while maintaining iron clearing efficacy and has led to three ligands being evaluated in human clinical trials. PMID:25207964

  3. Oxidation-Induced Degradable Nanogels for Iron Chelation

    PubMed Central

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

    2016-01-01

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

  4. Sirtuin inhibitor sirtinol is an intracellular iron chelator

    PubMed Central

    Gautam, R.; Akam, E. A.; Astashkin, A. V.; Loughrey, J. J.

    2015-01-01

    Sirtinol is a known inhibitor of sirtuin proteins, a family of deacetylases involved in the pathophysiology of aging. Spectroscopic and structural data reveal that this compound is also an iron chelator forming high-spin ferric species in vitro and in cultured leukemia cells. Interactions with the highly regulated iron pool therefore contribute to its overall intracellular agenda. PMID:25715179

  5. An Evaluation of the Chelating Agent EDDS for Floriculture Crop Production

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aminopolycarboxylic acid (APCA) ligands (chelating agents) like ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) are commonly used in soluble fertilizers to supply copper (Cu), iron (Fe), manganese (Mn), and/or zinc (Zn) to plants. When complexed with Fe, EDTA and...

  6. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, Kenneth; Xu, Jide

    1999-01-01

    Disclosed is a series of improved chelating agents and the chelates formed from these agents, which are highly effective upon both injection and oral administration. Several of the most effective are of low toxicity. These chelating agents incorporate within their structure 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy group of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity, as well as the chemical stability towards oxidation and reduction, of the hydroxypyridinones. In the metal complexes of the chelating agents, the amide protons form very strong hydrogen bonds with the adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provide a certain degree of lipophilicity to the 3,2-HOPO, increasing oral activity.

  7. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, K.; Xu, J.

    1999-04-06

    Disclosed is a series of improved chelating agents and the chelates formed from these agents, which are highly effective upon both injection and oral administration. Several of the most effective are of low toxicity. These chelating agents incorporate within their structure 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy group of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity, as well as the chemical stability towards oxidation and reduction, of the hydroxypyridinones. In the metal complexes of the chelating agents, the amide protons form very strong hydrogen bonds with the adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provide a certain degree of lipophilicity to the 3,2-HOPO, increasing oral activity. 2 figs.

  8. Nanoparticle and Iron Chelators as a Potential Novel Alzheimer Therapy

    PubMed Central

    Liu, Gang; Men, Ping; Perry, George; Smith, Mark A.

    2010-01-01

    Current therapies for Alzheimer disease (AD) such as the acetylcholinesterase inhibitors and the latest NMDA receptor inhibitor, Namenda, provide moderate symptomatic delay at various stages of the disease, but do not arrest the disease progression or bring in meaningful remission. New approaches to the disease management are urgently needed. Although the etiology of AD is largely unknown, oxidative damage mediated by metals is likely a significant contributor since metals such as iron, aluminum, zinc, and copper are dysregulated and/or increased in AD brain tissue and create a pro-oxidative environment. This role of metal ion-induced free radical formation in AD makes chelation therapy an attractive means of dampening the oxidative stress burden in neurons. The chelator desferrioxamine, FDA approved for iron overload, has shown some benefit in AD, but like many chelators, it has a host of adverse effects and substantial obstacles for tissue-specific targeting. Other chelators are under development and have shown various strengths and weaknesses. Here, we propose a novel system of chelation therapy through the use of nanoparticles. Nanoparticles conjugated to chelators show unique ability to cross the blood–brain barrier (BBB), chelate metals, and exit through the BBB with their corresponding complexed metal ions. This method may provide a safer and more effective means of reducing the metal load in neural tissue, thus attenuating the harmful effects of oxidative damage and its sequelae. Experimental procedures are presented in this chapter. PMID:20013176

  9. Targeting Chelatable Iron as a Therapeutic Modality in Parkinson's Disease

    PubMed Central

    Moreau, Caroline; Devedjian, Jean Christophe; Kluza, Jérome; Petrault, Maud; Laloux, Charlotte; Jonneaux, Aurélie; Ryckewaert, Gilles; Garçon, Guillaume; Rouaix, Nathalie; Duhamel, Alain; Jissendi, Patrice; Dujardin, Kathy; Auger, Florent; Ravasi, Laura; Hopes, Lucie; Grolez, Guillaume; Firdaus, Wance; Sablonnière, Bernard; Strubi-Vuillaume, Isabelle; Zahr, Noel; Destée, Alain; Corvol, Jean-Christophe; Pöltl, Dominik; Leist, Marcel; Rose, Christian; Defebvre, Luc; Marchetti, Philippe; Cabantchik, Z. Ioav; Bordet, Régis

    2014-01-01

    Abstract Aims: The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments. Results: For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRI-PET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson's patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30 mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n=19) compared to DS patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson's Disease Rating Scale motor indicators of disease progression (p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial. Innovation: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD. Conclusions: The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or disease-modifying potential of chelation in PD. Antioxid

  10. Iron chelation and related properties of Podophyllum hexandrum, a possible role in radioprotection.

    PubMed

    Kumar, I P; Goel, H C

    2000-10-01

    Aqueous extract of Podophyllum species has been reported to render significant protection against radiation induced mortality, cytogenetic damage and cell death. In view of this, present study was undertaken to investigate its antioxidant properties. Chelation, oxidation and reduction of Fe2+ and Fe3+ were measured using chelating agents 2-2' bipiridyl and potassium thiocyanate respectively. Podophyllum extract, in a dose dependent manner, chelated Fe2+ more efficiently than Fe3+ and also modulated Fe2+/Fe3+ ratio. Homogenate of mouse liver was used to measure TBARS for estimating lipid peroxidation. Podophyllum extract also inhibited lipid peroxidation in a dose dependent manner and maximum inhibition (92%) was achieved at 1000 micrograms/ml concentration. These results demonstrates that Podophyllum exhibits antioxidant properties as seen through chelation and modulation of redox state of iron ions and these may primarily contribute towards its radioprotective manifestation.

  11. The Utility of Iron Chelators in the Management of Inflammatory Disorders

    PubMed Central

    Lehmann, C.; Islam, S.; Jarosch, S.; Zhou, J.; Hoskin, D.; Greenshields, A.; Al-Banna, N.; Sharawy, N.; Sczcesniak, A.; Kelly, M.; Wafa, K.; Cheliak, W.; Holbein, B.

    2015-01-01

    Since iron can contribute to detrimental radical generating processes through the Fenton and Haber-Weiss reactions, it seems to be a reasonable approach to modulate iron-related pathways in inflammation. In the human organism a counterregulatory reduction in iron availability is observed during inflammatory diseases. Under pathological conditions with reduced or increased baseline iron levels different consequences regarding protection or susceptibility to inflammation have to be considered. Given the role of iron in development of inflammatory diseases, pharmaceutical agents targeting this pathway promise to improve the clinical outcome. The objective of this review is to highlight the mechanisms of iron regulation and iron chelation, and to demonstrate the potential impact of this strategy in the management of several acute and chronic inflammatory diseases, including cancer. PMID:25878400

  12. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, Kenneth N.; Xu, Jide

    1997-01-01

    Disclosed is a series of improved metal chelating agents, which are highly effective upon both injection and oral administration; several of the most effective are of low toxicity. These chelating agents incorporate within their structure 1-hydroxy-2-pyridinone (1,2-HOPO) and 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy or oxo groups of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity of the hydroxypyridinones. In the metal complexes of said chelating agents, the amide protons form very strong hydrogen bonds with its adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provides a certain degree of lipophilicity to said 3,2-HOPO, increasing oral activity. Also disclosed is a method of making the chelating agents and a method of producing a known compound, 3-hydroxy-1-alkyl-2(1H)pyridinone, used as a precursor to the chelating agent, safely and in large quantities.

  13. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, K.N.; Xu, J.

    1997-04-29

    Disclosed is a series of improved metal chelating agents, which are highly effective upon both injection and oral administration; several of the most effective are of low toxicity. These chelating agents incorporate within their structure 1-hydroxy-2-pyridinone (1,2-HOPO) and 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy or oxo groups of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity of the hydroxypyridinones. In the metal complexes of the chelating agents, the amide protons form very strong hydrogen bonds with its adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provides a certain degree of lipophilicity to the 3,2-HOPO, increasing oral activity. Also disclosed is a method of making the chelating agents and a method of producing a known compound, 3-hydroxy-1-alkyl-2(1H)pyridinone, used as a precursor to the chelating agent, safely and in large quantities. 2 figs.

  14. Mineral Levels in Thalassaemia Major Patients Using Different Iron Chelators.

    PubMed

    Genc, Gizem Esra; Ozturk, Zeynep; Gumuslu, Saadet; Kupesiz, Alphan

    2016-03-01

    The goal of the present study was to determine the levels of minerals in chronically transfused thalassaemic patients living in Antalya, Turkey and to determine mineral levels in groups using different iron chelators. Three iron chelators deferoxamine, deferiprone and deferasirox have been used to remove iron from patients' tissues. There were contradictory results in the literature about minerals including selenium, zinc, copper, and magnesium in thalassaemia major patients. Blood samples from the 60 thalassaemia major patients (the deferoxamine group, n = 19; the deferiprone group, n = 20 and the deferasirox group, n = 21) and the controls (n = 20) were collected. Levels of selenium, zinc, copper, magnesium, and iron were measured, and all of them except iron showed no significant difference between the controls and the patients regardless of chelator type. Serum copper levels in the deferasirox group were lower than those in the control and deferoxamine groups, and serum magnesium levels in the deferasirox group were higher than those in the control, deferoxamine and deferiprone groups. Iron levels in the patient groups were higher than those in the control group, and iron levels showed a significant correlation with selenium and magnesium levels. Different values of minerals in thalassaemia major patients may be the result of different dietary intake, chelator type, or regional differences in where patients live. That is why minerals may be measured in thalassaemia major patients at intervals, and deficient minerals should be replaced. Being careful about levels of copper and magnesium in thalassaemia major patients using deferasirox seems to be beneficial.

  15. Searching for new aluminium chelating agents: a family of hydroxypyrone ligands.

    PubMed

    Toso, Leonardo; Crisponi, Guido; Nurchi, Valeria M; Crespo-Alonso, Miriam; Lachowicz, Joanna I; Mansoori, Delara; Arca, Massimiliano; Santos, M Amélia; Marques, Sérgio M; Gano, Lurdes; Niclós-Gutíerrez, Juan; González-Pérez, Josefa M; Domínguez-Martín, Alicia; Choquesillo-Lazarte, Duane; Szewczuk, Zbigniew

    2014-01-01

    Attention is devoted to the role of chelating agents in the treatment of aluminium related diseases. In fact, in spite of the efforts that have drastically reduced the occurrence of aluminium dialysis diseases, they so far constitute a cause of great medical concern. The use of chelating agents for iron and aluminium in different clinical applications has found increasing attention in the last thirty years. With the aim of designing new chelators, we synthesized a series of kojic acid derivatives containing two kojic units joined by different linkers. A huge advantage of these molecules is that they are cheap and easy to produce. Previous works on complex formation equilibria of a first group of these ligands with iron and aluminium highlighted extremely good pMe values and gave evidence of the ability to scavenge iron from inside cells. On these bases a second set of bis-kojic ligands, whose linkers between the kojic chelating moieties are differentiated both in terms of type and size, has been designed, synthesized and characterized. The aluminium(III) complex formation equilibria studied by potentiometry, electrospray ionization mass spectroscopy (ESI-MS), quantum-mechanical calculations and (1)H NMR spectroscopy are here described and discussed, and the structural characterization of one of these new ligands is presented. The in vivo studies show that these new bis-kojic derivatives induce faster clearance from main organs as compared with the monomeric analog.

  16. Interaction of chelating agents with cadmium in mice and rats

    SciTech Connect

    Eybl, V.; Sykora, J.; Koutensky, J.; Caisova, D.; Schwartz, A.; Mertl, F.

    1984-03-01

    The influence of several chelating agents (CaDTPA, ZnDTPA, CaEDTA, ZnEDTA, DMSA, D-penicillamine and DMPS, DMP and DDC) on the acute toxicity of CdCl/sub 2/ and on the whole body retention and tissue distribution of cadmium after the IV application of /sup 115mCdCl/sub 2/ was compared in mice. The chelating agents were applied immediately after the application of cadmium. CaDTPA, ZnDTPA and DMSA appeared to be the most effective antidotes. However, DMSA increased the amount of cadmium retained in kidneys. The treatement of cadmium-poisoned mice with the combination of DMSA (IP) and ZnDTPA (SC) (all the compounds were injected in equimolar dose) decreased the toxicity of cadmium more than treatment with one chelating agents (given in a 2:1 dose). However, by studying the effect of these chelating agents and their combination application of the antidotes showed little or no improvement over the results obtained with the most effective of the individual components. In the urine of rats injected with CdCl/sub 2/ and treated with the chelating agents (CaDTPA, ZnDTPA, DMSA), the presence of cadmium complexes was demonstrated. The formation of mixed ligand chelates in vivo was not proved. Experiments in mice given a single injection of /sup 115m/Cd-labeled Cd complexes of DMPS, DMSA and DTPA showed a high retention of cadmium in the organisms after the IV application of CdDMPS and CdDMSA complexes.

  17. Metal based pharmacologically active agents: Synthesis, structural characterization, molecular modeling, CT-DNA binding studies and in vitro antimicrobial screening of iron(II) bromosalicylidene amino acid chelates

    NASA Astrophysics Data System (ADS)

    Abdel-Rahman, Laila H.; El-Khatib, Rafat M.; Nassr, Lobna A. E.; Abu-Dief, Ahmed M.; Ismael, Mohamed; Seleem, Amin Abdou

    2014-01-01

    In recent years, great interest has been focused on Fe(II) Schiff base amino acid complexes as cytotoxic and antitumor drugs. Thus a series of new iron(II) complexes based on Schiff bases amino acids ligands have been designed and synthesized from condensation of 5-bromosalicylaldehyde (bs) and α-amino acids (L-alanine (ala), L-phenylalanine (phala), L-aspartic acid (aspa), L-histidine (his) and L-arginine (arg)). The structure of the investigated iron(II) complexes was elucidated using elemental analyses, infrared, ultraviolet-visible, thermogravimetric analysis, as well as conductivity and magnetic susceptibility measurements. Moreover, the stoichiometry and the stability constants of the prepared complexes have been determined spectrophotometrically. The results suggest that 5-bromosalicylaldehyde amino acid Schiff bases (bs:aa) behave as dibasic tridentate ONO ligands and coordinate to Fe(II) in octahedral geometry according to the general formula [Fe(bs:aa)2]ṡnH2O. The conductivity values between 37 and 64 ohm-1 mol-1 cm2 in ethanol imply the presence of nonelectrolyte species. The structure of the complexes was validated using quantum mechanics calculations based on accurate DFT methods. Geometry optimization of the Fe-Schiff base amino acid complexes showed that all complexes had octahedral coordination. In addition, the interaction of these complexes with (CT-DNA) was investigated at pH = 7.2, by using UV-vis absorption, viscosity and agarose gel electrophoresis measurements. Results indicated that the investigated complexes strongly bind to calf thymus DNA via intercalative mode and showed a different DNA binding according to the sequence: bsari > bshi > bsali > bsasi > bsphali. Moreover, the prepared compounds are screened for their in vitro antibacterial and antifungal activity against three types of bacteria, Escherichia coli, Pseudomonas aeruginosa and Bacillus cereus and three types of anti fungal cultures, Penicillium purpurogenium, Aspergillus

  18. Metal based pharmacologically active agents: synthesis, structural characterization, molecular modeling, CT-DNA binding studies and in vitro antimicrobial screening of iron(II) bromosalicylidene amino acid chelates.

    PubMed

    Abdel-Rahman, Laila H; El-Khatib, Rafat M; Nassr, Lobna A E; Abu-Dief, Ahmed M; Ismael, Mohamed; Seleem, Amin Abdou

    2014-01-01

    In recent years, great interest has been focused on Fe(II) Schiff base amino acid complexes as cytotoxic and antitumor drugs. Thus a series of new iron(II) complexes based on Schiff bases amino acids ligands have been designed and synthesized from condensation of 5-bromosalicylaldehyde (bs) and α-amino acids (L-alanine (ala), L-phenylalanine (phala), L-aspartic acid (aspa), L-histidine (his) and L-arginine (arg)). The structure of the investigated iron(II) complexes was elucidated using elemental analyses, infrared, ultraviolet-visible, thermogravimetric analysis, as well as conductivity and magnetic susceptibility measurements. Moreover, the stoichiometry and the stability constants of the prepared complexes have been determined spectrophotometrically. The results suggest that 5-bromosalicylaldehyde amino acid Schiff bases (bs:aa) behave as dibasic tridentate ONO ligands and coordinate to Fe(II) in octahedral geometry according to the general formula [Fe(bs:aa)2]·nH2O. The conductivity values between 37 and 64 ohm(-1) mol(-1) cm(2) in ethanol imply the presence of nonelectrolyte species. The structure of the complexes was validated using quantum mechanics calculations based on accurate DFT methods. Geometry optimization of the Fe-Schiff base amino acid complexes showed that all complexes had octahedral coordination. In addition, the interaction of these complexes with (CT-DNA) was investigated at pH=7.2, by using UV-vis absorption, viscosity and agarose gel electrophoresis measurements. Results indicated that the investigated complexes strongly bind to calf thymus DNA via intercalative mode and showed a different DNA binding according to the sequence: bsari>bshi>bsali>bsasi>bsphali. Moreover, the prepared compounds are screened for their in vitro antibacterial and antifungal activity against three types of bacteria, Escherichia coli, Pseudomonas aeruginosa and Bacillus cereus and three types of anti fungal cultures, Penicillium purpurogenium, Aspergillus flavus

  19. Iron Chelators and Antioxidants Regenerate Neuritic Tree and Nigrostriatal Fibers of MPP+/MPTP-Lesioned Dopaminergic Neurons

    PubMed Central

    Aguirre, Pabla; Mena, Natalia P.; Carrasco, Carlos M.; Muñoz, Yorka; Pérez-Henríquez, Patricio; Morales, Rodrigo A.; Cassels, Bruce K.; Méndez-Gálvez, Carolina; García-Beltrán, Olimpo; González-Billault, Christian; Núñez, Marco T.

    2015-01-01

    Neuronal death in Parkinson’s disease (PD) is often preceded by axodendritic tree retraction and loss of neuronal functionality. The presence of non-functional but live neurons opens therapeutic possibilities to recover functionality before clinical symptoms develop. Considering that iron accumulation and oxidative damage are conditions commonly found in PD, we tested the possible neuritogenic effects of iron chelators and antioxidant agents. We used three commercial chelators: DFO, deferiprone and 2.2’-dypyridyl, and three 8-hydroxyquinoline-based iron chelators: M30, 7MH and 7DH, and we evaluated their effects in vitro using a mesencephalic cell culture treated with the Parkinsonian toxin MPP+ and in vivo using the MPTP mouse model. All chelators tested promoted the emergence of new tyrosine hydroxylase (TH)-positive processes, increased axodendritic tree length and protected cells against lipoperoxidation. Chelator treatment resulted in the generation of processes containing the presynaptic marker synaptophysin. The antioxidants N-acetylcysteine and dymetylthiourea also enhanced axodendritic tree recovery in vitro, an indication that reducing oxidative tone fosters neuritogenesis in MPP+-damaged neurons. Oral administration to mice of the M30 chelator for 14 days after MPTP treatment resulted in increased TH- and GIRK2-positive nigra cells and nigrostriatal fibers. Our results support a role for oral iron chelators as good candidates for the early treatment of PD, at stages of the disease where there is axodendritic tree retraction without neuronal death. PMID:26658949

  20. Iron Chelators and Antioxidants Regenerate Neuritic Tree and Nigrostriatal Fibers of MPP+/MPTP-Lesioned Dopaminergic Neurons.

    PubMed

    Aguirre, Pabla; Mena, Natalia P; Carrasco, Carlos M; Muñoz, Yorka; Pérez-Henríquez, Patricio; Morales, Rodrigo A; Cassels, Bruce K; Méndez-Gálvez, Carolina; García-Beltrán, Olimpo; González-Billault, Christian; Núñez, Marco T

    2015-01-01

    Neuronal death in Parkinson's disease (PD) is often preceded by axodendritic tree retraction and loss of neuronal functionality. The presence of non-functional but live neurons opens therapeutic possibilities to recover functionality before clinical symptoms develop. Considering that iron accumulation and oxidative damage are conditions commonly found in PD, we tested the possible neuritogenic effects of iron chelators and antioxidant agents. We used three commercial chelators: DFO, deferiprone and 2.2'-dypyridyl, and three 8-hydroxyquinoline-based iron chelators: M30, 7MH and 7DH, and we evaluated their effects in vitro using a mesencephalic cell culture treated with the Parkinsonian toxin MPP+ and in vivo using the MPTP mouse model. All chelators tested promoted the emergence of new tyrosine hydroxylase (TH)-positive processes, increased axodendritic tree length and protected cells against lipoperoxidation. Chelator treatment resulted in the generation of processes containing the presynaptic marker synaptophysin. The antioxidants N-acetylcysteine and dymetylthiourea also enhanced axodendritic tree recovery in vitro, an indication that reducing oxidative tone fosters neuritogenesis in MPP+-damaged neurons. Oral administration to mice of the M30 chelator for 14 days after MPTP treatment resulted in increased TH- and GIRK2-positive nigra cells and nigrostriatal fibers. Our results support a role for oral iron chelators as good candidates for the early treatment of PD, at stages of the disease where there is axodendritic tree retraction without neuronal death. PMID:26658949

  1. River-derived humic substances as iron chelators in seawater

    PubMed Central

    Krachler, Regina; Krachler, Rudolf F.; Wallner, Gabriele; Hann, Stephan; Laux, Monika; Cervantes Recalde, Maria F.; Jirsa, Franz; Neubauer, Elisabeth; von der Kammer, Frank; Hofmann, Thilo; Keppler, Bernhard K.

    2015-01-01

    The speciation of iron(III) in oxic seawater is dominated by its hydrolysis and sedimentation of insoluble iron(III)-oxyhydroxide. As a consequence, many oceanic areas have very low iron levels in surface seawater which leads to iron deficiency since phytoplankton require iron as a micronutrient in order to grow. Fortunately, iron solubility is not truly as low as Fe(III) solubility measurements in inorganic seawater would suggest, since oceanic waters contain organic molecules which tend to bind the iron and keep it in solution. Various iron-binding organic ligands which combine to stabilize dissolved iron have been detected and thoroughly investigated in recent years. However, the role of iron-binding ligands from terrestrial sources remains poorly constrained. Blackwater rivers supply large amounts of natural organic material (NOM) to the ocean. This NOM (which consists mainly of vascular plant-derived humic substances) is able to greatly enhance iron bioavailability in estuaries and coastal regions, however, breakdown processes lead to a rapid decrease of river-derived NOM concentrations with increasing distance from land. It has therefore been argued that the influence of river-derived NOM on iron biogeochemistry in offshore seawater does not seem to be significant. Here we used a standard method based on 59Fe as a radiotracer to study the solubility of Fe(III)-oxyhydroxide in seawater in the presence of riverine NOM. We aimed to address the question how effective is freshwater NOM as an iron chelator under open ocean conditions where the concentration of land-derived organic material is about 3 orders of magnitude smaller than in coastal regions, and does this iron chelating ability vary between NOM from different sources and between different size fractions of the river-borne NOM. Our results show that the investigated NOM fractions were able to substantially enhance Fe(III)-oxyhydroxide solubility in seawater at concentrations of the NOM ≥ 5

  2. Alteration of tissue disposition of cadmium by chelating agents.

    PubMed Central

    Klaassen, C D; Waalkes, M P; Cantilena, L R

    1984-01-01

    The effect of several chelating agents (diethyldithiocarbamic acid, DDC; nitrilotriacetic acid, NTA; 2,3-dimercaptopropanol, BAL; d,l-penicillamine, PEN; 2,3-dimercaptosuccinic acid, DMSA; ethylenediaminetetraacetic acid, EDTA; and diethylenetriaminepentaacetic acid, DTPA) on the toxicity, distribution and excretion of cadmium (Cd) was determined in mice. When chelators were administered immediately after Cd, significant increases in survival were noted after treatment with DMSA, EDTA, and DTPA. DTPA, followed by EDTA and then DMSA, were consistently the most effective in decreasing the tissue concentrations of Cd and increasing the excretion of Cd. NTA, BAL, DDC and PEN had no beneficial effects. The effects of increasing the time interval between Cd administration and initiation of chelation therapy was determined by using a single administration of DTPA, EDTA, and DMSA. Mice treated immediately after Cd administration excreted approximately 50% of the administered dose of Cd compared to 0.2% in controls. Treatment with chelator at later times significantly increased Cd excretion but the magnitude of the effect was much less than that seen in mice treated immediately after Cd. To determine the role of MT in the acute decrease in chelator efficacy following Cd poisoning, rats were injected IV with Cd followed by DTPA at various times after Cd. Although DTPA reduced Cd content in the various organs when given immediately after Cd, the chelator was ineffective at all later times. Increases in hepatic and renal metallothionein (MT) did not occur until 2 hr after Cd, and did not coincide with the earlier drop in chelator efficacy. Blockade of MT synthesis by actinomycin D failed to eliminate this decreased DTPA effectiveness. Therefore, it appears that MT does not play an important role in the acute decrease in efficacy of chelation therapy for Cd poisoning. The effect of repeated daily administration of chelators on the distribution and excretion of Cd was studied by

  3. Chelator free gallium-68 radiolabelling of silica coated iron oxide nanorods via surface interactions

    NASA Astrophysics Data System (ADS)

    Burke, Benjamin P.; Baghdadi, Neazar; Kownacka, Alicja E.; Nigam, Shubhanchi; Clemente, Gonçalo S.; Al-Yassiry, Mustafa M.; Domarkas, Juozas; Lorch, Mark; Pickles, Martin; Gibbs, Peter; Tripier, Raphaël; Cawthorne, Christopher; Archibald, Stephen J.

    2015-09-01

    The commercial availability of combined magnetic resonance imaging (MRI)/positron emission tomography (PET) scanners for clinical use has increased demand for easily prepared agents which offer signal or contrast in both modalities. Herein we describe a new class of silica coated iron-oxide nanorods (NRs) coated with polyethylene glycol (PEG) and/or a tetraazamacrocyclic chelator (DO3A). Studies of the coated NRs validate their composition and confirm their properties as in vivo T2 MRI contrast agents. Radiolabelling studies with the positron emitting radioisotope gallium-68 (t1/2 = 68 min) demonstrate that, in the presence of the silica coating, the macrocyclic chelator was not required for preparation of highly stable radiometal-NR constructs. In vivo PET-CT and MR imaging studies show the expected high liver uptake of gallium-68 radiolabelled nanorods with no significant release of gallium-68 metal ions, validating our innovation to provide a novel simple method for labelling of iron oxide NRs with a radiometal in the absence of a chelating unit that can be used for high sensitivity liver imaging.The commercial availability of combined magnetic resonance imaging (MRI)/positron emission tomography (PET) scanners for clinical use has increased demand for easily prepared agents which offer signal or contrast in both modalities. Herein we describe a new class of silica coated iron-oxide nanorods (NRs) coated with polyethylene glycol (PEG) and/or a tetraazamacrocyclic chelator (DO3A). Studies of the coated NRs validate their composition and confirm their properties as in vivo T2 MRI contrast agents. Radiolabelling studies with the positron emitting radioisotope gallium-68 (t1/2 = 68 min) demonstrate that, in the presence of the silica coating, the macrocyclic chelator was not required for preparation of highly stable radiometal-NR constructs. In vivo PET-CT and MR imaging studies show the expected high liver uptake of gallium-68 radiolabelled nanorods with no

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

    PubMed

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-03-26

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

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

    PubMed Central

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-01-01

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

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

    PubMed

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-03-26

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

  7. Method for preparing radionuclide-labeled chelating agent-ligand complexes

    DOEpatents

    Meares, Claude F.; Li, Min; DeNardo, Sally J.

    1999-01-01

    Radionuclide-labeled chelating agent-ligand complexes that are useful in medical diagnosis or therapy are prepared by reacting a radionuclide, such as .sup.90 Y or .sup.111 In, with a polyfunctional chelating agent to form a radionuclide chelate that is electrically neutral; purifying the chelate by anion exchange chromatography; and reacting the purified chelate with a targeting molecule, such as a monoclonal antibody, to form the complex.

  8. Synthesis and biological evaluation of 2-benzoylpyridine thiosemicarbazones in a dimeric system: structure-activity relationship studies on their anti-proliferative and iron chelation efficacy.

    PubMed

    Lukmantara, Adeline Y; Kalinowski, Danuta S; Kumar, Naresh; Richardson, Des R

    2014-12-01

    Thiosemicarbazone chelators represent an exciting class of biologically active compounds that show great potential as anti-tumor agents. Our previous studies demonstrated the potent anti-tumor activity of the 2'-benzoylpyridine thiosemicarbazone series. While extensive studies have been performed on monomeric thiosemicarbazone compounds, dimeric thiosemicarbazone chelators have received comparatively less attention. Thus, it was of interest to investigate the anti-proliferative activity and iron chelation efficacy of dimeric thiosemicarbazones. Two classes of dimeric thiosemicarbazones were designed and synthesized. The first class consisted of two benzoylpyridine-based thiosemicarbazone units connected via a hexane or dodecane alkyl bridge, while the second class of dimer consisted of two thiosemicarbazones attached to a 2,6-dibenzoylpyridine core. These dimeric ligands demonstrated greater anti-proliferative activity than the clinically used iron chelator, desferrioxamine. This study highlights the importance of optimal lipophilicity as a factor influencing the cytotoxicity and iron chelation efficacy of these chelators.

  9. An amidation/cyclization approach to the synthesis of N-hydroxyquinolinones and their biological evaluation as potential anti-plasmodial, anti-bacterial, and iron(II)-chelating agents.

    PubMed

    Teng, Yanbo; Suwanarusk, Rossarin; Ngai, Mun Hong; Srinivasan, Rajavel; Ong, Alice Soh Meoy; Ho, Bow; Rénia, Laurent; Chai, Christina L L

    2015-02-01

    A 26-member library of novel N-hydroxyquinolinone derivatives was synthesized by a one-pot Buchwald-type palladium catalyzed amidation and condensation sequence. The design of these rare scaffolds was inspired from N-hydroxypyridones and 2-quinolinones classes of compounds which have been shown to have rich biological activities. The synthesized compounds were evaluated for their anti-plasmodial and anti-bacterial properties. In addition, these compounds were screened for their iron(II)-chelation properties. Notably, four of these compounds exhibited anti-plasmodial activities comparable to that of the natural product cordypyridone B.

  10. Iron chelation with salicylaldehyde isonicotinoyl hydrazone protects against catecholamine autoxidation and cardiotoxicity.

    PubMed

    Hašková, Pavlína; Kovaříková, Petra; Koubková, Lucie; Vávrová, Anna; Macková, Eliška; Simůnek, Tomáš

    2011-02-15

    Elevated catecholamine levels are known to induce damage of the cardiac tissue. This catecholamine cardiotoxicity may stem from their ability to undergo oxidative conversion to aminochromes and concomitant production of reactive oxygen species (ROS), which damage cardiomyocytes via the iron-catalyzed Fenton-type reaction. This suggests the possibility of cardioprotection by iron chelation. Our in vitro experiments have demonstrated a spontaneous decrease in the concentration of the catecholamines epinephrine and isoprenaline during their 24-h preincubation in buffered solution as well as their gradual conversion to oxidation products. These changes were significantly augmented by addition of iron ions and reduced by the iron-chelating agent salicylaldehyde isonicotinoyl hydrazone (SIH). Oxidized catecholamines were shown to form complexes with iron that had significant redox activity, which could be suppressed by SIH. Experiments using the H9c2 cardiomyoblast cell line revealed higher cytotoxicity of oxidized catecholamines than of the parent compounds, apparently through the induction of caspase-independent cell death, whereas co-incubation of cells with SIH was able to significantly preserve cell viability. A significant increase in intracellular ROS formation was observed after the incubation of cells with catecholamine oxidation products; this could be significantly reduced by SIH. In contrast, parent catecholamines did not increase, but rather decreased, cellular ROS production. Hence, our results demonstrate an important role for redox-active iron in catecholamine autoxidation and subsequent toxicity. The iron chelator SIH has shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity.

  11. Self-assembled polymeric chelate nanoparticles as potential theranostic agents.

    PubMed

    Škodová, M; Černoch, P; Štěpánek, P; Chánová, E; Kučka, J; Kálalová, Z; Kaňková, D; Hrubý, M

    2012-12-21

    Improvements in cancer diagnostics and therapy have recently attracted the interest of many different branches of science. This study presents one of the new possible approaches in the diagnostics and therapy of cancer by using polymeric chelates as carriers. Graft copolymers with a backbone containing 8-hydroxyquinoline-5-sulfonic acid chelating groups and poly(ethylene oxide) hydrophilic grafts are synthesized and characterized. The polymers assemble and form particles after the addition of a biometal cation, such as iron or copper. The obtained nanoparticles exhibit a hydrodynamic diameter of around 25 nm and a stability of at least several hours, which are counted as essential parameters for biomedical purposes. To prove their biodegradability, a model degradation with deferoxamine is performed and, together with high radiolabeling efficiency with copper-64, their possible use for nuclear medicine purposes is demonstrated.

  12. Curcumin inhibits growth of Saccharomyces cerevisiae through iron chelation.

    PubMed

    Minear, Steven; O'Donnell, Allyson F; Ballew, Anna; Giaever, Guri; Nislow, Corey; Stearns, Tim; Cyert, Martha S

    2011-11-01

    Curcumin, a polyphenol derived from turmeric, is an ancient therapeutic used in India for centuries to treat a wide array of ailments. Interest in curcumin has increased recently, with ongoing clinical trials exploring curcumin as an anticancer therapy and as a protectant against neurodegenerative diseases. In vitro, curcumin chelates metal ions. However, although diverse physiological effects have been documented for this compound, curcumin's mechanism of action on mammalian cells remains unclear. This study uses yeast as a model eukaryotic system to dissect the biological activity of curcumin. We found that yeast mutants lacking genes required for iron and copper homeostasis are hypersensitive to curcumin and that iron supplementation rescues this sensitivity. Curcumin penetrates yeast cells, concentrates in the endoplasmic reticulum (ER) membranes, and reduces the intracellular iron pool. Curcumin-treated, iron-starved cultures are enriched in unbudded cells, suggesting that the G(1) phase of the cell cycle is lengthened. A delay in cell cycle progression could, in part, explain the antitumorigenic properties associated with curcumin. We also demonstrate that curcumin causes a growth lag in cultured human cells that is remediated by the addition of exogenous iron. These findings suggest that curcumin-induced iron starvation is conserved from yeast to humans and underlies curcumin's medicinal properties.

  13. Mercury removal in utility wet scrubber using a chelating agent

    DOEpatents

    Amrhein, Gerald T.

    2001-01-01

    A method for capturing and reducing the mercury content of an industrial flue gas such as that produced in the combustion of a fossil fuel or solid waste adds a chelating agent, such as ethylenediaminetetraacetic acid (EDTA) or other similar compounds like HEDTA, DTPA and/or NTA, to the flue gas being scrubbed in a wet scrubber used in the industrial process. The chelating agent prevents the reduction of oxidized mercury to elemental mercury, thereby increasing the mercury removal efficiency of the wet scrubber. Exemplary tests on inlet and outlet mercury concentration in an industrial flue gas were performed without and with EDTA addition. Without EDTA, mercury removal totaled 42%. With EDTA, mercury removal increased to 71%. The invention may be readily adapted to known wet scrubber systems and it specifically provides for the removal of unwanted mercury both by supplying S.sup.2- ions to convert Hg.sup.2+ ions into mercuric sulfide (HgS) and by supplying a chelating agent to sequester other ions, including but not limited to Fe.sup.2+ ions, which could otherwise induce the unwanted reduction of Hg.sup.2+ to the form, Hg.sup.0.

  14. Chelator free gallium-68 radiolabelling of silica coated iron oxide nanorods via surface interactions.

    PubMed

    Burke, Benjamin P; Baghdadi, Neazar; Kownacka, Alicja E; Nigam, Shubhanchi; Clemente, Gonçalo S; Al-Yassiry, Mustafa M; Domarkas, Juozas; Lorch, Mark; Pickles, Martin; Gibbs, Peter; Tripier, Raphaël; Cawthorne, Christopher; Archibald, Stephen J

    2015-09-28

    The commercial availability of combined magnetic resonance imaging (MRI)/positron emission tomography (PET) scanners for clinical use has increased demand for easily prepared agents which offer signal or contrast in both modalities. Herein we describe a new class of silica coated iron-oxide nanorods (NRs) coated with polyethylene glycol (PEG) and/or a tetraazamacrocyclic chelator (DO3A). Studies of the coated NRs validate their composition and confirm their properties as in vivo T2 MRI contrast agents. Radiolabelling studies with the positron emitting radioisotope gallium-68 (t1/2 = 68 min) demonstrate that, in the presence of the silica coating, the macrocyclic chelator was not required for preparation of highly stable radiometal-NR constructs. In vivo PET-CT and MR imaging studies show the expected high liver uptake of gallium-68 radiolabelled nanorods with no significant release of gallium-68 metal ions, validating our innovation to provide a novel simple method for labelling of iron oxide NRs with a radiometal in the absence of a chelating unit that can be used for high sensitivity liver imaging. PMID:26292197

  15. Chelator free gallium-68 radiolabelling of silica coated iron oxide nanorods via surface interactions.

    PubMed

    Burke, Benjamin P; Baghdadi, Neazar; Kownacka, Alicja E; Nigam, Shubhanchi; Clemente, Gonçalo S; Al-Yassiry, Mustafa M; Domarkas, Juozas; Lorch, Mark; Pickles, Martin; Gibbs, Peter; Tripier, Raphaël; Cawthorne, Christopher; Archibald, Stephen J

    2015-09-28

    The commercial availability of combined magnetic resonance imaging (MRI)/positron emission tomography (PET) scanners for clinical use has increased demand for easily prepared agents which offer signal or contrast in both modalities. Herein we describe a new class of silica coated iron-oxide nanorods (NRs) coated with polyethylene glycol (PEG) and/or a tetraazamacrocyclic chelator (DO3A). Studies of the coated NRs validate their composition and confirm their properties as in vivo T2 MRI contrast agents. Radiolabelling studies with the positron emitting radioisotope gallium-68 (t1/2 = 68 min) demonstrate that, in the presence of the silica coating, the macrocyclic chelator was not required for preparation of highly stable radiometal-NR constructs. In vivo PET-CT and MR imaging studies show the expected high liver uptake of gallium-68 radiolabelled nanorods with no significant release of gallium-68 metal ions, validating our innovation to provide a novel simple method for labelling of iron oxide NRs with a radiometal in the absence of a chelating unit that can be used for high sensitivity liver imaging.

  16. Iron-[S,S']-EDDS (FeEDDS) Chelate as an Iron Source for Horticultural Crop Production: Marigold Growth and Nutrition, Spectral Properties, and Photodegradation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aminopolycarboxylic acid (APCA) complexones, commonly referred to as ligands or chelating agents, like ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) are commonly used in soluble fertilizers to supply copper (Cu), iron (Fe), manganese (Mn), and/or zinc (Zn) to p...

  17. Mobilization of iron from cells by hydroxyquinoline-based chelators.

    PubMed

    Mouralian, C; Buss, J L; Stranix, B; Chin, J; Ponka, P

    2005-12-19

    With the aim of identifying an iron (Fe) chelator which is effective at mobilizing intracellular Fe, two novel ligands were synthesized and tested. Hydroxyquinoline is known to possess a high affinity for Fe and was thus chosen as the Fe binding motif for the hexadentate chelators, C1 (2,2'-[ethane-1,2-diylbis(iminomethylene)]diquinolin-8-ol) and C2 (2,2'-[cyclohexane-1,2-diylbis(iminomethylene)]diquinolin-8-ol). Both chelators are lipophilic, with Fe3+ complexes slightly more hydrophilic than the free ligands. C1 and C2 were equally toxic to K562 cells, and partial protection was afforded by supplementing the culture medium with human holotransferrin, suggesting that some of the toxicity of the ligands is due to cellular Fe depletion. Micromolar concentrations of both ligands effectively mobilized 59Fe from reticulocytes and K562 cells. In reticulocytes, 50 microM C1 caused the release of 60% of the cells' initial 59Fe uptake after a 4h incubation. Under the same conditions, C2 revealed a release of 50% of the 59Fe. Overall, both ligands merit in vivo study for oral activity. Their effectiveness at low concentrations makes them candidates for therapeutic use.

  18. Prevention by chelating agents of metal-induced developmental toxicity.

    PubMed

    Domingo, J L

    1995-01-01

    Chelating agents such as calcium disodium ethylenediaminetetraacetate (EDTA), 2,3-dimercaptopropanol (BAL), or D-penicillamine (D-PA) have been widely used for the past 4 decades as antidotes for the treatment of acute and chronic metal poisoning. In recent years, meso-2,3-dimercaptosuccinic acid (DMSA), sodium 2,3-dimercapto-1-propanesulfonate (DMPS) and sodium 4,5-dihydroxybenzene-1,3-disulfonate (Tiron) have also shown to be effective to prevent against toxicity induced by a number of heavy metals. The purpose of the present article was to review the protective activity of various chelating agents against the embryotoxic and teratogenic effects of well-known developmental toxicants (arsenic, cadmium, lead, mercury, uranium, and vanadium). DMSA and DMPS were found to be effective in alleviating arsenate- and arsenite-induced teratogenesis, whereas BAL afforded only some protection against arsenic-induced embryo/fetal toxicity. Also, DMSA, DMPS, and Tiopronin were effective in ameliorating methyl mercury-induced developmental toxicity. Although the embryotoxic and teratogenic effects of vanadate were significantly reduced by Tiron, no significant amelioration of uranium-induced embryotoxicity was observed after treatment with this chelator.

  19. Mobilization of metals during treatment of contaminated soils by modified Fenton's reagent using different chelating agents.

    PubMed

    Bennedsen, Lars R; Krischker, Anne; Jørgensen, Torben H; Søgaard, Erik G

    2012-01-15

    Changes in pH and redox conditions and the application of chelating agents when applying in situ chemical oxidation (ISCO) for remediation of contaminated sites can cause mobilization of metals to the groundwater above threshold limit values. The mechanisms causing the mobilization are not fully understood and have only been investigated in few studies. The present work investigated the mobilization of 9 metals from two very different contaminated soils in bench and pilot tests during treatment with modified Fenton's reagent (MFR) and found significant mobilization of Cu and Pb to the water in mg/l levels. Also Fe, As, Mn, Ni, Zn, Mg, and Ca mobilization was observed. These findings were confirmed in a pilot test where concentrations of Cu and Pb up to 52.2 and 33.7 mg/l were observed, respectively. Overall, the chelating agents tested (EDTA, citrate and pyrophosphate) did not seem to increase mobilization of metals compared to treatment with only hydrogen peroxide and iron. The results strongly indicate that the mobilization is caused by hydrogen peroxide and reactive species including oxidants and reductants formed with MFR. Based on these results, the use of chelating agents for ISCO will not cause an increase in metal mobilization.

  20. MRI guided iron assessment and oral chelator use improve iron status in thalassemia major patients.

    PubMed

    Nichols-Vinueza, Diana X; White, Matthew T; Powell, Andrew J; Banka, Puja; Neufeld, Ellis J

    2014-07-01

    Oral iron chelators and magnetic resonance imaging (MRI) assessment of heart and liver iron burden have become widely available since the mid 2000s, allowing for improved patient compliance with chelation and noninvasive monitoring of iron levels for titration of therapy. We evaluated the impact of these changes in our center for patients with thalassemia major and transfusional iron overload. This single center, retrospective observational study covered the period from 2005 through 2012. Liver iron content (LIC) was estimated both by a T2* method and by R2 (Ferriscan® ) technique. Cardiac iron was assessed as cT2*. Forty-two patients (55% male) with transfused thalassemia and at least two MRIs were included (median age at first MRI, 17.5 y). Over a mean follow-up period of 5.2 ± 1.9 y, 190 MRIs were performed (median 4.5 per patient). Comparing baseline to last MRI, 63% of patients remained within target ranges for cT2* and LIC, and 13% improved from high values to the target range. Both the median LIC and cT2* (cR2* = 1000/cT2*) status improved over time: LIC 7.3 to 4.5 mg/g dry weight, P = 0.0004; cR2* 33.4 to 28.3 Hz, P = 0.01. Individual responses varied widely. Two patients died of heart failure during the study period. Annual MRI iron assessments and availability of oral chelators both facilitate changes in chelation dose and strategies to optimize care.

  1. MRI guided iron assessment and oral chelator use improve iron status in thalassemia major patients.

    PubMed

    Nichols-Vinueza, Diana X; White, Matthew T; Powell, Andrew J; Banka, Puja; Neufeld, Ellis J

    2014-07-01

    Oral iron chelators and magnetic resonance imaging (MRI) assessment of heart and liver iron burden have become widely available since the mid 2000s, allowing for improved patient compliance with chelation and noninvasive monitoring of iron levels for titration of therapy. We evaluated the impact of these changes in our center for patients with thalassemia major and transfusional iron overload. This single center, retrospective observational study covered the period from 2005 through 2012. Liver iron content (LIC) was estimated both by a T2* method and by R2 (Ferriscan® ) technique. Cardiac iron was assessed as cT2*. Forty-two patients (55% male) with transfused thalassemia and at least two MRIs were included (median age at first MRI, 17.5 y). Over a mean follow-up period of 5.2 ± 1.9 y, 190 MRIs were performed (median 4.5 per patient). Comparing baseline to last MRI, 63% of patients remained within target ranges for cT2* and LIC, and 13% improved from high values to the target range. Both the median LIC and cT2* (cR2* = 1000/cT2*) status improved over time: LIC 7.3 to 4.5 mg/g dry weight, P = 0.0004; cR2* 33.4 to 28.3 Hz, P = 0.01. Individual responses varied widely. Two patients died of heart failure during the study period. Annual MRI iron assessments and availability of oral chelators both facilitate changes in chelation dose and strategies to optimize care. PMID:24652616

  2. Chemistry and bifunctional chelating agents for binding (177)Lu.

    PubMed

    Parus, Józef L; Pawlak, Dariusz; Mikolajczak, Renata; Duatti, Adriano

    2015-01-01

    A short overview of fundamental chemistry of lutetium and of structural characteristics of lutetium coordination complexes, as relevant for understanding the properties of lutetium-177 radiopharmaceuticals, is presented. This includes basic concepts on lutetium electronic structure, lanthanide contraction, coordination geometries, behavior in aqueous solution and thermodynamic stability. An illustration of the structure and binding properties of the most important chelating agents for the Lu(3+) ion in aqueous solution is also reported with specific focus on coordination complexes formed with linear and macrocyclic polydentate amino-carboxylate donor ligands.

  3. Mechanistic basis for overcoming platinum resistance using copper chelating agents.

    PubMed

    Liang, Zheng D; Long, Yan; Tsai, Wen-Bin; Fu, Siqing; Kurzrock, Razelle; Gagea-Iurascu, Mihai; Zhang, Fan; Chen, Helen H W; Hennessy, Bryan T; Mills, Gordon B; Savaraj, Niramol; Kuo, Macus Tien

    2012-11-01

    Platinum-based antitumor agents are widely used in cancer chemotherapy. Drug resistance is a major obstacle to the successful use of these agents because once drug resistance develops, other effective treatment options are limited. Recently, we conducted a clinical trial using a copper-lowering agent to overcome platinum drug resistance in ovarian cancer patients and the preliminary results are encouraging. In supporting this clinical study, using three pairs of cisplatin (cDDP)-resistant cell lines and two ovarian cancer cell lines derived from patients who had failed in platinum-based chemotherapy, we showed that cDDP resistance associated with reduced expression of the high-affinity copper transporter (hCtr1), which is also a cDDP transporter, can be preferentially resensitized by copper-lowering agents because of enhanced hCtr1 expression, as compared with their drug-sensitive counterparts. Such a preferential induction of hCtr1 expression in cDDP-resistant variants by copper chelation can be explained by the mammalian copper homeostasis regulatory mechanism. Enhanced cell-killing efficacy by a copper-lowering agent was also observed in animal xenografts bearing cDDP-resistant cells. Finally, by analyzing a public gene expression dataset, we found that ovarian cancer patients with elevated levels of hCtr1 in their tumors, but not ATP7A and ATP7B, had more favorable outcomes after platinum drug treatment than those expressing low hCtr1 levels. This study reveals the mechanistic basis for using copper chelation to overcome cDDP resistance in clinical investigations.

  4. The iron chelator desferrioxamine attenuates postischemic ventricular dysfunction

    SciTech Connect

    Bolli, R.; Patel, B.S.; Zhu, Weixi; O'Neill, P.G.; Hartley, C.J.; Charlat, M.L.; Roberts, R. )

    1987-12-01

    Recent evidence suggests that postischemic myocardial dysfunction (stunning) may be mediated by oxygen free radicals, but the mechanism by which they produce myocellular damage remains unknown. Since iron catalyzes formation of hydroxyl radicals (HO{center dot}) as well as HO{center dot}-initiated lipid peroxidation, the authors explored the potential role of this metal in the pathogenesis of myocardial stunning. Open-chest dogs undergoing a 15-min occlusion of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion (REP) received the iron chelator desferrioxamine intravenously or normal saline. Regional myocardial function was assessed by measuring systolic wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under base-line conditions and similar degrees of dyskinesis during ischemia. After REP, however, recovery of contractile function as considerably greater in desferrioxamine-treated compared with control dogs. These differences could not be ascribed to hemodynamic factors. The results suggest that iron-catalyzed reactions (possibly HO{center dot} generation) play a significant role in myocardial stunning after a brief episode of reversible regional ischemia.

  5. Chelation of dietary iron prevents iron accumulation and macrophage infiltration in the type I diabetic kidney

    PubMed Central

    Morita, Tatsuyori; Nakano, Daisuke; Kitada, Kento; Morimoto, Satoshi; Ichihara, Atsuhiro; Hitomi, Hirofumi; Kobori, Hiroyuki; Shiojima, Ichiro; Nishiyama, Akira

    2015-01-01

    We previously reported that the functional deletion of p21, a cyclin-dependent kinase inhibitor, in mice attenuated renal cell senescence in streptozotocin (STZ)-induced type 1 diabetic mice. In the present study, we investigated the effect of iron chelation on renal cell senescence and inflammation in the type 1 diabetic kidney. STZ-treated mice showed increase in iron accumulation, tubular cell senescence and macrophage infiltration at week 28 in the kidney. Administering deferasirox, which removes only dietary iron, significantly attenuated iron accumulation in proximal tubules and the number of infiltrating F4/80-positive cells without effecting blood glucose, hematocrit or hemoglobin levels. In contrast however, deferasirox did not influence renal cell senescence. The lack of p21 decreased the renal tubular iron accumulation and did not change tubular cell senescence. Interestingly, the STZ-treated animals showed an increase in p16, another cyclin-dependent kinase inhibitor. The results suggest that type 1 diabetes increases renal tubular iron accumulation and macrophage infiltration through a p21-dependent mechanism, and that the chelation of dietary iron attenuates these responses. PMID:25820160

  6. Longitudinal analysis of heart and liver iron in thalassemia major patients according to chelation treatment.

    PubMed

    Danjou, F; Origa, R; Anni, F; Saba, L; Cossa, S; Podda, G; Galanello, R

    2013-10-01

    Iron chelators and nuclear magnetic resonance imaging (MRI) techniques for assessing iron loading in liver and heart have greatly improved survival of thalassemic patients suffering iron overload-associated cardiomyopathy. However, the correlation between liver iron concentration and myocardial siderosis is ambiguous. Using an objective metric of time delay, scientists have demonstrated a lag in the loading and unloading of cardiac iron with respect to that of the liver. In the present study, we further tested this hypothesis with different chelation treatments. We analyzed the effect of three chelating treatment approaches on liver and cardiac iron content in 24 highly compliant patients who underwent 3 or more MRIs under each chelation treatment. Of the 84 MRIs considered, 32 were performed on deferoxamine (DFO - 8 patients), 24 on deferiprone (DFP - 7 patients), and 28 on combined therapy (DFO+DFP - 9 patients). In patients treated with DFO, changes in cardiac iron significantly lagged changes in liver iron but the opposite pattern was observed in patients treated with DFP (p=0.005), while combined therapy showed a pattern in-between DFO and DFP. We conclude that the temporality of changes of cardiac and liver iron is chelator-dependent, so that chelation therapy can be tailored to balance iron elimination from the liver and the heart.

  7. Clinical monitoring and management of complications related to chelation therapy in patients with β-thalassemia.

    PubMed

    Saliba, Antoine N; El Rassi, Fuad; Taher, Ali T

    2016-01-01

    Iron chelating agents - deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX) - are used to treat chronic iron overload in patients with β-thalassemia in an attempt to reduce morbidity and mortality related to siderosis. Each of the approved iron chelating agents has its own advantages over the others and also has its own risks, whether related to over-chelation or not. In this review, we briefly discuss the methods to monitor the efficacy of iron chelation therapy (ICT) and the evidence behind the use of each iron chelating agent. We also portray the risks and complications associated with each iron chelating agent and recommend strategies to manage adverse events.

  8. Iron chelating active packaging: Influence of competing ions and pH value on effectiveness of soluble and immobilized hydroxamate chelators.

    PubMed

    Ogiwara, Yoshiko; Roman, Maxine J; Decker, Eric A; Goddard, Julie M

    2016-04-01

    Many packaged foods utilize synthetic chelators (e.g. ethylenediaminetetraacetic acid, EDTA) to inhibit iron-promoted oxidation or microbial growth which would result in quality loss. To address consumer demands for all natural products, we have previously developed a non-migratory iron chelating active packaging material by covalent immobilization of polyhydroxamate and demonstrated its efficacy in delaying lipid oxidation. Herein, we demonstrate the ability of this hydroxamate-functionalized iron chelating active packaging to retain iron chelating capacity; even in the presence of competing ions common in food. Both immobilized and soluble hydroxamate chelators retained iron chelating capacity in the presence of calcium, magnesium, and sodium competing ions, although at pH 5.0 the presence of calcium reduced immobilized hydroxamate iron chelation. A strong correlation was found between colorimetric and mass spectral analysis of iron chelation by the chelating packaging material. Such chelating active packaging may support reducing additive use in product formulations, while retaining quality and shelf life.

  9. Mobilization of iron from neoplastic cells by some iron chelators is an energy-dependent process.

    PubMed

    Richardson, D R

    1997-05-16

    Iron (Fe) chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class may be useful agents to treat Fe overload disease and also cancer. These ligands possess high activity at mobilizing 59Fe from neoplastic cells, and the present study has been designed to examine whether their marked activity may be related to an energy-dependent transport process across the cell membrane. Initial experiments examined the release of 59Fe from SK-N-MC neuroblastoma (NB) cells prelabelled for 3 h at 37 degrees C with 59Fe-transferrin (1.25 microM) and then reincubated in the presence and absence of the chelators for 3 h at 4 degrees C or 37 degrees C. Prelabelled cells released 4-5% of total cellular 59Fe when reincubated in minimum essential medium at 4 degrees C or 37 degrees C. When the chelators desferrioxamine (DFO; 0.1 mM) or PIH (0.1 mM) were reincubated with labelled cells at 4 degrees C, they mobilized only 4-5% of cellular 59Fe, whereas as 37 degrees C, these ligands mobilized 21% and 48% of cell 59Fe, respectively. The lipophilic PIH analogue, 311 (2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; 0.1 mM), which exhibits high anti-proliferative activity, released 10% and 53% of cellular 59Fe when reincubated with prelabelled cells at 4 degrees C and 37 degrees C, respectively. Almost identical results were obtained using the SK-Mel-28 melanoma cell line. These data suggest that perhaps temperature-dependent mechanisms are essential for 59Fe mobilization from these cells. Interestingly, the metabolic inhibitors, 2,4-dinitrophenol, oligomycin, rotenone, and sodium azide, markedly decreased 59Fe mobilization mediated by PIH, but had either no effect or much less effect on 59Fe release by 311. Considering that an ATP-dependent process was involved in 59Fe release by PIH, further studies examined 4 widely used inhibitors of the multi-drug efflux pump P-glycoprotein (P-gp). All of these inhibitors, namely, verapamil (Ver), cyclosporin A (CsA), reserpine (Res) and

  10. Clinically approved iron chelators influence zebrafish mortality, hatching morphology and cardiac function.

    PubMed

    Hamilton, Jasmine L; Hatef, Azadeh; Imran ul-Haq, Muhammad; Nair, Neelima; Unniappan, Suraj; Kizhakkedathu, Jayachandran N

    2014-01-01

    Iron chelation therapy using iron (III) specific chelators such as desferrioxamine (DFO, Desferal), deferasirox (Exjade or ICL-670), and deferiprone (Ferriprox or L1) are the current standard of care for the treatment of iron overload. Although each chelator is capable of promoting some degree of iron excretion, these chelators are also associated with a wide range of well documented toxicities. However, there is currently very limited data available on their effects in developing embryos. In this study, we took advantage of the rapid development and transparency of the zebrafish embryo, Danio rerio to assess and compare the toxicity of iron chelators. All three iron chelators described above were delivered to zebrafish embryos by direct soaking and their effects on mortality, hatching and developmental morphology were monitored for 96 hpf. To determine whether toxicity was specific to embryos, we examined the effects of chelator exposure via intra peritoneal injection on the cardiac function and gene expression in adult zebrafish. Chelators varied significantly in their effects on embryo mortality, hatching and morphology. While none of the embryos or adults exposed to DFO were negatively affected, ICL -treated embryos and adults differed significantly from controls, and L1 exerted toxic effects in embryos alone. ICL-670 significantly increased the mortality of embryos treated with doses of 0.25 mM or higher and also affected embryo morphology, causing curvature of larvae treated with concentrations above 0.5 mM. ICL-670 exposure (10 µL of 0.1 mM injection) also significantly increased the heart rate and cardiac output of adult zebrafish. While L1 exposure did not cause toxicity in adults, it did cause morphological defects in embryos at 0.5 mM. This study provides first evidence on iron chelator toxicity in early development and will help to guide our approach on better understanding the mechanism of iron chelator toxicity.

  11. Clinically Approved Iron Chelators Influence Zebrafish Mortality, Hatching Morphology and Cardiac Function

    PubMed Central

    Hamilton, Jasmine L.; Hatef, Azadeh; Imran ul-haq, Muhammad; Nair, Neelima; Unniappan, Suraj; Kizhakkedathu, Jayachandran N.

    2014-01-01

    Iron chelation therapy using iron (III) specific chelators such as desferrioxamine (DFO, Desferal), deferasirox (Exjade or ICL-670), and deferiprone (Ferriprox or L1) are the current standard of care for the treatment of iron overload. Although each chelator is capable of promoting some degree of iron excretion, these chelators are also associated with a wide range of well documented toxicities. However, there is currently very limited data available on their effects in developing embryos. In this study, we took advantage of the rapid development and transparency of the zebrafish embryo, Danio rerio to assess and compare the toxicity of iron chelators. All three iron chelators described above were delivered to zebrafish embryos by direct soaking and their effects on mortality, hatching and developmental morphology were monitored for 96 hpf. To determine whether toxicity was specific to embryos, we examined the effects of chelator exposure via intra peritoneal injection on the cardiac function and gene expression in adult zebrafish. Chelators varied significantly in their effects on embryo mortality, hatching and morphology. While none of the embryos or adults exposed to DFO were negatively affected, ICL -treated embryos and adults differed significantly from controls, and L1 exerted toxic effects in embryos alone. ICL-670 significantly increased the mortality of embryos treated with doses of 0.25 mM or higher and also affected embryo morphology, causing curvature of larvae treated with concentrations above 0.5 mM. ICL-670 exposure (10 µL of 0.1 mM injection) also significantly increased the heart rate and cardiac output of adult zebrafish. While L1 exposure did not cause toxicity in adults, it did cause morphological defects in embryos at 0.5 mM. This study provides first evidence on iron chelator toxicity in early development and will help to guide our approach on better understanding the mechanism of iron chelator toxicity. PMID:25329065

  12. Ascorbate status modulates reticuloendothelial iron stores and response to deferasirox iron chelation in ascorbate-deficient rats.

    PubMed

    Brewer, Casey; Otto-Duessel, Maya; Lykkesfeldt, Jens; Nick, Hanspeter; Wood, John C

    2012-10-01

    Iron chelation is essential to patients on chronic blood transfusions to prevent toxicity from iron overload and remove excess iron. Deferasirox (DFX) is the most commonly used iron chelator in the United States; however, some patients are relatively refractory to DFX therapy. We postulated that vitamin C supplementation would improve the availability of transfusional iron to DFX treatment by promoting iron's redox cycling, increasing its soluble ferrous form and promoting its release from reticuloendothelial cells. Osteogenic dystrophy rats (n = 54) were given iron dextran injections for 10 weeks. Cardiac and liver iron levels were measured after iron loading (n = 18), 12 weeks of sham chelation (n = 18), and 12 weeks of DFX chelation (n = 18) at 75 mg/kg/day. Ascorbate supplementation of 150 ppm, 900 ppm, and 2250 ppm was used in the chow to mimic a broad range of ascorbate status; plasma ascorbate levels were 5.4 ± 1.9, 8.2 ± 1.4, 23.6 ± 9.8 μM, respectively (p < 0.0001). The most severe ascorbate deficiency produced reticuloenthelial retention, lowering total hepatic iron by 29% at the end of iron loading (p < 0.05) and limiting iron redistribution from cardiac and hepatic macrophages during 12 weeks of sham chelation. Most importantly, ascorbate supplementation at 2250 ppm improved DFX efficiency, allowing DFX to remove 21% more hepatic iron than ascorbate supplementation with 900 ppm or 150 ppm (p < 0.05). We conclude that vitamin C status modulates the release of iron from the reticuloendothelial system and correlates positively with DFX chelation efficiency. Our findings suggest that ascorbate status should be probed in patients with unsatisfactory response to DFX.

  13. Generation, Fractionation, and Characterization of Iron-Chelating Protein Hydrolysate from Palm Kernel Cake Proteins.

    PubMed

    Zarei, Mohammad; Ghanbari, Rahele; Tajabadi, Naser; Abdul-Hamid, Azizah; Bakar, Fatimah Abu; Saari, Nazamid

    2016-02-01

    Palm kernel cake protein was hydrolyzed with different proteases namely papain, bromelain, subtilisin, flavourzyme, trypsin, chymotrypsin, and pepsin to generate different protein hydrolysates. Peptide content and iron-chelating activity of each hydrolysate were evaluated using O-phthaldialdehyde-based spectrophotometric method and ferrozine-based colorimetric assay, respectively. The results revealed a positive correlation between peptide contents and iron-chelating activities of the protein hydrolysates. Protein hydrolysate generated by papain exhibited the highest peptide content of 10.5 mM and highest iron-chelating activity of 64.8% compared with the other hydrolysates. Profiling of the papain-generated hydrolysate by reverse phase high performance liquid chromatography fractionation indicated a direct association between peptide content and iron-chelating activity in most of the fractions. Further fractionation using isoelectric focusing also revealed that protein hydrolysate with basic and neutral isoelectric point (pI) had the highest iron-chelating activity, although a few fractions in the acidic range also exhibited good metal chelating potential. After identification and synthesis of papain-generated peptides, GGIF and YLLLK showed among the highest iron-chelating activities of 56% and 53%, whereas their IC50 were 1.4 and 0.2 μM, respectively.

  14. Cardiac iron removal and functional cardiac improvement by different iron chelation regimens in thalassemia major patients.

    PubMed

    Cassinerio, Elena; Roghi, Alberto; Pedrotti, Patrizia; Brevi, Francesca; Zanaboni, Laura; Graziadei, Giovanna; Pattoneri, Paolo; Milazzo, Angela; Cappellini, Maria Domenica

    2012-09-01

    Heart failure due to myocardial iron overload remains the leading cause of morbidity and mortality in adult thalassemia major (TM) patients. We evaluated the removal of cardiac iron and the changes of cardiac function by different iron chelation in TM patients by T2* cardiac magnetic resonance (CMR). Sixty-seven TM patients (27 males/40 females; mean age, 35 ± 6 years) on different chelation regimens underwent T2* CMR at baseline (t (0)), after 6-14 months (t (1)) and after 32 ± 7 months (t (2)). Patients were divided in four groups according to chelation treatment: group A (deferasirox), group B (deferoxamine), group C (combined treatment, deferoxamine plus deferiprone) and group D (deferiprone alone). Myocardial T2* at t (0) was <10 ms in 8 patients, between 10 and 20 ms in 22 patients and ≥ 20 ms in 37 patients. Progressive changes in T2* were observed at t (1) and t (2). Ten patients (10/36, 27.8 %) in group A, three patients (3/15, 20 %) in group B and three patients (3/12, 25 %) in group C moved from an abnormal T2* to normal values. We observed an improvement of left ventricular ejection fraction and a reduction of end-systolic and end-diastolic left ventricular volumes only in patients in group A with baseline cardiac T2* between 10 and 20 ms. Rigorous compliance to any chelation therapy at proper doses significantly improve myocardial T2*. Treatment with deferasirox significantly improves left ventricular function. Combination therapy seems to ameliorate cardiac T2* in a shorter period of time in severe siderosis.

  15. Influence of iron chelation on R1 and R2 calibration curves in gerbil liver and heart.

    PubMed

    Wood, John C; Aguilar, Michelle; Otto-Duessel, Maya; Nick, Hanspeter; Nelson, Marvin D; Moats, Rex

    2008-07-01

    MRI is gaining increasing importance for the noninvasive quantification of organ iron burden. Since transverse relaxation rates depend on iron distribution as well as iron concentration, physiologic and pharmacologic processes that alter iron distribution could change MRI calibration curves. This article compares the effect of three iron chelators, deferoxamine, deferiprone, and deferasirox, on R1 and R2 calibration curves according to two iron loading and chelation strategies. Thirty-three Mongolian gerbils underwent iron loading (iron dextran 500 mg/kg/wk) for 3 weeks followed by 4 weeks of chelation. An additional 56 animals received less aggressive loading (200 mg/kg/week) for 10 weeks, followed by 12 weeks of chelation. R1 and R2 calibration curves were compared to results from 23 iron-loaded animals that had not received chelation. Acute iron loading and chelation-biased R1 and R2 from the unchelated reference calibration curves but chelator-specific changes were not observed, suggesting physiologic rather than pharmacologic differences in iron distribution. Long-term chelation deferiprone treatment increased liver R1 50% (P < 0.01), while long-term deferasirox lowered liver R2 30.9% (P < 0.0001). The relationship between R1 and R2 and organ iron concentration may depend on the acuity of iron loading and unloading as well as the iron chelator administered.

  16. New hydroxypyridinone iron-chelators as potential anti-neurodegenerative drugs.

    PubMed

    Arduino, Daniela; Silva, Daniel; Cardoso, Sandra M; Chaves, Silvia; Oliveira, Catarina R; Santos, M Amelia

    2008-05-01

    The neuroprotective action of a set of new hydroxypyridinone-based (3,4-HP) compounds (A, B and C), which are iron chelators extra-functionalized with a propargylamino group for potential MAO-B inhibition, was evaluated after cell treatment with MPP+ (an in vivo inducer of parkinsonism) and Abeta(1-40) and/or Abeta(1-42) peptides. Our results show that all these compounds improved cell viability in cells treated with MPP+ and Abeta(1-40) peptide or Abeta(1-42) peptide. In order to evaluate the cellular mechanisms underlying the activity of these compounds, we studied their protective role in caspase activation. All compounds tested were able to prevent MPP+ and Brefeldin A induced caspase-2 activation. They also showed quite effective in the inhibition of caspase-4 and caspase-3 activity, an effector caspase in the apoptotic process. Finally, detection of apoptotic-like cell death after cell exposure to MPP+ was also performed by TUNEL assay. Our results demonstrated that all tested compounds prevented DNA fragmentation by decreasing TUNEL positive cells. A, B and C were more effective than DFP (a 3,4-HP iron-chelating agent in clinical use) in MPP+ induced cell death. Therefore, these results evidenced a neuroprotective and antiapoptotic role for the compounds studied.

  17. 21 CFR 176.150 - Chelating agents used in the manufacture of paper and paperboard.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Chelating agents used in the manufacture of paper... for Use Only as Components of Paper and Paperboard § 176.150 Chelating agents used in the manufacture... the manufacture of paper and paperboard, in accordance with the conditions prescribed in paragraphs...

  18. 21 CFR 176.150 - Chelating agents used in the manufacture of paper and paperboard.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Chelating agents used in the manufacture of paper... Chelating agents used in the manufacture of paper and paperboard. The substances named in paragraph (a) of this section may be safely used in the manufacture of paper and paperboard, in accordance with...

  19. 21 CFR 176.150 - Chelating agents used in the manufacture of paper and paperboard.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Chelating agents used in the manufacture of paper... Chelating agents used in the manufacture of paper and paperboard. The substances named in paragraph (a) of this section may be safely used in the manufacture of paper and paperboard, in accordance with...

  20. 21 CFR 176.150 - Chelating agents used in the manufacture of paper and paperboard.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Chelating agents used in the manufacture of paper... Chelating agents used in the manufacture of paper and paperboard. The substances named in paragraph (a) of this section may be safely used in the manufacture of paper and paperboard, in accordance with...

  1. Metal distribution and spectroscopic analysis after soil washing with chelating agents and humic substances.

    PubMed

    Tsang, Daniel C W; Hartley, Neil R

    2014-03-01

    Biodegradable chelating agents ([S,S]-ethylenediamine-N,N-disuccinic acid (EDDS) and glutamic-N,N-diacetic acid (GLDA)) and natural humic substances (lignite-derived, standard, and commercially available humic acids) are potentially useful for enhancing soil remediation of timber treatment sites. This study integrated macroscopic and spectroscopic analyses to assess their influence on the distribution and chemical speciation of the remaining metals as well as their interaction with the soil surface after 48-h washing of a field-contaminated soil. The results demonstrated that EDDS and GLDA were an appealing alternative to non-biodegradable ethylenediamine-tetraacetic acid, but the three humic substances were less effective. As shown by sequential extractions, Cu was primarily extracted from the carbonate fraction while Cr and As extraction resulted from (co-)dissolution of the oxide fraction. As a result, the relative proportion of strongly bound organic matter and residual fractions increased by 7-16 %. However, it was noteworthy that the exchangeable fraction also increased by 5-11 %, signifying that a portion of the remaining metals was destabilized by chelating agents and transformed to be more labile in the treated soil. The X-ray photoelectron spectroscopy spectra confirmed the substantial removal of readily accessible Cu from the soil surface, but Cr maintained its original chemical forms of trivalent chromium oxides and iron-chromium coprecipitates, whereas As remained as arsenic trioxide/pentoxide and copper arsenate precipitates. On the other hand, the absence of characteristic peaks of adsorbed carboxylate groups in the Fourier-transform infrared (FTIR) spectra inferred that the extent of adsorption of chelating agents and humic substances on the bulk soil was insufficient to be characterized by FTIR analysis. These results suggested that attention should be paid to the exchangeable fraction of Cu and oxides/coprecipitates of As prior to possible on

  2. Cationic albumin-conjugated chelating agent as a novel brain drug delivery system in neurodegeneration.

    PubMed

    Kamalinia, Golnaz; Khodagholi, Fariba; Shaerzadeh, Fatemeh; Tavssolian, Faranak; Chaharband, Farkhondeh; Atyabi, Fatemeh; Sharifzadeh, Mohammad; Amini, Mohsen; Dinarvand, Rassoul

    2015-11-01

    The critical role of metal ions and in particular iron in oxidative stress and protein aggregation offers chelation therapy as a sensible pharmaceutical strategy in oxidative stress-induced neuronal damages. In this research, we conjugated an iron-chelating agent, deferasirox, to cationized human serum albumin molecules in order to develop a novel brain delivery system for the management of neurodegenerative disorders due to the significant role of oxidative stress-induced neuronal injury in such diseases. Cationized albumin is known to be able to transport to brain tissue via adsorptive-mediated transcytosis. The developed structures were molecularly characterized, and their conjugation ratio was determined. PC12 cell line was utilized to evaluate the neuroprotective features of these newly developed molecules in the presence of hydrogen peroxide neuronal damage and to identify the mechanisms behind the observed neuronal protection including apoptotic and autophagic pathways. Furthermore, a rat model of Alzheimer's disease was utilized to evaluate the impact of conjugated structures in vivo. Data analysis revealed that the conjugated species were able to hinder apoptotic cell death while enhancing autophagic process. The developed conjugated species were also able to attenuate amyloid beta-induced learning deficits when administered peripherally.

  3. Synthesis and characterization of dihexyldithiocarbamate as a chelating agent in extraction of gold(III)

    NASA Astrophysics Data System (ADS)

    Fatimah, Soja Siti; Bahti, Husein H.; Hastiawan, Iwan; Permanasari, Anna

    2016-02-01

    The use of dialkyldithiocarbamates as chelating agents of transition metals have been developing for decades. Many chelating agents have been synthesized and used in the extraction of the metals. Studies on particular aspects of extraction of the metals, such as the effect of increasing hydrophobicity of chelating agents on the effectiveness of the extraction, have been done. However, despite the many studies on the synthesis and applications of this type of chelating agents, interests in the aspect of molecular structure of the synthesized ligands and of their complexes, have been limited. This study aimed at synthesizing and characterizing dihexylthiocarbamate, and using the ligand for the extraction of gold III). Characterization of the ligand and of its metal complex were done by using elemental analysis, DTG, and spectroscopic methods to include NMR, (1H, and 13C), FTIR, and MS-ESI. Data on the synthesis, characterization, and the application of the ligand as a chelating agent are presented.

  4. Regulation of copper and iron homeostasis by metal chelators: a possible chemotherapy for Alzheimer's disease.

    PubMed

    Robert, Anne; Liu, Yan; Nguyen, Michel; Meunier, Bernard

    2015-05-19

    With the increase of life expectancy of humans in more than two-thirds of the countries in the World, aging diseases are becoming the frontline health problems. Alzheimer's disease (AD) is now one of the major challenges in drug discovery, since, with the exception of memantine in 2003, all clinical trials with drug candidates failed over the past decade. If we consider that the loss of neurons is due to a high level of oxidative stress produced by nonregulated redox active metal ions like copper linked to amyloids of different sizes, regulation of metal homeostasis is a key target. The difficulty for large copper-carrier proteins to directly extract copper ions from metalated amyloids might be considered as being at the origin of the rupture of the copper homeostasis regulation in AD brains. So, there is an urgent need for new specific metal chelators that should be able to regulate the homeostasis of metal ions, specially copper and iron, in AD brains. As a consequence of that concept, chelators promoting metal excretion from brain are not desired. One should favor ligands able to extract copper ions from sinks (amyloids being the major one) and to transfer these redox-active metal ions to copper-carrier proteins or copper-containing enzymes. Obviously, the affinity of these chelators for the metal ion should not be a sufficient criterion, but the metal specificity and the ability of the chelators to release the metal under specific biological conditions should be considered. Such an approach is still largely unexplored. The requirements for the chelators are very high (ability to cross the brain-blood barrier, lack of toxicity, etc.), few chemical series were proposed, and, among them, biochemical or biological data are scarce. As a matter of fact, the bioinorganic pharmacology of AD represents less than 1% of all articles dedicated to AD drug research. The major part of these articles deals with an old and rather toxic drug, clioquinol and related analogs, that

  5. Metal chelators coupled with nanoparticles as potential therapeutic agents for Alzheimer's disease

    PubMed Central

    Liu, Gang; Men, Ping; Perry, George; Smith, Mark A.

    2009-01-01

    Alzheimer's disease (AD) is a devastating neuro-degenerative disorder characterized by the progressive and irreversible loss of memory followed by complete dementia. Despite the disease's high prevalence and great economic and social burden, an explicative etiology or viable cure is not available. Great effort has been made to better understand the disease's pathogenesis, and to develop more effective therapeutic agents. However, success is greatly hampered by the presence of the blood-brain barrier that limits a large number of potential therapeutics from entering the brain. Nanoparticle-mediated drug delivery is one of the few valuable tools for overcoming this impediment and its application as a potential AD treatment shows promise. In this review, the current studies on nanoparticle delivery of chelation agents as possible therapeutics for AD are discussed because several metals are found excessive in the AD brain and may play a role in the disease development. Specifically, a novel approach involving transport of iron chelation agents into and out of the brain by nanoparticles is highlighted. This approach may provide a safer and more effective means of simultaneously reducing several toxic metals in the AD brain. It may also provide insights into the mechanisms of AD pathophysiology, and prove useful in treating other iron-associated neurodegenerative diseases such as Friedreich's ataxia, Parkinson's disease, Huntington's disease and Hallervorden-Spatz Syndrome. It is important to note that the use of nanoparticle-mediated transport to facilitate toxicant excretion from diseased sites in the body may advance nanoparticle technology, which is currently focused on targeted drug delivery for disease prevention and treatment. The application of nanoparticle-mediated drug transport in the treatment of AD is at its very early stages of development and, therefore, more studies are warranted. PMID:19936278

  6. A competition model between Pseudomonas fluorescens and pathogens via iron chelation.

    PubMed

    Fgaier, Hedia; Eberl, Hermann J

    2010-04-21

    In this study we present a competition model between a non-chelator (e.g. pathogen) microorganism and an iron chelator microorganism (e.g. Pseudomonas fluorescens). This latter is a beneficial bacteria that can inhibit the growth of the non-chelator through its iron chelating capability. This phenomena of iron chelation is shown to prevent the pathogen from proliferating to numbers capable of causing disease. A mathematical model is formulated and used to study this competition. The model proposes a new and simple conceptual explanation of interactions. It is a nonlinear system of ordinary differential equations. A qualitative analysis of the model for the batch case (no inflow or outflow from the system) is carried out and the global behavior of the model variables is studied. For the chemostat case, the equilibrium points were derived and their stability was performed through extensive numerical simulations. It is found that iron chelation is able to control the non-chelator microorganism growth under a wide range of conditions. PMID:20005236

  7. Randomized controlled trials of iron chelators for the treatment of cardiac siderosis in thalassaemia major.

    PubMed

    Baksi, A John; Pennell, Dudley J

    2014-01-01

    In conditions requiring repeated blood transfusion or where iron metabolism is abnormal, heart failure may result from accumulation of iron in the heart (cardiac siderosis). Death due to heart failure from cardiac iron overload has accounted for considerable early mortality in β-thalassemia major. The ability to detect iron loading in the heart by cardiovascular magnetic resonance using T2* sequences has created an opportunity to intervene in the natural history of such conditions. However, effective and well tolerated therapy is required to remove iron from the heart. There are currently three approved commercially available iron chelators: deferoxamine, deferiprone and deferasirox. We review the high quality randomized controlled trials in this area for iron chelation therapy in the management of cardiac siderosis.

  8. Effective sulfur and energy recovery from hydrogen sulfide through incorporating an air-cathode fuel cell into chelated-iron process.

    PubMed

    Sun, Min; Song, Wei; Zhai, Lin-Feng; Cui, Yu-Zhi

    2013-12-15

    The chelated-iron process is among the most promising techniques for the hydrogen sulfide (H2S) removal due to its double advantage of waste minimization and resource recovery. However, this technology has encountered the problem of chelate degradation which made it difficult to ensure reliable and economical operation. This work aims to develop a novel fuel-cell-assisted chelated-iron process which employs an air-cathode fuel cell for the catalyst regeneration. By using such a process, sulfur and electricity were effectively recovered from H2S and the problem of chelate degradation was well controlled. Experiment on a synthetic sulfide solution showed the fuel-cell-assisted chelated-iron process could maintain high sulfur recovery efficiencies generally above 90.0%. The EDTA was preferable to NTA as the chelating agent for electricity generation, given the Coulombic efficiencies (CEs) of 17.8 ± 0.5% to 75.1 ± 0.5% for the EDTA-chelated process versus 9.6 ± 0.8% to 51.1 ± 2.7% for the NTA-chelated process in the pH range of 4.0-10.0. The Fe (III)/S(2-) ratio exhibited notable influence on the electricity generation, with the CEs improved by more than 25% as the Fe (III)/S(2-) molar ratio increased from 2.5:1 to 3.5:1. Application of this novel process in treating a H2S-containing biogas stream achieved 99% of H2S removal efficiency, 78% of sulfur recovery efficiency, and 78.6% of energy recovery efficiency, suggesting the fuel-cell-assisted chelated-iron process was effective to remove the H2S from gas streams with favorable sulfur and energy recovery efficiencies.

  9. Effective sulfur and energy recovery from hydrogen sulfide through incorporating an air-cathode fuel cell into chelated-iron process.

    PubMed

    Sun, Min; Song, Wei; Zhai, Lin-Feng; Cui, Yu-Zhi

    2013-12-15

    The chelated-iron process is among the most promising techniques for the hydrogen sulfide (H2S) removal due to its double advantage of waste minimization and resource recovery. However, this technology has encountered the problem of chelate degradation which made it difficult to ensure reliable and economical operation. This work aims to develop a novel fuel-cell-assisted chelated-iron process which employs an air-cathode fuel cell for the catalyst regeneration. By using such a process, sulfur and electricity were effectively recovered from H2S and the problem of chelate degradation was well controlled. Experiment on a synthetic sulfide solution showed the fuel-cell-assisted chelated-iron process could maintain high sulfur recovery efficiencies generally above 90.0%. The EDTA was preferable to NTA as the chelating agent for electricity generation, given the Coulombic efficiencies (CEs) of 17.8 ± 0.5% to 75.1 ± 0.5% for the EDTA-chelated process versus 9.6 ± 0.8% to 51.1 ± 2.7% for the NTA-chelated process in the pH range of 4.0-10.0. The Fe (III)/S(2-) ratio exhibited notable influence on the electricity generation, with the CEs improved by more than 25% as the Fe (III)/S(2-) molar ratio increased from 2.5:1 to 3.5:1. Application of this novel process in treating a H2S-containing biogas stream achieved 99% of H2S removal efficiency, 78% of sulfur recovery efficiency, and 78.6% of energy recovery efficiency, suggesting the fuel-cell-assisted chelated-iron process was effective to remove the H2S from gas streams with favorable sulfur and energy recovery efficiencies. PMID:24220197

  10. Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators

    PubMed Central

    Akam, Eman A.; Chang, Tsuhen M.; Astashkin, Andrei V.

    2014-01-01

    Iron scavengers (chelators) offer therapeutic opportunities in anticancer drug design by targeting the increased demand for iron in cancer cells as compared to normal cells. Prochelation approaches are expected to avoid systemic iron depletion as chelators are liberated under specific intracellular conditions. In the strategy described herein, a disulfide linkage is employed as a redox-directed switch within the binding unit of an antiproliferative thiosemicarbazone prochelator, which is activated for iron coordination following reduction to the thiolate chelator. In glutathione redox buffer, this reduction event occurs at physiological concentrations and half-cell potentials. Consistent with concurrent reduction and activation, higher intracellular thiol concentrations increase cell susceptibility to prochelator toxicity in cultured cancer cells. The reduction of the disulfide switch and intracellular iron chelation are confirmed in cell-based assays using calcein as a fluorescent probe for paramagnetic ions. The resulting low-spin Fe(III) complex is identified in intact Jurkat cells by EPR spectroscopy measurements, which also document a decreased concentration of active ribonucleotide reductase following exposure to the prochelator. Cell viability and fluorescence-based assays show that the iron complex presents low cytotoxicity and does not participate in intracellular redox chemistry, indicating that this antiproliferative chelation strategy does not rely on the generation of reactive oxygen species. PMID:25100578

  11. Bifunctional chelating agent for the design and development of site specific radiopharmaceuticals and biomolecule conjugation strategy

    DOEpatents

    Katti, Kattesh V.; Prabhu, Kandikere R.; Gali, Hariprasad; Pillarsetty, Nagavara Kishore; Volkert, Wynn A.

    2003-10-21

    There is provided a method of labeling a biomolecule with a transition metal or radiometal in a site specific manner to produce a diagnostic or therapeutic pharmaceutical compound by synthesizing a P.sub.2 N.sub.2 -bifunctional chelating agent intermediate, complexing the intermediate with a radio metal or a transition metal, and covalently linking the resulting metal-complexed bifunctional chelating agent with a biomolecule in a site specific manner. Also provided is a method of synthesizing the --PR.sub.2 containing biomolecules by synthesizing a P.sub.2 N.sub.2 -bifunctional chelating agent intermediate, complexing the intermediate with a radiometal or a transition metal, and covalently linking the resulting radio metal-complexed bifunctional chelating agent with a biomolecule in a site specific manner. There is provided a therapeutic or diagnostic agent comprising a --PR.sub.2 containing biomolecule.

  12. Inhibitory activity of chelating agent against bacteria associated with poultry processing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ethylenediaminetetraacetic acid (EDTA) and ethylenediamine-N, N’-disuccinic acid (EDDS) are chelating agents that can bind minerals that produce water hardness. By sequestering minerals in hard water, chelators reduce water hardness and increase the ability of cleansers to remove dirt and debris dur...

  13. Thumbnail Sketches: EDTA-Type Chelating Agents in Everyday Consumer Products: Some Medicinal and Personal Care Products.

    ERIC Educational Resources Information Center

    Hart, J. Roger

    1984-01-01

    Discusses various ethylenediaminetetraacetate (EDTA)-type chelating agents found in ophthalmic products, personal care products, and disinfectants. Also discusses the properties and action of these EDTA agents. (JN)

  14. Identification and characterization of thiosemicarbazones with antifungal and antitumor effects: cellular iron chelation mediating cytotoxic activity.

    PubMed

    Opletalová, Veronika; Kalinowski, Danuta S; Vejsová, Marcela; Kunes, Jirí; Pour, Milan; Jampílek, Josef; Buchta, Vladimír; Richardson, Des R

    2008-09-01

    Thiosemicarbazones derived from acetylpyrazines were prepared by condensing an acetylpyrazine or a ring-substituted acetylpyrazine with thiosemicarbazide. Using the same procedure, N, N-dimethylthiosemicarbazones were synthesized from acetylpyrazines and N, N-dimethylthiosemicarbazide. A total of 20 compounds (16 novel) were chemically characterized and then tested for antifungal effects on eight strains of fungi and also for antitumor activity against SK-N-MC neuroepithelioma cells. The most effective compound identified in terms of both antifungal and antitumor activity was N, N-dimethyl-2-(1-pyrazin-2-ylethylidene)hydrazinecarbothioamide (5a). The mechanism of action of this and its related thiosemicarbazones was due, at least in part, to its ability to act as a tridentate ligand that binds metal ions. This was deduced from preparation of the related thiosemicarbazones [acetophenone thiosemicarbazone (6) and acetophenone N, N-dimethylthiosemicarbazone (7)] that do not possess a coordinating ring-N, which plays a vital role in metal ion chelation. Furthermore, 5a and several other thiosemicarbazones that showed high antiproliferative activity were demonstrated to have marked iron (Fe) chelation efficacy. In fact, these agents were highly effective at mobilizing (59)Fe from prelabeled SK-N-MC cells and preventing (59)Fe uptake from the serum Fe transport protein, transferrin. In contrast, compounds 6 and 7 that do not possess a tridentate metal-binding site showed little activity. Further studies examining ascorbate oxidation demonstrated that the Fe complexes of the most effective compounds were redox-inactive. Thus, in contrast to other thiosemicarbazones with potent antiproliferative activity, Fe chelation and mobilization rather than free radical generation played a significant role in the cytotoxic effects of the current ligands. PMID:18698850

  15. Diethylentriaminepenta acetic acid glucose conjugates as a cell permeable iron chelator

    PubMed Central

    Mosayebnia, Mona; Shafiee-Ardestani, Mehdi; Pasalar, Parvin; Mashayekhi, Mojgan; Amanlou, Massoud

    2014-01-01

    Objective: To find out whether DTPA-DG complex can enhance clearance of intracellular free iron. Materials and Methods: Diethylenetriaminepentaacetic acid-D-deoxy-glucosamine (DTPA-DG) was synthesized and examined for its activity as a cell-permeable iron chelator in human hepatocellular carcinoma (HEPG2) cell line exposed to high concentration of iron sulfate and compared with deferoxamine (DFO), a prototype iron chelator. The effect of DTPA-DG on cell viability was monitored using the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide MTT assay as well. Results: There was a significant increase of iron level after iron overload induction in HEPG2 cell culture. DTPA-DG presented a remarkable capacity to iron burden reducing with estimated 50% inhibitory concentration value of 65.77 nM. In fact, glycosyl moiety was gained access of DTPA to intracellular iron deposits through glucose transporter systems. Conclusion: DTPA-DG, more potent than DFO to sequester deposits of free iron with no profound toxic effect. The results suggest the potential of DTPA-DG in chelating iron and permitting its excretion from primary organ storage. PMID:24554907

  16. Role of pH in metal adsorption from aqueous solutions containing chelating agents on chitosan

    SciTech Connect

    Wu, F.C.; Tseng, R.L.; Juang, R.S.

    1999-01-01

    The role of pH in adsorption of Cu(II) from aqueous solutions containing chelating agents on chitosan was emphasized. Four chelating agents including ethylenediaminetetraacetic acid (EDTA), citric acid, tartaric acid, and sodium gluconate were used. It was shown that the adsorption ability of Cu(II) on chitosan from its chelated solutions varied significantly with pH variations. The competition between coordination of Cu(II) with unprotonated chitosan and electrostatic interaction of the Cu(II) chelates with protonated chitosan took place because of the change in solution pH during adsorption. The maximum adsorption capacity was obtained within each optimal pH range determined from titration curves of the chelated solutions. Coordination of Cu(II) with the unprotonated chitosan was found to dominate at pH below such an optimal pH value.

  17. Predicting stability constants of various chelating agents using QSAR technology

    SciTech Connect

    Okey, R.W.; Lin, S.W.; Hong, P.K.A.

    1995-12-31

    The practice of capturing metals from contaminated soil slurry often involves the use of organics as chelators. This work was undertaken to develop information on the molecular characteristics which optimize the removal or the complexation of cadmium, copper, lead and zinc. Quantitative structure-activity relationship (QSAR) technology was employed using special techniques developed for the determination of the correct set of variables. The linear free energy relationship was applied using a 183 case data set to obtain regression coefficients. Equations obtained are provided. The differences in the coefficients and variables may be used as a guide in selecting the optimum chelator for a specific metal. The use of QSAR technology appears effective in furthering the understanding of metal-chelator relationships. A variable set combining molecular connectivity indices and fragments or groups can be used to minimize the size of the data set required for a valid regression and for the avoidance of collinearity problems.

  18. Controlling lipid oxidation via a biomimetic iron chelating active packaging material.

    PubMed

    Tian, Fang; Decker, Eric A; Goddard, Julie M

    2013-12-18

    Previously, a siderophore-mimetic metal chelating active packaging film was developed by grafting poly(hydroxamic acid) (PHA) from the surface of polypropylene (PP) films. The objective of the current work was to demonstrate the potential applicability of this PP-g-PHA film to control iron-promoted lipid oxidation in food emulsions. The iron chelating activity of this film was investigated, and the surface chemistry and color intensity of films were also analyzed after iron chelation. In comparison to the iron chelating activity in the free Fe(3+) solution, the PP-g-PHA film retained approximately 50 and 30% of its activity in nitrilotriacetic acid (NTA)/Fe(3+) and citric acid/Fe(3+) solutions, respectively (pH 5.0), indicating a strong chelating strength for iron. The ability of PP-g-PHA films to control lipid oxidation was demonstrated in a model emulsion system (pH 3.0). PP-g-PHA films performed even better than ethylenediaminetetraacetic acid (EDTA) in preventing the formation of volatile oxidation products. The particle size and ζ potential results of emulsions indicated that PP-g-PHA films had no adverse effects on the stability of the emulsion system. Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) analysis suggested a non-migratory nature of the PP-g-PHA film surface. These results suggest that such biomimetic, non-migratory metal chelating active packaging films have commercial potential in protecting foods against iron-promoted lipid oxidation. PMID:24313833

  19. Toxicity of chelated iron (Fe-DTPA) in American cranberry

    Technology Transfer Automated Retrieval System (TEKTRAN)

    American cranberry (Vaccinium macrocarpon) is naturally adapted to environments with high concentrations of soluble iron. Yet, there is a need to further explore iron nutrition in cranberry given concerns of toxicity problems from irrigation with iron-rich water. This study investigated the threat o...

  20. Specific sequestering agents for iron and the actinides

    SciTech Connect

    Raymond, K.N.

    1983-06-01

    The transuranium actinide ions represent one unique environmental hazard associated with the waste of the nuclear power industry. A major component associated with that waste and a potential hazard is plutonium. The synthesis of metal-ion-specific complexing agents for ions such as Pu(IV) potentially represents a powerful new approach to many of the problems posed by waste treatment. This document is a progress report of a rational approach to the synthesis of such chelating agents based on the similarities of Pu(IV) and Fe(III), the structures of naturally-occurring complexing agents which are highly specific for Fe(III), and the incorporation of the same kinds of ligating groups present in the iron complexes to make octadentate complexes highly specific for plutonium. Both thermodynamic and animal test results indicate that a relatively high degree of success has already been achieved in this aim.

  1. The Iron Chelator, Dp44mT, Effectively Inhibits Human Oral Squamous Cell Carcinoma Cell Growth in Vitro and in Vivo

    PubMed Central

    Lee, Jehn-Chuan; Chiang, Kun-Chun; Feng, Tsui-Hsia; Chen, Yu-Jen; Chuang, Sung-Ting; Tsui, Ke-Hung; Chung, Li-Chuan; Juang, Horng-Heng

    2016-01-01

    Oral squamous cell carcinoma (OSCC) is a common malignancy with a growing worldwide incidence and prevalence. The N-myc downstream regulated gene (NDRG) family of NDRG1, 2, 3, and mammary serine protease inhibitor (Maspin) gene are well-known modulators in the neoplasia process. Current research has considered iron chelators as new anti-cancer agents; however, the anticancer activities of iron chelators and their target genes in OSCC have not been well investigated. We showed that iron chelators (Dp44mT, desferrioxamine (DFO), and deferasirox) all significantly inhibit SAS cell growth. Flow cytometry further indicated that Dp44mT inhibition of SAS cells growth was partly due to induction of G1 cell cycle arrest. Iron chelators enhanced expressions of NDRG1 and NDRG3 while repressing cyclin D1 expression in OSCC cells. The in vivo antitumor effect on OSCC and safety of Dp44mT were further confirmed through a xenograft animal model. The Dp44mT treatment also increased Maspin protein levels in SAS and OECM-1 cells. NDRG3 knockdown enhanced the growth of OECM-1 cells in vitro and in vivo. Our results indicated that NDRG3 is a tumor suppressor gene in OSCC cells, and Dp44mT could be a promising therapeutic agent for OSCC treatment. PMID:27589737

  2. The Iron Chelator, Dp44mT, Effectively Inhibits Human Oral Squamous Cell Carcinoma Cell Growth in Vitro and in Vivo.

    PubMed

    Lee, Jehn-Chuan; Chiang, Kun-Chun; Feng, Tsui-Hsia; Chen, Yu-Jen; Chuang, Sung-Ting; Tsui, Ke-Hung; Chung, Li-Chuan; Juang, Horng-Heng

    2016-01-01

    Oral squamous cell carcinoma (OSCC) is a common malignancy with a growing worldwide incidence and prevalence. The N-myc downstream regulated gene (NDRG) family of NDRG1, 2, 3, and mammary serine protease inhibitor (Maspin) gene are well-known modulators in the neoplasia process. Current research has considered iron chelators as new anti-cancer agents; however, the anticancer activities of iron chelators and their target genes in OSCC have not been well investigated. We showed that iron chelators (Dp44mT, desferrioxamine (DFO), and deferasirox) all significantly inhibit SAS cell growth. Flow cytometry further indicated that Dp44mT inhibition of SAS cells growth was partly due to induction of G1 cell cycle arrest. Iron chelators enhanced expressions of NDRG1 and NDRG3 while repressing cyclin D1 expression in OSCC cells. The in vivo antitumor effect on OSCC and safety of Dp44mT were further confirmed through a xenograft animal model. The Dp44mT treatment also increased Maspin protein levels in SAS and OECM-1 cells. NDRG3 knockdown enhanced the growth of OECM-1 cells in vitro and in vivo. Our results indicated that NDRG3 is a tumor suppressor gene in OSCC cells, and Dp44mT could be a promising therapeutic agent for OSCC treatment. PMID:27589737

  3. Iron removal from milk and other nutrient media with a chelating resin.

    PubMed

    Feng, M; van der Does, L; Bantjes, A; de Groote, J M

    1995-01-01

    A water-insoluble iron(III)-chelating resin was used to study iron removal from milk and other nutrient media. Seventy to 85% of the iron could be removed from wine and beer with the resin, which was a crosslinked copolymer of 1-(beta-acrylamidoethyl)-3-hydroxy-2-methyl-4(1H)- pyridinone and N,N-dimethylacrylamide. Iron removal from milk was dependent on the pH of milk and on the concentration of soluble chelators added. Under the same conditions as used for the removal of iron from wine and beer, only 11 to 19% of the iron could be removed from milk. However, in combination with water-soluble chelators, the resin removed 60 to 75% of the iron from the milk. Preliminary results showed that the growth of spores of Clostridium tyrobutyricum in the treated milk was reduced. Moreover, addition of the resin and sodium bicarbonate to the milk completely inhibited the growth of the spores. PMID:7738259

  4. Evolution of iron overload in patients with low-risk myelodysplastic syndrome: iron chelation therapy and organ complications.

    PubMed

    Remacha, Ángel F; Arrizabalaga, Beatriz; Villegas, Ana; Durán, María Soledad; Hermosín, Lourdes; de Paz, Raquel; Garcia, Marta; Diez Campelo, Maria; Sanz, Guillermo

    2015-05-01

    This study aimed to evaluate the evolution of iron overload, assessed by serum ferritin (SF), in transfusion-dependent lower risk patients with myelodysplastic syndrome (MDS), as well as to describe the occurrence of organ complications, and to analyze its relationship with iron chelation therapy. This observational retrospective study was conducted from March 2010 to March 2011 in 47 Spanish hospitals. A total of 263 patients with lower risk MDS (International Prognostic Scoring System [IPSS] low/intermediate-1 risk or Spanish Prognostic Index [SPI] 0-1 risk), transfusion-dependent, and who had received ≥10 packed red blood cells (PRBC) were included. At MDS diagnosis, patients received a mean of 2.8 ± 3.9 PRBC/month, and 8.7% of patients showed SF ≥1000 μg/L. Over the course of the disease, patients received a mean of 83.4 ± 83.3 PRBC, and 36.1% of patients presented SF ≥2500 μg/L. Cardiac, hepatic, endocrine, or arthropathy complications appeared/worsened in 20.2, 11.4, 9.9, and 3.8% of patients, respectively. According to investigator, iron overload was a main cause of hepatic (70.0%) and endocrine (26.9%) complications. A total of 96 (36.5%) patients received iron chelation therapy for ≥6 months, being deferasirox the most frequent first chelation treatment (71.9%). Chelation-treated patients showed longer overall survival (p < 0.001), leukemia-free survival (p = 0.007), and cardiac event-free survival (p = 0.017) than non-chelated patients. In multivariable analyses, age (p = 0.011), IPSS (p < 0.001), and chelation treatment (p = 0.015) were predictors for overall survival; IPSS (p = 0.014) and transfusion frequency (p = 0.001) for leukemia-free survival; and chelation treatment (p = 0.040) and Sorror comorbidity index (p = 0.039) for cardiac event-free survival. In conclusion, these results confirm the potential survival benefit of iron chelation therapy and provide additional evidence on the

  5. Chelation in metal intoxication XVI. Influence of chelating agents on chromate poisoned rats

    SciTech Connect

    Tandon, S.K.; Srivastava, L.

    1985-01-01

    The ability of selective polyaminocarboxylic acids and common drugs to reduce the body burden of chromium and restore Cr induced biochemical alterations in chromate intoxicated rats was investigated. 1,2 Cychlohexylene dinitrilotetraacetic acid (CDTA) and triethylenetetramine hexacetic acid (TTHA) were more effective than p-aminosalicylic acid (PAS) and isoniazid (INH) in enhancing urinary excretion of Cr, lowering hepatic and blood levels of Cr and restoring inhibited activity of hepatic aldolase. The chromate antidotal property of chelators seem to be related to the combination of nitrogen and oxygen as the electron donating centres.

  6. Combined Iron Chelator and Antioxidant Exerted Greater Efficacy on Cardioprotection Than Monotherapy in Iron-Overloaded Rats

    PubMed Central

    Wongjaikam, Suwakon; Kumfu, Sirinart; Khamseekaew, Juthamas; Sripetchwandee, Jirapas; Srichairatanakool, Somdet; Fucharoen, Suthat; Chattipakorn, Siriporn C.; Chattipakorn, Nipon

    2016-01-01

    Background Iron chelators are used to treat iron overload cardiomyopathy patients. However, a direct comparison of the benefits of three common iron chelators (deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX)) or an antioxidant (N-acetyl cysteine (NAC)) with a combined DFP and NAC treatments on left ventricular (LV) function with iron overload has not been investigated. Methods and Findings Male Wistar rats were fed with either a normal diet or a high iron diet (HFe group) for 4 months. After 2 months, the HFe-fed rats were divided into 6 groups to receive either: a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day) or the combined DFP and NAC for 2 months. Our results demonstrated that HFe rats had increased plasma non-transferrin bound iron (NTBI), malondialdehyde (MDA), cardiac iron and MDA levels and cardiac mitochondrial dysfunction, leading to LV dysfunction. Although DFO, DFP, DFX or NAC improved these parameters, leading to improved LV function, the combined DFP and NAC therapy caused greater improvement, leading to more extensively improved LV function. Conclusions The combined DFP and NAC treatment had greater efficacy than monotherapy in cardioprotection through the reduction of cardiac iron deposition and improved cardiac mitochondrial function in iron-overloaded rats. PMID:27428732

  7. (Bifunctional chelates of Rh-105, Au-199, and other metallic radionuclides as potential radiotherapeutic agents)

    SciTech Connect

    Not Available

    1991-01-01

    Progress during this period is reported under the following headings: Diethylenetriamine based and related bifunctional chelating agents and their complexation with Rh-105, Au-198, Pd-109, cu-67, In-111, and Co-57; studies of Pd-109, Rh-105 and Tc-99m with bifunctional chelates based on phenylenediamine; establishment of an appropriate protein assay method for conjugated proteins; studies of new bifunctional Bi, Tri and tetradentate amine oxime ligands with Rh-105; IgG and antibody B72.3 conjugation studies by HPLC Techniques with bifunctional metal chelates; and progress on ligand systems for Au(III).

  8. [Bifunctional chelates of Rh-105, Au-199, and other metallic radionuclides as potential radiotherapeutic agents

    SciTech Connect

    Not Available

    1991-12-31

    Progress during this period is reported under the following headings: Diethylenetriamine based and related bifunctional chelating agents and their complexation with Rh-105, Au-198, Pd-109, cu-67, In-111, and Co-57; studies of Pd-109, Rh-105 and Tc-99m with bifunctional chelates based on phenylenediamine; establishment of an appropriate protein assay method for conjugated proteins; studies of new bifunctional Bi, Tri and tetradentate amine oxime ligands with Rh-105; IgG and antibody B72.3 conjugation studies by HPLC Techniques with bifunctional metal chelates; and progress on ligand systems for Au(III).

  9. Potentiometric responses of polymeric liquid membranes based on hydrophobic chelating agents to metal ions.

    PubMed

    Itoh, Y; Ueda, Y; Hirano, A; Sugawara, M; Tohda, K; Akaiwa, H; Umezawa, Y

    2001-05-01

    The effect of hydrophobicity of acidic chelating agents as sensing materials on the potentiometric responses of polymeric liquid membranes was investigated. The chelating agents tested were 8-quinolinol (HOx), dithizone (HDz), 1-(2-pyridylazo)-2-naphthol (PAN) and their alkylated analogues, 5-octyloxymethyl-8-quinolinol (HO8Q), di(phexylphenyl)thiocarbazone (C6HDz), 7-pentadecyloxy-1-(2-pyridylazo)-2-naphthol (C15PAN) and a series of N-alkylcarbonyl-N-phenylhydroxylamines (CnPHA, n = 3, 6, 9, 12). The distribution coefficients between membrane solvent and water were determined to evaluate the hydrophobicity of the agents. The potential-pH profiles of the membranes containing hydrophobic chelating agents demonstrated the generation of potentiometric responses, while less hydrophobic agents gave no response. A possible model for the generation of membrane potential is proposed. The charge separation is attained by the permselective uptake of metal cations by the chelating agent anion at membrane/solution interface, where the high hydrophobicity of the agent enables the anionic or deprotonated form of the agents to remain at the membrane/solution interface.

  10. Efficiency of chelated iron compounds as catalysts for the Haber-Weiss reaction.

    PubMed

    Sutton, H C

    1985-01-01

    The oxidation of formate to CO2 has been used to quantify . OH yields produced in oxygenated solutions by chelated iron salts reacting either directly with H2O2 in the Fenton reaction, or as catalysts in the Haber-Weiss reaction between H2O2 and radiolytically generated superoxide. This system involves a chain sequence since . OH regenerates O2- when producing CO2. Kinetic studies have been employed to show that catalysis by Fe-EDTA occurs by reduction of Fe3+-EDTA by O2- followed by its reoxidation by H2O2, and to show how O2- is ultimately consumed. At pH 7.3 more than 50 . OH radicals can be produced per molecule of Fe-EDTA and CO2 yields can exceed five per molecule of radiolytically generated O2-. Iron chelated with pyrophosphate, DTPA, citrate, ATP or ADP in phosphate or Tris buffer at pH 7.3 has less than 7% of the catalytic ability of Fe-EDTA (considerably less in most cases) even though all these ferrous chelates give appreciable yields of . OH in the Fenton reaction. Unchelated iron has no catalytic ability. Catalysis of the Haber-Weiss reaction in homogenous solution by iron salts, either free or chelated with nucleotides or citrate, is evidently a very inefficient process, and its possible role in superoxide toxicity must be viewed with these reservations.

  11. Toxicology and safety of Ferrochel and other iron amino acid chelates.

    PubMed

    Jeppsen, R B

    2001-03-01

    Iron is estimated to be deficient in the diets of one fifth of the world's population. Iron is commonly provided as a supplemental nutrient in industrialized countries for uses of choice. In other countries of the world, it may be required as an overt addition to the diet to prevent iron deficiency. This may be accomplished through fortification of a common food. As a micronutrient, iron has a relatively narrow range of safety--whether given as a supplement or fortificant, it must be in a high enough dose to be appreciably absorbed, but low enough to avoid toxicity. This concern can be ameliorated by careful choice of the form of iron administered. A source of iron which has proven to be highly bioavailable, yet regulated by dietary need, is iron chelated with amino acids. The structural integrity and longevity of these compounds have been proven by valid chemical and instrumental tests. Proofs of safety of iron amino acid chelate in the dietary administration of iron to swine in both multigenerational and longevity studies are reported. Formal tests of toxicity utilizing ferrous bisglycinate chelate (Ferrochel) carried out in accordance to US-FDA guidelines are also summarized. Ferrochel has been demonstrated to have a No Observable Adverse Effect Level (NOAEL) of at least 500 mg per kg rat body weight, the highest dose tested. This and other results of the detailed toxicity test, as well as other tests of safety and efficacy, have resulted in the US-FDA acknowledging that this product is Generally Recognized As Safe (GRAS) under its approved conditions of use as a source of iron for food enrichment and fortification purposes.

  12. Detection of decontamination solution chelating agents using ion selective coated-wire electrodes

    SciTech Connect

    Banks, M.L.

    1992-12-31

    This thesis explores feasibility of using coated-wire electrodes to measure chelating agent concentration. Chelating agents are often found in radioactive decontamination solutions because they aid in the removal of radionuclides from contaminated surfaces by increasing their solubility. However, this characteristic will also enhance the mobility of the radionuclide and thus its transport out of a waste disposal site. Coated-wire ion selective electrodes, based on a polyvinylchloride membrane using dioctylphthalate as a plasticizer and dinonylnaphthalenesulfonic acid as a counterion, were constructed for five commonly utilized chelating agents (ethylenediaminetetracetic acid (EDTA), nitrilotriacetic acid (NTA), citric acid, oxalic acid and tartaric add). The EDTA and NTA electrodes` calibration characteristics exhibited acceptable behavior in pure standard solutions. From data obtained while using the EDTA and NTA electrodes in a cement environment, further research needs to be done in the area of ion interference.

  13. Oxidation of aqueous sulfur dioxide. 3. The effects of chelating agents and phenolic antioxidants

    SciTech Connect

    Lim, P.K.; Huss, A. Jr.; Eckert, C.A.

    1982-10-14

    The inhibiting effects of chelating agents (1,10-phenanthroline and EDTA) and phenolic antioxidants (phenol, hydroquinone, resorcinol, pyrocatechol, phloroglucinol, and pyrogallol) on the catalyzed oxidations of low- and high-pH aqueous S(IV) solutions were investigated. Both the low-pH Mn(II)- and Fe(II)-catalyzed reactions were inhibited by phenolic antioxidants, with the effect on the Mn(II)-catalyzed reaction being much more pronounced. The chelating agents, on the other hand, had a far greater inhibiting influence on the Fe(II)-catalyzed reaction. The high-pH Cu(II)-catalyzed reaction was markedly inhibited by both chelating agents and antioxidants. The results support our previous conclusion that the previously accepted uncatalyzed oxidations of S(IV) were in fact primarily trace-metal catalyzed. 7 figures.

  14. Antimalarial Iron Chelator FBS0701 Blocks Transmission by Plasmodium falciparum Gametocyte Activation Inhibition

    PubMed Central

    Ferrer, Patricia; Vega-Rodriguez, Joel; Tripathi, Abhai K.; Jacobs-Lorena, Marcelo

    2014-01-01

    Reducing the transmission of the malarial parasite by Anopheles mosquitoes using drugs or vaccines remains a main focus in the efforts to control malaria. Iron chelators have been studied as potential antimalarial drugs due to their activities against different stages of the parasite. The iron chelator FBS0701 affects the development of Plasmodium falciparum early gametocytes and lowers blood-stage parasitemia. Here, we tested the effect of FBS0701 on stage V gametocyte infectivity for mosquitoes. The incubation of stage V gametocytes for up to 3 days with increasing concentrations of FBS0701 resulted in a significant dose-related reduction in mosquito infectivity, as measured by the numbers of oocysts per mosquito. The reduction in mosquito infectivity was due to the inhibition of male and female gametocyte activation. The preincubation of FBS0701 with ferric chloride restored gametocyte infectivity, showing that the inhibitory effect of FBS0701 was quenched by iron. Deferoxamine, another iron chelator, also reduced gametocyte infectivity but to a lesser extent. Finally, the simultaneous administration of drug and gametocytes to mosquitoes without previous incubation did not significantly reduce the numbers of oocysts. These results show the importance of gametocyte iron metabolism as a potential target for new transmission-blocking strategies. PMID:25512427

  15. Effect of chelating agents and solubility of cadmium complexes on uptake from soil by Brassica juncea.

    PubMed

    Van Engelen, Debra L; Sharpe-Pedler, Rachel C; Moorhead, Kevin K

    2007-06-01

    Brassica juncea, or Indian mustard, was grown in soil artificially contaminated with either a soluble salt, CdCl(2), at 186mg Cdkg(-1), or alternately an insoluble, basic salt, CdCO(3), at 90mg Cdkg(-1). These experiments study the range of Cd uptake by Indian mustard from conditions of very high Cd concentration in a soluble form to the other extreme with an insoluble Cd salt. After plants were established, four different chelating agents were applied. Chelating agents increased plant uptake of Cd from the CdCl(2) soil but did not significantly increase plant uptake of Cd from the CdCO(3) contaminated soil. Addition of ethylenediaminetetraacetic acid (EDTA) increased the plant concentration of Cd by almost 10-fold in soils contaminated with CdCl(2), with a concentration of 1283mg Cdkg(-1) in the dried EDTA-treated plants over a concentration of 131mg Cdkg(-1) in plants without added chelate. However, EDTA increased the aqueous solubility of Cd by 36 times over the soil matrix without added chelator, and thereby, increased the possibility of leaching. Other chelators used in both experiments were ethylenebis(oxyethylenenitrilo)tetraacetic acid, trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid, and diethylenetriaminepentaacetic acid (DTPA) increasing Cd in plants to 1240, 962, and 437mg Cdkg(-1), respectively. The other chelating agents increased the solubility of Cd in the leachate but not to the extent of EDTA. Comparing all chelating agents studied, DTPA increased plant uptake in terms of Cd in dried plant concentration most relative to the solubility of complexed Cd in runoff water.

  16. Involvement of type VI secretion system in secretion of iron chelator pyoverdine in Pseudomonas taiwanensis

    PubMed Central

    Chen, Wen-Jen; Kuo, Tzu-Yen; Hsieh, Feng-Chia; Chen, Pi-Yu; Wang, Chang-Sheng; Shih, Yu-Ling; Lai, Ying-Mi; Liu, Je-Ruei; Yang, Yu-Liang; Shih, Ming-Che

    2016-01-01

    Rice bacterial blight caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of the most destructive rice diseases worldwide. Therefore, in addition to breeding disease-resistant rice cultivars, it is desirable to develop effective biocontrol agents against Xoo. Here, we report that a soil bacterium Pseudomonas taiwanensis displayed strong antagonistic activity against Xoo. Using matrix-assisted laser desorption/ionization imaging mass spectrometry, we identified an iron chelator, pyoverdine, secreted by P. taiwanensis that could inhibit the growth of Xoo. Through Tn5 mutagenesis of P. taiwanensis, we showed that mutations in genes that encode components of the type VI secretion system (T6SS) as well as biosynthesis and maturation of pyoverdine resulted in reduced toxicity against Xoo. Our results indicated that T6SS is involved in the secretion of endogenous pyoverdine. Mutations in T6SS component genes affected the secretion of mature pyoverdine from the periplasmic space into the extracellular medium after pyoverdine precursor is transferred to the periplasm by the inner membrane transporter PvdE. In addition, we also showed that other export systems, i.e., the PvdRT-OpmQ and MexAB-OprM efflux systems (for which there have been previous suggestions of involvement) and the type II secretion system (T2SS), are not involved in pyoverdine secretion. PMID:27605490

  17. Involvement of type VI secretion system in secretion of iron chelator pyoverdine in Pseudomonas taiwanensis.

    PubMed

    Chen, Wen-Jen; Kuo, Tzu-Yen; Hsieh, Feng-Chia; Chen, Pi-Yu; Wang, Chang-Sheng; Shih, Yu-Ling; Lai, Ying-Mi; Liu, Je-Ruei; Yang, Yu-Liang; Shih, Ming-Che

    2016-01-01

    Rice bacterial blight caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of the most destructive rice diseases worldwide. Therefore, in addition to breeding disease-resistant rice cultivars, it is desirable to develop effective biocontrol agents against Xoo. Here, we report that a soil bacterium Pseudomonas taiwanensis displayed strong antagonistic activity against Xoo. Using matrix-assisted laser desorption/ionization imaging mass spectrometry, we identified an iron chelator, pyoverdine, secreted by P. taiwanensis that could inhibit the growth of Xoo. Through Tn5 mutagenesis of P. taiwanensis, we showed that mutations in genes that encode components of the type VI secretion system (T6SS) as well as biosynthesis and maturation of pyoverdine resulted in reduced toxicity against Xoo. Our results indicated that T6SS is involved in the secretion of endogenous pyoverdine. Mutations in T6SS component genes affected the secretion of mature pyoverdine from the periplasmic space into the extracellular medium after pyoverdine precursor is transferred to the periplasm by the inner membrane transporter PvdE. In addition, we also showed that other export systems, i.e., the PvdRT-OpmQ and MexAB-OprM efflux systems (for which there have been previous suggestions of involvement) and the type II secretion system (T2SS), are not involved in pyoverdine secretion. PMID:27605490

  18. Iron chelation with deferasirox in a patient with de-novo ferroportin mutation.

    PubMed

    Unal, Sule; Piperno, Alberto; Gumruk, Fatma

    2015-04-01

    Ferroportin disease is a rare type of autosomal dominantly inherited hemochromatosis caused with mutations in the ferroportin gene (SLC40A1). The patients characteristically have hyperferritinemia but normal transferin saturations. Herein, we present a 15-year-old female whose chief complaint was persistent nausea for the last one year. Extensive work-up including brain imaging revealed nothing to explain the etiology of nausea. The serum ferritin level of 1474ng/mL was suggestive for hemochromatosis syndromes and the molecular testing revealed de-novo c.485_487delTTG (P.Val162del) ferroportin gene mutation. Mild hepatic iron loading, in addition to the cumbersome nausea were accepted as indications for chelation treatment in this particular patient and deferasirox was initiated (10mg/kg/day) since family did not consent for phlebotomy. Deferasirox was stopped by the 9th month of initiation, since nausea subsided and hepatic iron content was normalized, in order to prevent over chelation. There are no well-established guidelines for the chelation of patients with hereditary hemochromatosis syndromes. However, lifelong monitorization for iron loading and re-initiation of chelation when necessary was planned in our patient.

  19. Geographical variations in current clinical practice on transfusions and iron chelation therapy across various transfusion-dependent anaemias

    PubMed Central

    Viprakasit, Vip; Gattermann, Norbert; Lee, Jong Wook; Porter, John B.; Taher, Ali T.; Habr, Dany; Martin, Nicolas; Domokos, Gabor; Cappellini, Maria Domenica

    2013-01-01

    Background and objectives Many patients with chronic anaemia require blood transfusions as part of their treatment regimen. As a result, iron overload will inevitably develop if not adequately managed by iron chelation therapy. There are many guidelines relating to transfusion and chelation practices for patients with transfusion-dependent anaemia; however, there is a lack of information on how treatment practices differ around the world. The objective of this manuscript is to highlight key features of current transfusion and chelation management, including similarities and differences across various anaemias and between geographical regions worldwide. Materials and methods Data collected at study entry to the multicentre Evaluation of Patients’ Iron Chelation with Exjade (EPIC) study, which recruited 1,744 patients with a variety of transfusion-dependent anaemias across 23 countries from three geographic regions, were assessed. These analyses compared transfusion and chelation treatment prior to the start of study treatment, together with iron burden assessed at study entry by serum ferritin, liver iron concentration and labile plasma iron levels. Results and conclusions Data show that transfusion and iron chelation practices differ between anaemias and between geographical regions; this may be linked to availability and accessibility of transfusion and chelation therapy, patients’ compliance, physicians’ attitudes, costs and use of treatment guidelines. Approximately 60% of these transfusion-dependent patients were severely iron overloaded with a serum ferritin level over 2,500 ng/mL, indicating that the risks of iron burden may have been underestimated and current iron chelation therapy, if considered, may not have been adequate to control iron burden. PMID:22871821

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-02-01

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

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

    PubMed

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

    2016-02-01

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

  3. Alteration of tissue disposition of cadmium by chelating agents. [Mice; rats

    SciTech Connect

    Klaassen, C.D.; Waalkes, M.P.; Cantilena, L.R. Jr.

    1984-03-01

    The effect of several chelating agents (diethyldithiocarbamic acid, DDC; nitrilotriacetic acid, NTA; 2,3-dimercaptopropanol, BAL; d,l-penicillamine, PEN; 2,3-dimercaptosuccinic acid, DMSA; ethylenediaminetetraacetic acid, EDTA; and diethylenetriaminepentaacetic acid, DTPA) on the toxicity, distribution and excretion of cadmium (Cd) was determined in mice. When chelators were administered immediately after Cd, significant increases in survival were noted after treatment with DMSA, EDTA, and DTPA. DTPA, followed by EDTA and then DMSA, were consistently the most effective in decreasing the tissue concentrations of Cd and increasing the excretion of Cd. NTA, BAL, DDC and PEN had no beneficial effects. To determine the role of MT in the acute decrease in chelator efficacy following Cd poisoning, rats were injected IV with Cd followed by DTPA at various times after Cd. Although DTPA reduced Cd content in the various organs when given immediately after Cd, the chelator was ineffective at all later times. Increases in hepatic and renal metallothionein (MT) did not occur until 2 hr after Cd, and did not coincide with the earlier drop in chelator efficacy. Blockade of MT synthesis by actinomycin D failed to eliminate this decreased DTPA effectiveness. Therefore, it appears that MT does not play an important role in the acute decrease in efficacy of chelation therapy for Cd poisoning. The effect of repeated daily administration of chelators on the distribution and excretion of Cd was studied by administering chelators daily for 5 days starting 48 hr after Cd. DTPA, EDTA, DMSA and BAL significantly increased the urinary elimination of Cd. Thus, mobilization of Cd into urine occurs with repeated chelation therapy, which may decrease tissue concentrations of Cd and reduce the toxicity of the metal. 4 references, 15 figures, 2 tables.

  4. Antimicrobial action of chelating agents: repercussions on the microorganism development, virulence and pathogenesis.

    PubMed

    Santos, A L S; Sodre, C L; Valle, R S; Silva, B A; Abi-Chacra, E A; Silva, L V; Souza-Goncalves, A L; Sangenito, L S; Goncalves, D S; Souza, L O P; Palmeira, V F; d'Avila-Levy, C M; Kneipp, L F; Kellett, A; McCann, M; Branquinha, M H

    2012-01-01

    Infections caused by resistant microorganisms often fail to respond to conventional therapy, resulting in prolonged illness, increased treatment costs and greater risk of death. Consequently, the development of novel antimicrobial drugs is becoming more demanding every day since the existing drugs either have too many side-effects or they tend to lose effectiveness due to the selection of resistant strains. In view of these facts, a number of new strategies to obstruct vital biological processes of a microbial cell have emerged; one of these is focused on the use of metal-chelating agents, which are able to selectively disturb the essential metal metabolism of the microorganism by interfering with metal acquisition and bioavailability for crucial reactions. The chelation activity is able to inhibit the biological role of metal-dependent proteins (e.g., metalloproteases and transcription factors), disturbing the microbial cell homeostasis and culminating in the blockage of microbial nutrition, growth and development, cellular differentiation, adhesion to biotic (e.g., extracellular matrix components, cell and/or tissue) and abiotic (e.g., plastic, silicone and acrylic) structures as well as controlling the in vivo infection progression. Interestingly, chelating agents also potentiate the activity of classical antimicrobial compounds. The differences between the microorganism and host in terms of the behavior displayed in the presence of chelating agents could provide exploitable targets for the development of an effective chemotherapy for these diseases. Consequently, metal chelators represent a novel group of antimicrobial agents with potential therapeutic applications. This review will focus on the anti-fungal and anti-protozoan action of the most common chelating agents, deciphering and discussing their mode of action.

  5. [Extraction of Heavy Metals from Sludge Using Biodegradable Chelating Agent N,N-bis(carboxymethyl) Glutamic Acid Tetrasodium].

    PubMed

    Wu, Qing; Cui, Yan-rui; Tang, Xiao-xiao; Yang, Hui-juan; Sun, Jian-hui

    2015-05-01

    N, N-bis (carboxymethyl) glutamic acid tetrasodium (GLDA), a novel biodegradable and green chelating agent, has excellent metal chelating ability. Batch experiment was conducted to study the extraction process of Cd, Ni, Cu and Zn in industrial sludge using GLDA. The effects of contact time, pH of the system, content of chelating agent were investigated, and the forms of heavy metals in sludge pre- and post-extraction using the modified BCR sequential extraction procedure were studied. The results showed that GLDA was effective for cadmium extraction in sludge. Several heavy metals could be effectively extracted under the condition of pH 4 and molar ratio of chelating agent to total heavy metal 3:1. Residual fraction took the largest fraction in Zn, which caused the low extraction efficiency of this metal. Chelating properties were related not only to contact time, pH, chelating agent's concentration, and stability constant but also to species distribution of metals.

  6. Chelating Properties of Peptides from Red Seaweed Pyropia columbina and Its Effect on Iron Bio-Accessibility.

    PubMed

    Cian, Raúl E; Garzón, Antonela G; Ancona, David Betancur; Guerrero, Luis Chel; Drago, Silvina R

    2016-03-01

    The aim of this work was to evaluate copper-chelating, iron-chelating and anticariogenic activity of peptides obtained by enzymatic hydrolysis of P. columbina protein concentrate and to study the effects of chelating peptides on iron bio-accessibility. Two hydrolyzates were obtained from P. columbina protein concentrate (PC) using two hydrolysis systems: alkaline protease (A) and alkaline protease + Flavourzyme (AF). FPLC gel filtration profile of PC shows a peak having molecular weight (MW) higher than 7000 Da (proteins). A and AF hydrolyzates had peptides with medium and low MW (1013 and 270 Da), respectively. Additionally, AF presented free amino acids with MW around 82 Da and higher content of His and Ser. Peptides from AF showed the highest chelating properties measured as copper-chelating activity (the lowest β-carotene oxidation rate: Ro; 0.7 min(-1)), iron-chelating activity (33%), and phosphorous and Ca(2+) release inhibition (87 and 81%, respectively). These properties could indicate antioxidant properties, promotion of iron absorption and anticariogenic activity, respectively. In fact, hydrolyzates promoted iron dialyzability (≈ 16%), values being higher than that found for P. columbina seaweed. Chelating peptides from both hydrolyzates can maintain the iron in a soluble and bio-accessible form after gastrointestinal digestion. PMID:26860526

  7. Mobilization of intracellular iron by analogs of pyridoxal isonicotinoyl hydrazone (PIH) is determined by the membrane permeability of the iron-chelator complexes.

    PubMed

    Buss, Joan L; Arduini, Emmanuele; Ponka, Prem

    2002-12-15

    In the ongoing search for an effective, orally active iron-chelator, the capacity of a series of halogenated analogs of pyridoxal isonicotinoyl hydrazone (PIH) to bind intracellular 59Fe and cause its release from cells was investigated. Reticulocytes labeled with 59Fe(2)-transferrin in which heme synthesis was inhibited by succinylacetone were used as a model of 59Fe mobilization. The kinetics of iron binding were similar for all the chelators tested (half-time of approximately 1 hr), and all bound more than twice as much 59Fe as PIH. The rate of release of the 59Fe-chelator complexes from cells depended upon the structure of the chelators. Ortho-substituted analogs were more effective at mobilizing cellular iron than meta and para isomers, due to a more efficient release of the iron complexes from the cell. The iron-chelator complexes which were released slowly from cells had a high affinity for erythrocyte ghost membranes, indicating the role of membrane permeability in the release mechanism of the complexes. The addition of BSA to the extracellular medium increased the extent of iron release by lipophilic analogs in a concentration-dependent manner, presumably by acting as a sink for the lipophilic complexes. The affinity of BSA for the chelators and their Fe(3+) complexes, determined spectrophotometrically, demonstrated that all chelators and their iron complexes bound BSA with dissociation constants ranging from 7,000 to >500,000 M(-1). Understanding the importance of the rate of release of the iron-chelator complex will direct the search for iron-chelators with improved efficacy.

  8. In vitro antioxidant properties of the iron chelator pyridoxal isonicotinoyl hydrazone and some of its analogs.

    PubMed

    Schulman, H M; Hermes-Lima, M; Wang, E M; Ponka, P

    1995-11-01

    Since there are several problems with desferrioxamine (DFO) therapy, pyridoxal isonicotinoyl hydrazone (PIH) has been studied for more than 10 years as a promising new candidate for iron chelation therapy in iron-overload diseases. Iron chelation could also be helpful for experimental treatment of several other pathologies including rheumatoid arthritis and heart ischemia/reperfusion, due to the generation of oxyradicals and lipid peroxidation mediated by delocalized iron. We demonstrate here that sub-millimolar levels of PIH can inhibit the Fe(III)-EDTA/ascorbate-mediated formation of hydroxyl-like radicals as tested by the release of ethylene from 2-keto-4-methylthiobutyric acid (KMB assay) and the formation of malonaldehyde from 2-deoxyribose damage. PIH could also decrease the rates of Fe(III)-EDTA-mediated oxidation of ascorbate and block the peroxidation of liposomes of rat brain phospholipids induced by ferrous iron-EDTA. In all cases the in vitro antioxidant effectiveness of PIH was comparable to its analogs-including salicylaldehyde isonicotinoyl hydrazone-and to DFO. We conclude that PIH and its analogs are effective new candidates against iron-mediated oxidative stress for use in experimental medicine. PMID:27405837

  9. Crystallization kinetics and densification of YAG nanoparticles from various chelating agents

    SciTech Connect

    Hou, J.G.; Kumar, R.V.; Qu, Y.F.; Krsmanovic, Dalibor

    2009-08-05

    Yttrium aluminium garnet (YAG, Y{sub 3}Al{sub 5}O{sub 12}) nanoparticles were prepared using sonochemical sol-gel method with three different chelating agents and the effect of crystallization kinetics was investigated with differential scanning calorimetry-thermogravimetry (DSC-TG). The activation energy values of crystallization for the as-synthesized YAG nanoparticles using citric acid (CA), glycine (G) or a mixture of citric acid-glycine (CA-G), as chelating agents were found to be 160.5, 142.2 and 140.4 kJ mol{sup -1} and the corresponding Avarami constants were 2.2, 2.1 and 1.9, respectively. Samples produced with the mixed chelating agent under sonification, could be crystallized to single phase YAG nanoparticles (10-65 nm) after annealing at 1100 deg. C. Pellets made from the annealed YAG particles could be sintered to a relative density greater than 99% at 1500 deg. C with a grain size of 4.5 {mu}m, made up of secondary particles formed from primary nano-crystals within the grains. Grain size and relative density increased with different chelating agents from CA to G and CA-G in the increasing order when YAG samples were sintered. Grain growth and densification occurred at a relatively low temperature of 1500 deg. C as compared to over 1800 deg. C in solid-state reactions.

  10. 21 CFR 176.150 - Chelating agents used in the manufacture of paper and paperboard.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Chelating agents used in the manufacture of paper and paperboard. 176.150 Section 176.150 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) INDIRECT FOOD...

  11. Extraction of Micronutrient Metals from Peat-based Media Using Various Chelate-ligand and Iron-source Extractants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objectives of the study were to determine effects of chelate-ligand (experiment 1) and iron-source (experiment 2) unbuffrered extractant solutions on substrate pH and Cu, Fe, Mn, and Zn extraction from peat-based media. Chelate-ligand extractants consisted of 5 mM solutions of ethylenediaminedisucc...

  12. Heart cells in culture: a model of myocardial iron overload and chelation.

    PubMed

    Link, G; Pinson, A; Hershko, C

    1985-08-01

    The effect of iron loading and chelation was studied in heart cell cultures obtained from newborn rats. Radioactive iron uptake per 2 X 10(6) cells/24 hr was 3.8% for 59Fe-transferrin, 15.8% for 59Fe-ferric ammonium citrate (FeAC) at 20 micrograms Fe/ml in 20% serum, and 37.1% for 59FeAC at 20 micrograms Fe/ml in serum-free medium. About one third of the cellular radioactive iron was in ferritin and the rest in an insoluble lysosomal fraction. Iron uptake was almost completely inhibited by reducing the incubation temperature from 37 degrees C to 10 degrees C. Intracellular concentrations of malonyldialdehyde (MDA) were doubled after 15 minutes of iron loading and reached maximal concentrations at 3 hours. Conversely, iron mobilization by deferoxamine at concentrations ranging from 0.025 mmol/L to 0.3 mmol/L resulted in normalization of cellular MDA concentrations, in direct proportion to the amounts of iron removed. These findings indicate that cultured myocardial cells are able to assimilate large amounts of nontransferrin iron and that iron uptake and mobilization are associated with striking changes in lipid peroxidation as manifested by the respective increase and decrease in cellular MDA concentrations.

  13. Heart cells in culture: a model of myocardial iron overload and chelation

    SciTech Connect

    Link, G.; Pinson, A.; Hershko, C.

    1985-08-01

    The effect of iron loading and chelation was studied in heart cell cultures obtained from newborn rats. Radioactive iron uptake per 2 X 10(6) cells/24 hr was 3.8% for /sup 59/Fe-transferrin, 15.8% for /sup 59/Fe-ferric ammonium citrate (FeAC) at 20 micrograms Fe/ml in 20% serum, and 37.1% for /sup 59/FeAC at 20 micrograms Fe/ml in serum-free medium. About one third of the cellular radioactive iron was in ferritin and the rest in an insoluble lysosomal fraction. Iron uptake was almost completely inhibited by reducing the incubation temperature from 37 degrees C to 10 degrees C. Intracellular concentrations of malonyldialdehyde (MDA) were doubled after 15 minutes of iron loading and reached maximal concentrations at 3 hours. Conversely, iron mobilization by deferoxamine at concentrations ranging from 0.025 mmol/L to 0.3 mmol/L resulted in normalization of cellular MDA concentrations, in direct proportion to the amounts of iron removed. These findings indicate that cultured myocardial cells are able to assimilate large amounts of nontransferrin iron and that iron uptake and mobilization are associated with striking changes in lipid peroxidation as manifested by the respective increase and decrease in cellular MDA concentrations.

  14. CIPK23 is involved in iron acquisition of Arabidopsis by affecting ferric chelate reductase activity.

    PubMed

    Tian, Qiuying; Zhang, Xinxin; Yang, An; Wang, Tianzuo; Zhang, Wen-Hao

    2016-05-01

    Iron deficiency is one of the major limiting factors affecting quality and production of crops in calcareous soils. Numerous signaling molecules and transcription factors have been demonstrated to play a regulatory role in adaptation of plants to iron deficiency. However, the mechanisms underlying the iron deficiency-induced physiological processes remain to be fully dissected. Here, we demonstrated that the protein kinase CIPK23 was involved in iron acquisition. Lesion of CIPK23 rendered Arabidopsis mutants hypersensitive to iron deficiency, as evidenced by stronger chlorosis in young leaves and lower iron concentration than wild-type plants under iron-deficient conditions by down-regulating ferric chelate reductase activity. We found that iron deficiency evoked an increase in cytosolic Ca(2+) concentration and the elevated Ca(2+) would bind to CBL1/CBL9, leading to activation of CIPK23. These novel findings highlight the involvement of calcium-dependent CBL-CIPK23 complexes in the regulation of iron acquisition. Moreover, mutation of CIPK23 led to changes in contents of mineral elements, suggesting that CBL-CIPK23 complexes could be as "nutritional sensors" to sense and regulate the mineral homeostasis in Arabisopsis.

  15. Biodegradable chelating agents for industrial, domestic, and agricultural applications--a review.

    PubMed

    Pinto, Isabel S S; Neto, Isabel F F; Soares, Helena M V M

    2014-10-01

    Aminopolycarboxylates, like ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA), are chelating agents widely used in several industrial, agricultural, and domestic applications. However, the fact that they are not biodegradable leads to the presence of considerable amounts in aquatic systems, with serious environmental consequences. The replacement of these compounds by biodegradable alternatives has been the object of study in the last three decades. This paper reviews the most relevant studies towards the use of environmentally friendly chelating agents in a large number of applications: oxidative bleaching, detergents and cleaning compositions, scale prevention and reduction, remediation of soils, agriculture, electroplating, waste treatment, and biocides. Nitrilotriacetic acid (NTA), ethylenediaminedisuccinic acid (EDDS), and iminodisuccinic acid (IDS) are the most commonly suggested to replace the nonbiodegradable chelating agents. Depending on the application, the requirements for metal complexation might differ. Metal chelation ability of the most promising compounds [NTA, EDDS, IDS, methylglycinediacetic acid (MGDA), L-glutamic acid N,N-diacetic acid (GLDA), ethylenediamine-N,N'-diglutaric acid (EDDG), ethylenediamine-N,N'-dimalonic acid (EDDM), 3-hydroxy-2,2-iminodisuccinic acid (HIDS), 2-hydroxyethyliminodiacetic acid (HEIDA), pyridine-2,6-dicarboxylic acid (PDA)] with Fe, Mn, Cu, Pb, Cd, Zn, Ca, and Mg was simulated by computer calculations. The advantages or disadvantages of each compound for the most important applications were discussed.

  16. Changes in transferrin saturation after treatment with the oral iron chelator deferiprone in patients with iron overload.

    PubMed Central

    al-Refaie, F N; De Silva, C E; Wonke, B; Hoffbrand, A V

    1995-01-01

    AIMS--To evaluate the changes in transferrin saturation in patients with iron overload following the oral administration of the iron chelator deferiprone; to assess the correlation between the degree of transferrin desaturation, the deferiprone dose, and urinary iron excretion. METHODS--Serum samples were obtained from 16 patients with iron overload at different time intervals following the oral administration of deferiprone (50 mg/kg). These samples were analysed using 6M urea/polyacrylamide gel electrophoresis (UPAGE). This method is able to resolve serum transferrin into four different forms (free iron, two forms of monoferric, and diferric). The deferiprone concentration in these samples was estimated using high pressure liquid chromatography (HPLC). Zero time samples (t0) from 10 patients were incubated with 150 microM deferiprone or normal saline either at room temperature or at 37 degrees C for 30 minutes and 24 hours, and also at -20 degrees C for six weeks. Samples were then analysed using UPAGE. RESULTS--A maximum decrease in transferrin saturation from (mean (SD)) 93.0 (10.6)% to 54.5 (17.2)% was observed 72.5 (50.0) minutes after deferiprone administration and in most of the patients coincided with peak deferiprone concentration. This was associated with a maximum rise in the percentage of iron free transferrin (apotransferrin) from 2.9 (7.0)% to 27.3 (17.8)%. The total amount of iron estimated to be removed from transferrin constituted 21.3 (20.2)% of the 24 hour urinary iron excretion measured during the study. When deferiprone (150 mumol/l) was incubated in vitro with t0 samples from 10 patients for 30 minutes and 24 hours at room temperature, 37 degrees C, and at -20 degrees C for six weeks, deferiprone was more efficient at removing iron from transferrin at 37 degrees C, with maximum transferrin desaturation accomplished within 30 minutes compared with 24 hours at room temperature. CONCLUSIONS--The results confirm that deferiprone can remove iron

  17. Preparation and Bioavailability Analysis of Ferrous Bis Alanine Chelate as a New Micronutrient for Treatment of Iron Deficiency Anemia

    PubMed Central

    Zargaran, Marzieh; Saadat, Ebrahim; Dinarvand, Rassoul; Sharifzadeh, Mohammad; Dorkoosh, Farid

    2016-01-01

    Purpose: One of the most nutritional disorders around the world is iron deficiency. A novel iron compound was synthesized by chelating ferrous ions with alanine for prevention and treatment of iron deficiency anemia. Methods: The newly synthesized compound was characterized both qualitatively and quantitatively by Fourier Transform Infrared (FT-IR) spectroscopy. The bioavailability of newly synthesized iron micronutrient was evaluated in four groups of Wistar rats. The group I was a negative control group and the other three groups received three different iron formulations. After 14 days, the blood samples were taken and analyzed accordingly. Results: Calculations showed that more than 91.8% of iron was incorporated in the chelate formulation. In vivo studies showed that serum iron, total iron binding capacity and hemoglobin concentrations were significantly increased in group IV, which received ferrous bis alanine chelate compared with the negative control group (p<0.05) and also group II, which received ferrous sulfate.7H2O (p<0.05). It indicates that the new formulation considerably improves the blood iron status compared with the conventional iron compounds. There were no significant differences (p<0.05) in the serum iron between group IV and group III, which received ferrous bis glycine. Conclusion: The results showed better bioavailability of ferrous bis alanine as a new micronutrient for treatment of iron deficiency anemia in comparison with ferrous sulfate. Ferrous bis alanine could be considered as a suitable supplement for prevention and treatment of iron deficiency anemia. PMID:27766225

  18. Iron chelation in myocardial preservation after ischemia-reperfusion injury: the importance of pretreatment and toxicity.

    PubMed

    DeBoer, D A; Clark, R E

    1992-03-01

    Oxygen-derived free radicals have been implicated in myocardial ischemia-reperfusion injury. It has been proposed that deferoxamine, an iron chelator, improves myocardial preservation by reducing the iron-catalyzed production of the hydroxyl radical. The objectives of this study were to define the appropriate timing of iron chelation therapy and the dose-response properties of deferoxamine. Isolated working rat hearts were subjected to 25 minutes of normothermic global ischemia. Deferoxamine was given as pretreatment (n = 39; doses of 10 or 30 mg/kg), added to cardioplegic solution (n = 43; doses 0.46 to 1.90 mmol/L), or administered upon reperfusion (n = 52; doses 0.15 to 0.76 mmol/L) and compared with saline controls (n = 25). Deferoxamine pretreatment improved survival at each dose from a control value of 44% to 71% and 72% (p less than 0.05), respectively. A cardioplegia dose of 0.46 mmol/L improved survival from 48% to 75%. Higher doses reduced survival and implied a toxic effect. Reperfusion therapy did not alter survival. Regardless of time of administration, deferoxamine did not improve ventricular function or adenosine triphosphate levels. Deferoxamine given as pretreatment 1 hour before ischemia at doses of 30 mg/kg, and perhaps as low as 10 mg/kg, significantly improved survival. The addition of deferoxamine to cardioplegic solution was safe and may be protective at approximately 0.50 mmol/L; however, toxicity should be considered at concentrations greater than 0.76 mmol/L. These data support the postulate that iron catalysis is involved in the production of oxygen-derived free radicals during ischemia-reperfusion injury. We conclude that pretreatment before ischemia is an important component of iron chelation therapy in myocardial preservation.

  19. Iron-Chelating Activity of Tetracyclines and Its Impact on the Susceptibility of Actinobacillus actinomycetemcomitans to These Antibiotics

    PubMed Central

    Grenier, Daniel; Huot, Marie-Pierre; Mayrand, Denis

    2000-01-01

    Three tetracyclines (tetracycline, doxycycline, and minocycline) were found to possess iron-chelating activity in a colorimetric siderophore assay. Determination of MICs indicated that the activity of doxycycline against the periodontopathogen Actinobacillus actinomycetemcomitans was only slightly influenced by the presence of an excess of iron that likely saturates the antibiotic. On the other hand, the MICs of doxycycline and minocycline were significantly lower for A. actinomycetemcomitans cultivated under iron-poor conditions than under iron-rich conditions. PMID:10681353

  20. Iron chelators and free radical scavengers in naturally occurring polyhydroxylated 1,4-naphthoquinones.

    PubMed

    Lebedev, Alexander V; Ivanova, Marina V; Levitsky, Dmitri O

    2008-01-01

    The cardioprotective effect of polyhydroxylated 1,4-naphthoquinones on the experimental model of myocardial ischemia-reperfusion has been demonstrated previously. In this study, using different models, such as bulk organic phase, liposomes and sarcoplasmic reticulum (SR) vesicles, we have shown the ability of naturally occurring polyhydroxynaphthoquinones, echinochrome (Ech), spinochromes C, D and E (SpC, SpD and SpE) to inhibit free-radical oxidation induced by heme iron (hemin) or by free iron ions (in ferrous/ascorbate system). The polyhydroxy-1,4-naphthoquinones (PHNQs) were more effective in inhibiting the phosphatidyl choline liposome peroxidation induced by ferrous/ascorbate than that induced by hemin. The iron chelating ability of PHNQs was determined spectrophotometrically. Prevention of the ferrous/ascorbate-induced leakage of calcium by Ech was demonstrated in isolated SR vesicles from rabbit skeletal muscle. The PHNQs displayed high scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals. We concluded that iron chelation predominates in the overall antioxidant potential of the polyhydroxynaphthoquinones. PMID:18274994

  1. Influence of chelating agents on the distribution and excretion of cadmium in rats

    SciTech Connect

    Planas-Bohne, F.; Lehmann, M.

    1983-03-15

    The effects of the chelating agents CaNa2-ethylenediaminetetraacetate (EDTA), CaNa3-diethylenetriaminepentaacetate (DTPA), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropanol (BAL), and 2,3-dimercaptopropane-1-sulfonate (DMPS) and of the lipophilic chelating agents Puchel, Puchel-bisamidocysteineethyl ester (Puch-D), and EDTA-bis-amidocysteineethyl ester (EDTA-D) on the distribution of iv injected Cd were studied in male Sprague-Dawley rats. The chelating agents were injected iv as single doses given 10 sec, 1 hr, or 3 hr after 3 mumol/kg Cd + 115mCd. When the chelating agents were injected within 10 sec after the metal, all agents reduced the total body cadmium burden by varying extents ranging from 3% of that in untreated control rats after 0.01 mmol BAL/kg to 94% following 0.1 mmol DTPA/kg. When given 1 hr after Cd injection, the efficacy of all the agents tested was markedly reduced or abolished; at this time only Puchel and Puch-D provoked significant reductions in the body burden of Cd by 21 and 32%, respectively. When treatment was delayed until 3 hr after Cd injection, only Puch-D was able to reduce the body and liver burden of the metal by 14 and 9%, respectively. Combined treatment with Puchel + DTPA, BAL + DTPA, or BAL + DMPS did not enhance Cd removal to an extent greater than that expected from the equivalent dose of the more effective agent of that pair alone. Repeated administration of DTPA, 20 X 0.1 mmol/kg, during 4 weeks by ip or po administration of the same dose in the drinking water over 4 weeks, was no no more effective than the first dose of the chelating agent alone. Gel chromatographic studies of the distribution of Cd among the proteins of the liver cytosol in treated and untreated animals indicate that neither DTPA nor Puchel was able to release Cd from the metallothionein complex.

  2. Degradation of toluene, ethylbenzene, and xylene using heat and chelated-ferrous iron activated persulfate oxidation

    NASA Astrophysics Data System (ADS)

    Mondal, P.; Sleep, B.

    2014-12-01

    Toluene, ethylbenze, and xylene (TEX) are common contaminants in the subsurface. Activated persulfate has shown promise for degrading a wide variety of organic compounds. However, studies of persulfate application for in situ degradation of TEX and effects on the subsequent bioremediation are limited. In this work, degradation studies of TEX in aqueous media and soil are being conducted using heat activated and chelated-ferrous iron activated persulfate oxidation in batch and flow-through column experiments. In the batch experiments, sodium persulfate is being used at different concentrations to provide an initial persulfate to TEX molar ratios between 10:1 and 100:1. Sodium persulfate solutions are being activated at 20, 37, 60, and 80 oC temperatures for the heat activated oxidation. For the chelated-ferrous iron activated oxidation, ferrous iron and citric acid, both are being used at concentration of 5 mM. In the experiments with soil slurry, a soil to water ratio of 1 to 5 is being used. Flow through water saturated column experiments are being conducted with glass columns (45 cm in length and 4 cm in diameter) uniformly packed with soils, and equilibrated with water containing TEX at the target concentrations. Both the heat activation and chelated-ferrous iron activation of persulfate are being employed in the column experiments. Future experiments are planned to determine the suitability of persulfate oxidation of TEX on the subsequent biodegradation using batch microcosms containing TEX degrading microbial cultures. In these experiments, the microbial biomass will be monitored using total phospholipids, and the microbial community will be determined using quantitative real-time polymerase chain reaction (qPCR) on the extracted DNA. This study is expected to provide suitable operating conditions for in situ chemical oxidation of TEX with activated persulfate followed by bioremediation.

  3. Hydrazone chelators for the treatment of iron overload disorders: iron coordination chemistry and biological activity.

    PubMed

    Bernhardt, Paul V; Chin, Piao; Sharpe, Philip C; Richardson, Des R

    2007-08-14

    The potentially tridentate ligand 2-pyridinecarbaldehyde isonicotinoyl hydrazone (HPCIH) and its analogues are an emerging class of orally effective Fe chelators that show great promise for the treatment of Fe overload diseases. Herein, we present an extensive study of the Fe coordination chemistry of the HPCIH analogues including the first crystallographically characterised Fe(II) complex of these chelators. Unlike most other clinically effective Fe chelators, the HPCIH analogues bind Fe(II) and not Fe(III). In fact, these chelators form low-spin bis-ligand Fe(II) complexes, although NMR suggests that the complexes are close to the high-spin/low-spin crossover. All the Fe complexes show a high potential Fe(III/II) redox couple (> 500 mV vs. NHE) and cyclic voltammetry in aqueous or mixed aqueous/organic solvents is irreversible as a consequence of a rapid hydration reaction that occurs upon oxidation. A number of the HPCIH analogues show high activity at inducing Fe efflux from cells and also at preventing Fe uptake by cells from the serum Fe transport protein transferrin. As a class of ligands, these chelators are more effective at reducing Fe uptake from transferrin than inducing Fe mobilisation from cells. This may be related to their ability to intercept Fe(II) after its release from transferrin within the cell. Our studies indicate that their Fe chelation efficacy is due, at least in part, to the fact that these ligands and their Fe(II) complexes are neutral at physiological pH (7.4) and sufficiently lipophilic to permeate cell membranes. PMID:17893768

  4. Solution mining dawsonite from hydrocarbon containing formations with a chelating agent

    DOEpatents

    Vinegar, Harold J.

    2009-07-07

    A method for treating an oil shale formation comprising dawsonite includes providing heat from one or more heaters to the formation to heat the formation. Hydrocarbon fluids are produced from the formation. At least some dawsonite in the formation is decomposed with the provided heat. A chelating agent is provided to the formation to dissolve at least some dawsonite decomposition products. The dissolved dawsonite decomposition products are produced from the formation.

  5. Synthesis and spectroscopic investigations of hydroxyapatite using a green chelating agent as template

    NASA Astrophysics Data System (ADS)

    Gopi, D.; Bhuvaneshwari, N.; Indira, J.; Kavitha, L.

    2013-03-01

    Hydroxyapatite [Ca10(PO4)6(OH)2, HAP] particles have been successfully synthesized by a cost-effective, eco-friendly green template method using natural and commercially available sucrose as a chelating agent. The sucrose used in this method has been extracted from various sources, three from natural and one from commercially available sources are exploited in our study to achieve a controlled crystallinity, particle size as well as uniform morphology. Spectral characterizations involving Fourier transform infrared spectroscopy (FT-IR) for the functional group analysis of sucrose and HAP; carbon-13 nuclear magnetic resonance spectroscopy (13C NMR) for the identification of the carbon atoms in sucrose and in HAP; liquid chromatography/mass spectrometry (LC-MS) for the determination of the hydrolyzed products of sucrose; and X-ray diffraction (XRD) techniques for the phase identification of the HAP particles were performed. The morphology of the HAP particles were assessed thoroughly using a scanning electron microscope (SEM) equipped with energy dispersive X-ray analysis (EDAX). The experimental results indicate that the obtained HAP using the natural sucrose as a chelating agent is of phase pure, with a well defined morphology having discrete particles without any agglomeration than the HAP from commercially available sucrose. Further, the reduced particle size can be achieved from the stem sugarcane extract as the source of the chelating agent.

  6. Synthesis and spectroscopic investigations of hydroxyapatite using a green chelating agent as template.

    PubMed

    Gopi, D; Bhuvaneshwari, N; Indira, J; Kavitha, L

    2013-03-01

    Hydroxyapatite [Ca(10)(PO(4))(6)(OH)(2), HAP] particles have been successfully synthesized by a cost-effective, eco-friendly green template method using natural and commercially available sucrose as a chelating agent. The sucrose used in this method has been extracted from various sources, three from natural and one from commercially available sources are exploited in our study to achieve a controlled crystallinity, particle size as well as uniform morphology. Spectral characterizations involving Fourier transform infrared spectroscopy (FT-IR) for the functional group analysis of sucrose and HAP; carbon-13 nuclear magnetic resonance spectroscopy ((13)C NMR) for the identification of the carbon atoms in sucrose and in HAP; liquid chromatography/mass spectrometry (LC-MS) for the determination of the hydrolyzed products of sucrose; and X-ray diffraction (XRD) techniques for the phase identification of the HAP particles were performed. The morphology of the HAP particles were assessed thoroughly using a scanning electron microscope (SEM) equipped with energy dispersive X-ray analysis (EDAX). The experimental results indicate that the obtained HAP using the natural sucrose as a chelating agent is of phase pure, with a well defined morphology having discrete particles without any agglomeration than the HAP from commercially available sucrose. Further, the reduced particle size can be achieved from the stem sugarcane extract as the source of the chelating agent. PMID:23270888

  7. Modulatory effect of iron chelators on adenosine deaminase activity and gene expression in Trichomonas vaginalis.

    PubMed

    Primon-Barros, Muriel; Rigo, Graziela Vargas; Frasson, Amanda Piccoli; Santos, Odelta dos; Smiderle, Lisiane; Almeida, Silvana; Macedo, Alexandre José; Tasca, Tiana

    2015-11-01

    Trichomonas vaginalis is a flagellate protozoan that parasitises the urogenital human tract and causes trichomoniasis. During the infection, the acquisition of nutrients, such as iron and purine and pyrimidine nucleosides, is essential for the survival of the parasite. The enzymes for purinergic signalling, including adenosine deaminase (ADA), which degrades adenosine to inosine, have been characterised in T. vaginalis. In the evaluation of the ADA profile in different T. vaginalis isolates treated with different iron sources or with limited iron availability, a decrease in activity and an increase in ADA gene expression after iron limitation by 2,2-bipyridyl and ferrozine chelators were observed. This supported the hypothesis that iron can modulate the activity of the enzymes involved in purinergic signalling. Under bovine serum limitation conditions, no significant differences were observed. The results obtained in this study allow for the assessment of important aspects of ADA and contribute to a better understanding of the purinergic system in T. vaginalis and the role of iron in establishing infection and parasite survival.

  8. Curcumin Inhibits Growth of Saccharomyces cerevisiae through Iron Chelation ▿ ††

    PubMed Central

    Minear, Steven; O'Donnell, Allyson F.; Ballew, Anna; Giaever, Guri; Nislow, Corey; Stearns, Tim; Cyert, Martha S.

    2011-01-01

    Curcumin, a polyphenol derived from turmeric, is an ancient therapeutic used in India for centuries to treat a wide array of ailments. Interest in curcumin has increased recently, with ongoing clinical trials exploring curcumin as an anticancer therapy and as a protectant against neurodegenerative diseases. In vitro, curcumin chelates metal ions. However, although diverse physiological effects have been documented for this compound, curcumin's mechanism of action on mammalian cells remains unclear. This study uses yeast as a model eukaryotic system to dissect the biological activity of curcumin. We found that yeast mutants lacking genes required for iron and copper homeostasis are hypersensitive to curcumin and that iron supplementation rescues this sensitivity. Curcumin penetrates yeast cells, concentrates in the endoplasmic reticulum (ER) membranes, and reduces the intracellular iron pool. Curcumin-treated, iron-starved cultures are enriched in unbudded cells, suggesting that the G1 phase of the cell cycle is lengthened. A delay in cell cycle progression could, in part, explain the antitumorigenic properties associated with curcumin. We also demonstrate that curcumin causes a growth lag in cultured human cells that is remediated by the addition of exogenous iron. These findings suggest that curcumin-induced iron starvation is conserved from yeast to humans and underlies curcumin's medicinal properties. PMID:21908599

  9. Modulatory effect of iron chelators on adenosine deaminase activity and gene expression in Trichomonas vaginalis

    PubMed Central

    Primon-Barros, Muriel; Rigo, Graziela Vargas; Frasson, Amanda Piccoli; dos Santos, Odelta; Smiderle, Lisiane; Almeida, Silvana; Macedo, Alexandre José; Tasca, Tiana

    2015-01-01

    Trichomonas vaginalis is a flagellate protozoan that parasitises the urogenital human tract and causes trichomoniasis. During the infection, the acquisition of nutrients, such as iron and purine and pyrimidine nucleosides, is essential for the survival of the parasite. The enzymes for purinergic signalling, including adenosine deaminase (ADA), which degrades adenosine to inosine, have been characterised in T. vaginalis. In the evaluation of the ADA profile in different T. vaginalis isolates treated with different iron sources or with limited iron availability, a decrease in activity and an increase in ADA gene expression after iron limitation by 2,2-bipyridyl and ferrozine chelators were observed. This supported the hypothesis that iron can modulate the activity of the enzymes involved in purinergic signalling. Under bovine serum limitation conditions, no significant differences were observed. The results obtained in this study allow for the assessment of important aspects of ADA and contribute to a better understanding of the purinergic system in T. vaginalis and the role of iron in establishing infection and parasite survival. PMID:26517498

  10. Combination therapy with iron chelation and vancomycin in treating murine staphylococcemia.

    PubMed

    Luo, G; Spellberg, B; Gebremariam, T; Lee, H; Xiong, Y Q; French, S W; Bayer, A; Ibrahim, A S

    2014-05-01

    Iron acquisition is a virulence factor for Staphylococcus aureus. We assessed the efficacy of the iron chelator, deferasirox (Def), alone or in combination with vancomycin (Van) against two methicillin-resistant S. aureus (MRSA) strains in vitro and in a murine bacteremia model. In vitro time-kill assays were carried out against MRSA or vancomycin-intermediate S. aureus (VISA) strains. The impact of Def on Van binding to the surface of S. aureus was measured by flow cytometry. Furthermore, we compared the efficacy of Def, Van, or both drugs in treating S. aureus bacteremia in a murine model. Combination therapy reduced MRSA and VISA viability in vitro versus either drug alone or untreated controls (p < 0.005); this outcome was correlated with enhanced Van surface binding to S. aureus cells. In vivo, Def + Van combination therapy significantly reduced the bacterial burden in mice kidneys (p = 0.005) and spleen (p < 0.001), and reduced the severity of infection with MRSA or VISA strains compared to placebo-treated mice. Our results show that Def enhances the in vitro and in vivo capacity of Van-mediated MRSA killing via a mechanism that appears to involve increased binding of Van to the staphylococcal surface. Iron chelation is a promising, novel adjunctive therapeutic strategy for MRSA and VISA infections.

  11. The iron chelator deferasirox affects redox signalling in haematopoietic stem/progenitor cells.

    PubMed

    Tataranni, Tiziana; Agriesti, Francesca; Mazzoccoli, Carmela; Ruggieri, Vitalba; Scrima, Rosella; Laurenzana, Ilaria; D'Auria, Fiorella; Falzetti, Franca; Di Ianni, Mauro; Musto, Pellegrino; Capitanio, Nazzareno; Piccoli, Claudia

    2015-07-01

    The iron chelator deferasirox (DFX) prevents complications related to transfusional iron overload in several haematological disorders characterized by marrow failure. It is also able to induce haematological responses in a percentage of treated patients, particularly in those affected by myelodysplastic syndromes. The underlying mechanisms responsible for this feature, however, are still poorly understood. In this study, we investigated the effect of DFX-treatment in human haematopoietic/progenitor stem cells, focussing on its impact on the redox balance, which proved to control the interplay between stemness maintenance, self-renewal and differentiation priming. Here we show, for the first time, that DFX treatment induces a significant diphenyleneiodonium-sensitive reactive oxygen species (ROS) production that leads to the activation of POU5F1 (OCT4), SOX2 and SOX17 gene expression, relevant in reprogramming processes, and the reduction of the haematopoietic regulatory proteins CTNNB1 (β-Catenin) and BMI1. These DFX-mediated events were accompanied by decreased CD34 expression, increased mitochondrial mass and up-regulation of the erythropoietic marker CD71 (TFRC) and were compound-specific, dissimilar to deferoxamine. Our findings would suggest a novel mechanism by which DFX, probably independently on its iron-chelating property but through ROS signalling activation, may influence key factors involved in self-renewal/differentiation of haematopoietic stem cells.

  12. Chemical, physical, and sensory characteristics of mozzarella cheese fortified using protein-chelated iron or ferric chloride.

    PubMed

    Rice, W H; McMahon, D J

    1998-02-01

    Mozzarella cheese containing 25 and 50 mg of iron/kg of cheese was manufactured from milk that had been fortified with casein-chelated iron, whey protein-chelated iron, or FeCl3. Chemical, physical, and sensory characteristics were compared with those of a control cheese. Physical properties were assessed by testing melting, apparent viscosity, and browning of heated cheese. Cheeses were evaluated by trained panelists for the presence of metallic flavors, oxidized flavors, and other undesirable flavors. Addition of 25 mg iron/kg of cheese had no effects on the physical properties of Mozzarella cheese. Apparent viscosity of cheese fortified with 50 mg of iron/kg of cheese tended to be slightly higher than the control cheese, although this difference was not statistically significant at all storage times. Cook color was not affected by iron fortification. No increase in chemical oxidation (measured using thiobarbituric acid assay) was observed between the control and iron-fortified cheeses. Slight but statistically significant increases in metallic flavors, oxidized flavors, and off-flavors in the iron-fortified cheese were observed by the trained sensory panel, but the flavor defects were of very low intensity. For metallic flavors, oxidized flavors, and off-flavors, the control cheese scored 1.5, 1.5, and 1.3, respectively; the iron-fortified cheese scored 2.1, 2.0, and 1.6 based on a nine-point scale (where 1 = not perceptible to 3 = slightly perceptible). Sensory scores for iron-fortified cheese made using casein-chelated iron or whey protein-chelated iron was not significantly different from those of cheese made using ferric chloride. When used on pizza, consumer panels rated the iron-fortified cheeses as comparable with the control cheese.

  13. [Physico-chemical and toxicological profile of gadolinium chelates as contrast agents for magnetic resonance imaging].

    PubMed

    Idée, J-M; Fretellier, N; Thurnher, M M; Bonnemain, B; Corot, C

    2015-07-01

    Gadolinium chelates (GC) are contrast agents widely used to facilitate or to enable diagnosis using magnetic resonance imaging (MRI). From a regulatory viewpoint, GC are drugs. GC have largely contributed to the success of MRI, which has become a major component of clinician's diagnostic armamentarium. GC are not metabolised and are excreted by the kidneys. They distribute into the extracellular compartment. Because of its high intrinsic toxicity, gadolinium must be administered as a chelate. GC can be classified according to two key molecular features: (a) nature of the chelating moiety: either macrocyclic molecules in which gadolinium is caged in the pre-organized cavity of the ligand, or linear, open-chain molecules, (b) ionicity: Gd chelates can be ionic (meglumine or sodium salts) or non-ionic. The thermodynamic and kinetic stabilities of the various GCs differ according to these structural characteristics. The kinetic stability of macrocyclic GCs is much higher than that of linear GCs and the thermodynamic stability of ionic GCs is generally higher than that of non-ionic GC, thus leading to a lower risk of gadolinium dissociation. This class of drugs has enjoyed an excellent reputation in terms of safety for a long time, until a causal link with a recently-described serious disease, nephrogenic systemic fibrosis (NSF), was evidenced. It is acknowledged that the vast majority of NSF cases are related to the administration of some linear CG in renally-impaired patients. Health authorities, worldwide, released recommendations which drastically reduced the occurrence of new cases. PMID:25731664

  14. Iron chelation monotherapy in transfusion-dependent beta-thalassemia major patients: a comparative study of deferasirox and deferoxamine

    PubMed Central

    Hassan, Mohamed Abdel Malik; Tolba, Omar Atef

    2016-01-01

    Introduction Iron overload is the primary cause of mortality and morbidity in thalassemia major (TM) despite advances in chelation therapy. The aim of this study was to compare the effectiveness and safety of deferasirox (DFX) and deferoxamine (DFO) as iron-chelating agents in patients with transfusion-dependent β-thalassemia major. Methods This prospective randomized study included 60 patients with transfusion-dependent β-TM during the period from September 2014 to September 2015. Their ages were ≥ 6 years, and they had serum ferritin above 1500 μg/L and were on irregular DFO therapy. Patients had regular packed red cell transfusion in a dose of 10 mL/kg/session. They were randomized to receive DFX (single oral daily dose of 20–40 mg/kg/day) or DFO (20–50 mg/kg/day via subcutaneous infusion over 8–10 hours, 5 days a week). Iron overload was determined by serum ferritin level. The primary endpoint was decrease of serum ferritin level below 1500 μg/L. The secondary endpoint was drug safety. Results Both drugs significantly reduced serum ferritin (p < 0.001). At the end of follow-up, there were no significant differences between the two groups in serum ferritin levels (p = 0.673) and in percent reduction of ferritin (p = 0.315). There were no significant differences between the two groups in the total amount of blood transfusion (p = 0.166) and average iron intake (p = 0.227). There were no mortalities or any serious adverse effects, neutropenia, arthropathy, or pulmonary toxicity. Gastrointestinal upset and skin rash occurred more frequently with DFX than with DFO (p = 0.254 and 0.095, respectively). Conclusion With appropriate dosing and compliance with drugs, both DFX and DFO are generally well tolerated, safe, and effective in reducing serum ferritin levels in iron-overloaded, regularly-transfused thalassemia major patients. Therefore, oral DFX is recommended for more convenience and adherence to the treatment regimen. PMID:27382454

  15. Iron chelates bind nitric oxide and decrease mortality in an experimental model of septic shock.

    PubMed

    Kazmierski, W M; Wolberg, G; Wilson, J G; Smith, S R; Williams, D S; Thorp, H H; Molina, L

    1996-08-20

    The hydroxamic acid siderophore ferrioxamine B [FeIII(HDFB)+] and the iron complex of diethylenetri-aminepentaacetic acid [FeIII(DTPA)2-] protected mice against death by septic shock induced by Corynebacterium parvum + lipopolysaccharide. Although FeIII(DTPA)2- was somewhat more effective than FeIII(HDFB)+, the iron-free ligand H4DFB+ was significantly more effective than DTPA. The hydroxamic acid chelator has a much higher iron affinity than the amine carboxylate, allowing for more efficient formation of the FeIII(HDFB)+ complex upon administration of the iron-free ligand. Electrochemical studies show that FeIII(DTPA)2- binds NO stoichiometrically upon reduction to iron(II) at biologically relevant potentials to form a stable NO adduct. In contrast, FeIII(HDFB)+ is a stable and efficient electrocatalyst for the reduction of NO to N2O at biologically relevant potentials. These results suggest that the mechanism of protection against death by septic shock involves NO scavenging and that particularly effective drugs that operate a low dosages may be designed based on the principle of redox catalysis. These complexes constitute a new family of drugs that rely on the special ability of transition metals to activate small molecules. In addition, the wealth of information available on siderophore chemistry and biology provides an intellectual platform for further development. PMID:8799167

  16. New chelating agent for attaching indium-111 to monoclonal antibodies: in vitro and in vivo evaluation.

    PubMed

    Subramanian, R; Colony, J; Shaban, S; Sidrak, H; Haspel, M V; Pomato, N; Hanna, M G; McCabe, R P

    1992-01-01

    111In possesses excellent radiophysical properties suitable for use in immunoscintigraphy of cancerous tissues when attached to an antitumor antibody. However, 111In has a tendency to accumulate in normal tissues such as liver. Instability of the linkage between 111In and antibody may contribute to this problem. To avoid this, we developed a new bifunctional chelating agent, 1,3-bis[N-[N-(2-aminoethyl)-2-aminoethyl]-2-aminoacetamido]-2-(4- isothiocyanatobenzyl)propane-N,N,N',N'',N''',N'''',N''''',N'''''- octaacetic acid (LiLo), that forms a kinetically stable chelate with metal ions such as indium. Using LiLo, indium-111 was conjugated to a human monoclonal antibody, 16.88. Competitive binding analysis revealed that the 16.88-LiLo conjugate is as immunoreactive as the unconjugated native antibody. This conjugate was compared with 111In-16.88, where diethylenetriaminepentaacetic acid dianhydride (DTPAa) was used as the chelating agent. In vitro stability studies showed that 111In was more stably bound to 16.88-LiLo than to 16.88-DTPA. Biodistribution studies in athymic mice bearing colorectal tumor xenografts indicated less liver retention with 16.88-LiLo than with 16.88-DTPA. These results demonstrate that LiLo is superior to DTPAa for attachment of 111In to the monoclonal antibodies.

  17. Novel enterobactin analogues as potential therapeutic chelating agents: Synthesis, thermodynamic and antioxidant studies

    PubMed Central

    Zhang, Qingchun; Jin, Bo; Shi, Zhaotao; Wang, Xiaofang; Liu, Qiangqiang; Lei, Shan; Peng, Rufang

    2016-01-01

    A series of novel hexadentate enterobactin analogues, which contain three catechol chelating moieties attached to different molecular scaffolds with flexible alkyl chain lengths, were prepared. The solution thermodynamic stabilities of the complexes with uranyl, ferric(III), and zinc(II) ions were then investigated. The hexadentate ligands demonstrate effective binding ability to uranyl ion, and the average uranyl affinities are two orders of magnitude higher than 2,3-dihydroxy-N1,N4-bis[(1,2-hydroxypyridinone-6-carboxamide)ethyl]terephthalamide [TMA(2Li-1,2-HOPO)2] ligand with similar denticity. The high affinity of hexadentate ligands could be due to the presence of the flexible scaffold, which favors the geometric agreement between the ligand and the uranyl coordination preference. The hexadentate ligands also exhibit higher antiradical efficiency than butylated hydroxyanisole (BHA). These results provide a basis for further studies on the potential applications of hexadentate ligands as therapeutic chelating agents. PMID:27671769

  18. Novel enterobactin analogues as potential therapeutic chelating agents: Synthesis, thermodynamic and antioxidant studies

    NASA Astrophysics Data System (ADS)

    Zhang, Qingchun; Jin, Bo; Shi, Zhaotao; Wang, Xiaofang; Liu, Qiangqiang; Lei, Shan; Peng, Rufang

    2016-09-01

    A series of novel hexadentate enterobactin analogues, which contain three catechol chelating moieties attached to different molecular scaffolds with flexible alkyl chain lengths, were prepared. The solution thermodynamic stabilities of the complexes with uranyl, ferric(III), and zinc(II) ions were then investigated. The hexadentate ligands demonstrate effective binding ability to uranyl ion, and the average uranyl affinities are two orders of magnitude higher than 2,3-dihydroxy-N1,N4-bis[(1,2-hydroxypyridinone-6-carboxamide)ethyl]terephthalamide [TMA(2Li-1,2-HOPO)2] ligand with similar denticity. The high affinity of hexadentate ligands could be due to the presence of the flexible scaffold, which favors the geometric agreement between the ligand and the uranyl coordination preference. The hexadentate ligands also exhibit higher antiradical efficiency than butylated hydroxyanisole (BHA). These results provide a basis for further studies on the potential applications of hexadentate ligands as therapeutic chelating agents.

  19. Characterization of the neuroprotective potential of derivatives of the iron chelating drug deferiprone.

    PubMed

    Maher, Pamela; Kontoghiorghes, George J

    2015-03-01

    There is growing evidence for alterations in iron homeostasis during aging that are exacerbated in neurodegenerative diseases such as Alzheimer's disease. However, since essentially all neurodegenerative diseases are multi-factorial in the sense that there are a large number of mechanisms that can be identified as contributing to nerve cell death, iron chelators that have additional activities might be the most useful for the treatment of age-related CNS diseases. We have described a series of cell culture-based assays that define molecular toxicity pathways relevant to neurodegenerative diseases and have used these assays to identify potential therapeutic compounds for the treatment of these diseases. Deferiprone is a blood brain barrier permeable, low molecular weight iron chelator that has been used for many years to treat systemic iron disease. In this study, we describe the use of our cell culture-based screening assays to identify deferiprone derivatives with the greatest therapeutic potential for the treatment of CNS diseases. We show that several derivatives are much more potent than deferiprone at reducing oxidative stress and preventing nerve cell death induced by multiple, age-related insults. In addition, we show that both deferiprone and the derivatives modulate several distinct signaling pathways associated with neuroprotection. All of the compounds were able to both inhibit the activation of p38 MAP kinase and JNK kinase and prevent the loss of PI3 kinase activity in response to a toxic stress. These results strongly suggest that these compounds have significant potential for the treatment of CNS diseases. PMID:25559767

  20. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes.

    PubMed

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-01-01

    The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM). Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI) variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30-40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO), oral deferiprone (L1), and DFO-L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX) increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve the use of the iron-chelating drugs and other drug combinations not only for increasing iron excretion but also for preventing iron absorption.

  1. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes

    PubMed Central

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-01-01

    The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM). Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI) variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30–40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO), oral deferiprone (L1), and DFO–L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX) increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve the use of the iron-chelating drugs and other drug combinations not only for increasing iron excretion but also for preventing iron absorption. PMID:26893541

  2. The Pseudomonas aeruginosa extracellular secondary metabolite, Paerucumarin, chelates iron and is not localized to extracellular membrane vesicles.

    PubMed

    Qaisar, Uzma; Kruczek, Cassandra J; Azeem, Muhammed; Javaid, Nasir; Colmer-Hamood, Jane A; Hamood, Abdul N

    2016-08-01

    Proteins encoded by the Pseudomonas aeruginosa pvcA-D operon synthesize a novel isonitrile functionalized cumarin termed paerucumarin. The pvcA-D operon enhances the expression of the P. aeruginosa fimbrial chaperone/usher pathway (cup) genes and this effect is mediated through paerucumarin. Whether pvcA-D and/or paerucumarin affect the expression of other P. aeruginosa genes is not known. In this study, we examined the effect of a mutation in pvcA-D operon the global transcriptome of the P. aeruginosa strain PAO1-UW. The mutation reduced the expression of several ironcontrolled genes including pvdS, which is essential for the expression of the pyoverdine genes. Additional transcriptional studies showed that the pvcA-D operon is not regulated by iron. Exogenously added paerucumarin enhanced pyoverdine production and pvdS expression in PAO1-UW. Iron-chelation experiments revealed that purified paerucumarin chelates iron. However, exogenously added paerucumarin significantly reduced the growth of a P. aeruginosa mutant defective in pyoverdine and pyochelin production. In contrast to other secondary metabolite, Pseudomonas quinolone signal (PQS), paerucumarin is not localized to the P. aeruginosa membrane vesicles. These results suggest that paerucumarin enhances the expression of iron-controlled genes by chelating iron within the P. aeruginosa extracellular environment. Although paerucumarin chelates iron, it does not function as a siderophore. Unlike PQS, paerucumarin is not associated with the P. aeruginosa cell envelope. PMID:27480638

  3. Iron Chelation Inhibits Osteoclastic Differentiation In Vitro and in Tg2576 Mouse Model of Alzheimer’s Disease

    PubMed Central

    Guo, Jun-Peng; Pan, Jin-Xiu; Xiong, Lei; Xia, Wen-Fang; Cui, Shun; Xiong, Wen-Cheng

    2015-01-01

    Patients of Alzheimer’s disease (AD) frequently have lower bone mineral density and higher rate of hip fracture. Tg2576, a well characterized AD animal model that ubiquitously express Swedish mutant amyloid precursor protein (APPswe), displays not only AD-relevant neuropathology, but also age-dependent bone deficits. However, the underlying mechanisms remain poorly understood. As APP is implicated as a regulator of iron export, and the metal chelation is considered as a potential therapeutic strategy for AD, we examined iron chelation’s effect on the osteoporotic deficit in Tg2576 mice. Remarkably, in vivo treatment with iron chelator, clinoquinol (CQ), increased both trabecular and cortical bone-mass, selectively in Tg2576, but not wild type (WT) mice. Further in vitro studies showed that low concentrations of CQ as well as deferoxamine (DFO), another iron chelator, selectively inhibited osteoclast (OC) differentiation, without an obvious effect on osteoblast (OB) differentiation. Intriguingly, both CQ and DFO’s inhibitory effect on OC was more potent in bone marrow macrophages (BMMs) from Tg2576 mice than that of wild type controls. The reduction of intracellular iron levels in BMMs by CQ was also more dramatic in APPswe-expressing BMMs. Taken together, these results demonstrate a potent inhibition on OC formation and activation in APPswe-expressing BMMs by iron chelation, and reveal a potential therapeutic value of CQ in treating AD-associated osteoporotic deficits. PMID:26575486

  4. Deferasirox, an oral iron chelator, prevents hepatocarcinogenesis and adverse effects of sorafenib

    PubMed Central

    Yamamoto, Naoki; Yamasaki, Takahiro; Takami, Taro; Uchida, Koichi; Fujisawa, Koichi; Matsumoto, Toshihiko; Saeki, Issei; Terai, Shuji; Sakaida, Isao

    2016-01-01

    Although sorafenib is expected to have a chemopreventive effect on hepatocellular carcinoma (HCC) recurrence, there are limitations to its use because of adverse effects, including effects on liver function. We have reported that the iron chelator, deferoxamine can prevent liver fibrosis and preneoplastic lesions. We investigated the influence of administering a new oral iron chelator, deferasirox (DFX), on the effects of sorafenib. We used the choline-deficient l-amino acid-defined (CDAA) diet-induced rat liver fibrosis and HCC model. We divided rats into four groups: CDAA diet only (control group), CDAA diet with sorafenib (sorafenib group), CDAA diet with DFX (DFX group), and CDAA diet with DFX and sorafenib (DFX + sorafenib group). Liver fibrosis and development of preneoplastic lesions were assessed. In addition, we assessed adverse effects such as changes in body and liver weight, skin damage (eruption, dryness, and hair loss), which is defined as hand-foot skin syndrome, in the sorafenib and DFX + sorafenib groups. The combination of DFX + sorafenib markedly prevented liver fibrosis and preneoplastic lesions better than the other treatments. Furthermore, the combination therapy significantly decreased adverse effects compared with the sorafenib group. In conclusion, the combination therapy with DFX and sorafenib may be a useful adjuvant therapy to prevent recurrence after curative treatment of HCC. PMID:27257345

  5. Echinochrome, a naturally occurring iron chelator and free radical scavenger in artificial and natural membrane systems.

    PubMed

    Lebedev, Alexander V; Ivanova, Marina V; Levitsky, Dmitri O

    2005-01-01

    Echinochrome, or 6-ethyl-2,3,5,7,8-pentahydroxy-1,4-naphthoquinone, possesses cardioprotective activity, and diminishes the myocardial ischemia/reperfusion injury that is known to be accompanied by free-radical oxidative damage and calcium overload. In this study, we investigated the lipophilicity of echinochrome, its ability to inhibit free-radical oxidation both in the bulk organic phase and in an artificial membrane system (liposomes), and to prevent the ferrous/ascorbate-induced leakage of calcium from the isolated sarcoplasmic reticulum (SR) of rabbit skeletal muscle. The experimentally-determined octanol/water partition coefficient (LogP) of echinochrome was +3.11, and the distribution coefficient (LogD) was +2.58 at pH 6.0 and -0.15 at pH 8.0. Echinochrome displayed high scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals with a stoichiometry of about 1:7. Echinochrome was more effective in inhibiting the phosphatidyl choline liposome peroxidation induced by Fe2+/ascorbate than that induced by hemin. The iron chelating ability of echinochrome was estimated spectrophotometrically. In isolated SR, echinochrome protected the ATP-dependent Ca2+-pump system from damage by Fe2+/ascorbate. It was concluded that iron chelation predominates in the overall antioxidant potential of echinochrome. PMID:15589964

  6. Characterization of radionuclide-chelating agent complexes found in low-level radioactive decontamination waste. Literature review

    SciTech Connect

    Serne, R.J.; Felmy, A.R.; Cantrell, K.J.; Krupka, K.M.; Campbell, J.A.; Bolton, H. Jr.; Fredrickson, J.K.

    1996-03-01

    The US Nuclear Regulatory Commission is responsible for regulating the safe land disposal of low-level radioactive wastes that may contain organic chelating agents. Such agents include ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), picolinic acid, oxalic acid, and citric acid, and can form radionuclide-chelate complexes that may enhance the migration of radionuclides from disposal sites. Data from the available literature indicate that chelates can leach from solidified decontamination wastes in moderate concentration (1--100 ppm) and can potentially complex certain radionuclides in the leachates. In general it appears that both EDTA and DTPA have the potential to mobilize radionuclides from waste disposal sites because such chelates can leach in moderate concentration, form strong radionuclide-chelate complexes, and can be recalcitrant to biodegradation. It also appears that oxalic acid and citric acid will not greatly enhance the mobility of radionuclides from waste disposal sites because these chelates do not appear to leach in high concentration, tend to form relatively weak radionuclide-chelate complexes, and can be readily biodegraded. In the case of picolinic acid, insufficient data are available on adsorption, complexation of key radionuclides (such as the actinides), and biodegradation to make definitive predictions, although the available data indicate that picolinic acid can chelate certain radionuclides in the leachates.

  7. Inhibitory effect of iron withdrawal by chelation on the growth of human and murine mammary carcinoma and fibrosarcoma cells.

    PubMed

    Power Coombs, Melanie R; Grant, Taryn; Greenshields, Anna L; Arsenault, Daniel J; Holbein, Bruce E; Hoskin, David W

    2015-10-01

    Since iron uptake is essential for cell growth, rapidly dividing cancer cells are sensitive to iron depletion. To explore the effect of iron withdrawal on cancer cell growth, mouse and human mammary carcinoma cells (4T1 and MDA-MB-468, respectively) and mouse and human fibrosarcoma cells (L929 and HT1080, respectively) were cultured in the absence or presence of DIBI, a novel iron-chelating polymer containing hydroxypyridinone iron-ligand functionality. Cell growth was measured by a colorimetric assay for cell metabolic activity. DIBI-treated 4T1, MDA-MB-468, L929 and HT1080 cells, as well as their normal counterparts, showed a dose- and time-dependent reduction in growth that was selective for human cancer cells and mouse fibrosarcoma cells. The inhibitory effect of DIBI on fibrosarcoma and mammary carcinoma cell growth was reversed by addition of exogenous iron in the form of iron (III) citrate, confirming the iron selectivity of DIBI and that its inhibitory activity was iron-related. Fibrosarcoma and mammary carcinoma cell growth inhibition by DIBI was associated with S-phase cell cycle arrest and low to moderate levels of cell death by apoptosis. Consistent with apoptosis induction following DIBI-mediated iron withdrawal, fibrosarcoma and mammary carcinoma cells exhibited mitochondrial membrane permeabilization. A comparison of DIBI to other iron chelators showed that DIBI was superior to deferiprone and similar to or better than deferoxamine for inhibition of fibrosarcoma and mammary carcinoma cell growth. These findings suggest that iron withdrawal from the tumor microenvironment with a selective and potent iron chelator such as DIBI may prevent or inhibit tumor progression.

  8. Development of Iron-Chelating Poly(ethylene terephthalate) Packaging for Inhibiting Lipid Oxidation in Oil-in-Water Emulsions.

    PubMed

    Johnson, David R; Tian, Fang; Roman, Maxine J; Decker, Eric A; Goddard, Julie M

    2015-05-27

    Foods such as bulk oils, salad dressings, and nutritionally fortified beverages that are susceptible to oxidative degradation are often packaged in poly(ethylene terephthalate) (PET) bottles with metal chelators added to the food to maintain product quality. In the present work, a metal-chelating active packaging material is designed and characterized, in which poly(hydroxamic acid) (PHA) metal-chelating moieties were grafted from the surface of PET. Biomimetic PHA groups were grafted in a two-step UV-initiated process without the use of a photoinitiator. Surface characterization of the films by attenuated total reflective Fourier transform infrared spectroscopy (ATR-FTIR) and scanning electron microscopy (SEM) suggested successful grafting and conversion of poly(hydroxyethyl acrylate) (PHEA) to PHA chelating moieties from the surface of PET. Colorimetric (ferrozine) and inductively coupled plasma mass spectroscopy (ICP-MS) assays demonstrated the ability of PET-g-PHA to chelate iron in a low-pH (3.0) environment containing a competitive metal chelator (citric acid). Lipid oxidation studies demonstrated the antioxidant activity of PET-g-PHA films in inhibiting iron-promoted oxidation in an acidified oil-in-water (O/W) emulsion model system (pH 3.0). Particle size and ζ-potential analysis indicated that the addition of PET-g-PHA films did not affect the physical stability of the emulsion system. This work suggests that biomimetic chelating moieties can be grafted from PET and effectively inhibit iron-promoted degradation reactions, enabling removal of metal-chelating additives from product formulations.

  9. Development of Iron-Chelating Poly(ethylene terephthalate) Packaging for Inhibiting Lipid Oxidation in Oil-in-Water Emulsions.

    PubMed

    Johnson, David R; Tian, Fang; Roman, Maxine J; Decker, Eric A; Goddard, Julie M

    2015-05-27

    Foods such as bulk oils, salad dressings, and nutritionally fortified beverages that are susceptible to oxidative degradation are often packaged in poly(ethylene terephthalate) (PET) bottles with metal chelators added to the food to maintain product quality. In the present work, a metal-chelating active packaging material is designed and characterized, in which poly(hydroxamic acid) (PHA) metal-chelating moieties were grafted from the surface of PET. Biomimetic PHA groups were grafted in a two-step UV-initiated process without the use of a photoinitiator. Surface characterization of the films by attenuated total reflective Fourier transform infrared spectroscopy (ATR-FTIR) and scanning electron microscopy (SEM) suggested successful grafting and conversion of poly(hydroxyethyl acrylate) (PHEA) to PHA chelating moieties from the surface of PET. Colorimetric (ferrozine) and inductively coupled plasma mass spectroscopy (ICP-MS) assays demonstrated the ability of PET-g-PHA to chelate iron in a low-pH (3.0) environment containing a competitive metal chelator (citric acid). Lipid oxidation studies demonstrated the antioxidant activity of PET-g-PHA films in inhibiting iron-promoted oxidation in an acidified oil-in-water (O/W) emulsion model system (pH 3.0). Particle size and ζ-potential analysis indicated that the addition of PET-g-PHA films did not affect the physical stability of the emulsion system. This work suggests that biomimetic chelating moieties can be grafted from PET and effectively inhibit iron-promoted degradation reactions, enabling removal of metal-chelating additives from product formulations. PMID:25985711

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

    PubMed

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

    2015-01-01

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

  11. Characterization of the effect of serum and chelating agents on Staphylococcus aureus biofilm formation; chelating agents augment biofilm formation through clumping factor B

    NASA Astrophysics Data System (ADS)

    Abraham, Nabil Mathew

    Staphylococcus aureus is the causative agent of a diverse array of acute and chronic infections, and some these infections, including infective endocarditis, joint infections, and medical device-associated bloodstream infections, depend upon its capacity to form tenacious biofilms on surfaces. Inserted medical devices such as intravenous catheters, pacemakers, and artificial heart valves save lives, but unfortunately, they can also serve as a substrate on which S. aureus can form a biofilm, attributing S. aureus as a leading cause of medical device-related infections. The major aim of this work was take compounds to which S. aureus would be exposed during infection and to investigate their effects on its capacity to form a biofilm. More specifically, the project investigated the effects of serum, and thereafter of catheter lock solutions on biofilm formation by S. aureus. Pre-coating polystyrene with serum is frequently used as a method to augment biofilm formation. The effect of pre-coating with serum is due to the deposition of extracellular matrix components onto the polystyrene, which are then recognized by MSCRAMMs. We therefore hypothesized that the major component of blood, serum, would induce biofilm formation. Surprisingly, serum actually inhibited biofilm formation. The inhibitory activity was due to a small molecular weight, heat-stable, non-proteinaceous component/s of serum. Serum-mediated inhibition of biofilm formation may represent a previously uncharacterized aspect of host innate immunity that targets the expression of a key bacterial virulence factor: the ability to establish a resistant biofilm. Metal ion chelators like sodium citrate are frequently chosen to lock intravenous catheters because they are regarded as potent inhibitors of bacterial biofilm formation and viability. We found that, while chelating compounds abolished biofilm formation in most strains of S. aureus, they actually augmented the phenotype in a subset of strains. We

  12. The influence of the synergistic anion on iron chelation by ferric binding protein, a bacterial transferrin.

    PubMed

    Dhungana, Suraj; Taboy, Celine H; Anderson, Damon S; Vaughan, Kevin G; Aisen, Philip; Mietzner, Timothy A; Crumbliss, Alvin L

    2003-04-01

    Although the presence of an exogenous anion is a requirement for tight Fe(3+) binding by the bacterial (Neisseria) transferrin nFbp, the identity of the exogenous anion is not specific in vitro. nFbp was reconstituted as a stable iron containing protein by using a number of different exogenous anions [arsenate, citrate, nitrilotriacetate, pyrophosphate, and oxalate (symbolized by X)] in addition to phosphate, predominantly present in the recombinant form of the protein. Spectroscopic characterization of the Fe(3+)anion interaction in the reconstituted protein was accomplished by UV-visible and EPR spectroscopies. The affinity of the protein for Fe(3+) is anion dependent, as evidenced by the effective Fe(3+) binding constants (K'(eff)) observed, which range from 1 x 10(17) M(-1) to 4 x 10(18) M(-1) at pH 6.5 and 20 degrees C. The redox potentials for Fe(3+)nFbpXFe(2+)nFbpX reduction are also found to depend on the identity of the synergistic anion required for Fe(3+) sequestration. Facile exchange of exogenous anions (Fe(3+)nFbpX + X' --> Fe(3+)nFbpX' + X) is established and provides a pathway for environmental modulation of the iron chelation and redox characteristics of nFbp. The affinity of the iron loaded protein for exogenous anion binding at pH 6.5 was found to decrease in the order phosphate > arsenate approximately pyrophosphate > nitrilotriacetate > citrate approximately oxalate carbonate. Anion influence on the iron primary coordination sphere through iron binding and redox potential modulation may have in vivo application as a mechanism for periplasmic control of iron delivery to the cytosol. PMID:12646708

  13. Ibuprofen prevents oxidant lung injury and in vitro lipid peroxidation by chelating iron.

    PubMed Central

    Kennedy, T P; Rao, N V; Noah, W; Michael, J R; Jafri, M H; Gurtner, G H; Hoidal, J R

    1990-01-01

    Because ibuprofen protects from septic lung injury, we studied the effect of ibuprofen in oxidant lung injury from phosgene. Lungs from rabbits exposed to 2,000 ppm-min phosgene were perfused with Krebs-Henseleit buffer at 50 ml/min for 60 min. Phosgene caused no increase in lung generation of cyclooxygenase metabolites and no elevation in pulmonary arterial pressure, but markedly increased transvascular fluid flux (delta W = 31 +/- 5 phosgene vs. 8 +/- 1 g unexposed, P less than 0.001), permeability to albumin (125I-HSA) lung leak index 0.274 +/- 0.035 phosgene vs. 0.019 +/- 0.001 unexposed, P less than 0.01; 125I-HSA lavage leak index 0.352 +/- 0.073 phosgene vs. 0.008 +/- 0.001 unexposed, P less than 0.01), and lung malondialdehyde (50 +/- 7 phosgene vs. 24 +/- 0.7 mumol/g dry lung unexposed, P less than 0.01). Ibuprofen protected lungs from phosgene (delta W = 10 +/- 2 g; lung leak index 0.095 +/- 0.013; lavage leak index 0.052 +/- 0.013; and malondialdehyde 16 +/- 3 mumol/g dry lung, P less than 0.01). Because iron-treated ibuprofen failed to protect, we studied the effect of ibuprofen in several iron-mediated reactions in vitro. Ibuprofen attenuated generation of .OH by a Fenton reaction and peroxidation of arachidonic acid by FeCl3 and ascorbate. Ibuprofen also formed iron chelates that lack the free coordination site required for iron to be reactive. Thus, ibuprofen may prevent iron-mediated generation of oxidants or iron-mediated lipid peroxidation after phosgene exposure. This suggests a new mechanism for ibuprofen's action. PMID:2173723

  14. Comparative evaluation of chelating agents on the mobilization of cadmium: A mechanistic approach

    SciTech Connect

    Srivastava, R.C.; Gupta, S.; Ahmad, N.

    1996-02-09

    A comparative evaluation of chelating agents, namely, diethyl dithiocarbamate (DDC), dimethyl dithiocarbamate (DMDC), 1,4,8,11-tetraazacyclotetradecane (CYCLAM), 1,4,8,12-tetraazacyclopentadecane (TACPD), 2,3-dimercaptosuccinic acid (DMSA), and 2,3-dimercapto-1-propane sulfonate (DMPS) was conducted to assess their efficacy against acute cadmium (Cd) toxicity. DMSA and DMPS appeared to be most effective in reducing mortality as well as Cd burden of liver, kidneys, and brain in cadmium intoxicated mice. DMDC reduced Cd levels only in liver and kidneys, while DDC significantly enhanced its level in brain. CYCLAM and TACPD significantly increased the Cd level in liver and kidneys and were ineffective in brain. The therapeutic index as well as therapeutic efficacy was highest for DMSA followed by DMPS and DMDC. A fair degree of correlation was found to exist between (1) stability constant of Cd chelates and percent survival (r = .438), (2) stability constant and percent transport (r=.479), and (3) percent survival and percent transport (r = .447). However, the lipophilicity did not show any appreciable correlation with percent survival and stability constant of Cd chelates. 24 refs., 1 fig., 6 tabs.

  15. Effects of Iron Chelators on the Formation and Development of Aspergillus fumigatus Biofilm.

    PubMed

    Nazik, Hasan; Penner, John C; Ferreira, Jose A; Haagensen, Janus A J; Cohen, Kevin; Spormann, Alfred M; Martinez, Marife; Chen, Vicky; Hsu, Joe L; Clemons, Karl V; Stevens, David A

    2015-10-01

    Iron acquisition is crucial for the growth of Aspergillus fumigatus. A. fumigatus biofilm formation occurs in vitro and in vivo and is associated with physiological changes. In this study, we assessed the effects of Fe chelators on biofilm formation and development. Deferiprone (DFP), deferasirox (DFS), and deferoxamine (DFM) were tested for MIC against a reference isolate via a broth macrodilution method. The metabolic effects (assessed by XTT [2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt]) on biofilm formation by conidia were studied upon exposure to DFP, DFM, DFP plus FeCl3, or FeCl3 alone. A preformed biofilm was exposed to DFP with or without FeCl3. The DFP and DFS MIC50 against planktonic A. fumigatus was 1,250 μM, and XTT gave the same result. DFM showed no planktonic inhibition at concentrations of ≤2,500 μM. By XTT testing, DFM concentrations of <1,250 μM had no effect, whereas DFP at 2,500 μM increased biofilms forming in A. fumigatus or preformed biofilms (P < 0.01). DFP at 156 to 2,500 μM inhibited biofilm formation (P < 0.01 to 0.001) in a dose-responsive manner. Biofilm formation with 625 μM DFP plus any concentration of FeCl3 was lower than that in the controls (P < 0.05 to 0.001). FeCl3 at ≥625 μM reversed the DFP inhibitory effect (P < 0.05 to 0.01), but the reversal was incomplete compared to the controls (P < 0.05 to 0.01). For preformed biofilms, DFP in the range of ≥625 to 1,250 μM was inhibitory compared to the controls (P < 0.01 to 0.001). FeCl3 at ≥625 μM overcame inhibition by 625 μM DFP (P < 0.001). FeCl3 alone at ≥156 μM stimulated biofilm formation (P < 0.05 to 0.001). Preformed A. fumigatus biofilm increased with 2,500 μM FeCl3 only (P < 0.05). In a strain survey, various susceptibilities of biofilms of A. fumigatus clinical isolates to DFP were noted. In conclusion, iron stimulates biofilm formation and preformed biofilms. Chelators can inhibit or enhance biofilms. Chelation

  16. Evidence for lipoxygenase activity in induction of histamine release from rat peritoneal mast cells by chelated iron.

    PubMed Central

    Magro, A M; Brai, M

    1983-01-01

    The ferric iron-desferrioxamine B chelate effectively induced histamine release from rat peritoneal mast cells. The release was maximum at exogenous ferric iron concentrations of 10-100 microM, and the chelate was non-toxic, as determined by trypan blue uptake. In many aspects the chelate-induced histamine release paralleled IgE-mediated release. The kinetics, temperature, and Ca2+ dependence resembled antigen-induced release. Phosphatidylserine potentiated the release in Wistar rats but not in fawn-hooded rats, a strain which does not respond to phosphatidylserine potentiation. The chelate-induced histamine release was blocked by the metabolic inhibitors dinitrophenol, potassium cyanide, 2-deoxyglucose, and antimycin A. Lipoxygenase inhibitors also effectively blocked release, indicating an involvement of fatty acid metabolism via the lipoxygenase pathway. Free radical scavengers and antioxidants antagonistic to lipid peroxidation also inhibited the chelate-induced histamine release. Overall the data raise the possibility that endogenous cellular iron may be involved in the generation of free radicals and lipid peroxidation and that these may be early events in IgE-mediated release of histamine. PMID:6188682

  17. Iron Hydride Detection and Intramolecular Hydride Transfer in a Synthetic Model of Mono-Iron Hydrogenase with a CNS Chelate.

    PubMed

    Durgaprasad, Gummadi; Xie, Zhu-Lin; Rose, Michael J

    2016-01-19

    We report the identification and reactivity of an iron hydride species in a synthetic model complex of monoiron hydrogenase. The hydride complex is derived from a phosphine-free CNS chelate that includes a Fe-C(NH)(═O) bond (carbamoyl) as a mimic of the active site iron acyl. The reaction of [((O═)C(HN)N(py)S(Me))Fe(CO)2(Br)] (1) with NaHBEt3 generates the iron hydride intermediate [((O═)C(HN)N(py)S(Me))Fe(H)(CO)2] (2; δFe-H = -5.08 ppm). Above -40 °C, the hydride species extrudes CH3S(-) via intramolecular hydride transfer, which is stoichiometrically trapped in the structurally characterized dimer μ2-(CH3S)2-[((O═)C(HN)N(Ph))Fe(CO)2]2 (3). Alternately, when activated by base ((t)BuOK), 1 undergoes desulfurization to form a cyclometalated species, [((O═)C(NH)NC(Ph))Fe(CO)2] (5); derivatization of 5 with PPh3 affords the structurally characterized species [((O═)C(NH)NC)Fe(CO)(PPh3)2] (6), indicating complex 6 as the common intermediate along each pathway of desulfurization.

  18. Dose titration of deferasirox iron chelation therapy by magnetic resonance imaging for chronic iron storage disease in three adult red bald-headed uakari (Cacajao calvus rubicundus).

    PubMed

    Brewer, Casey; Tyszka, J Michael; Stadler, Cynthia K; Garner, Michael; Baer, Janet; Wood, John C

    2014-06-01

    Iron overload is common in lemurs and some New World nonhuman primates raised in captivity, but there is no such documentation in the red bald-headed uakari (Cacajao calvus rubicundus). This study describes postmortem documentation of severe iron storage disease in one red bald-headed uakari and the use of iron chelation with oral deferasirox in the three surviving members of the colony. Magnetic resonance imaging was used to quantify pretreatment iron burden and to follow the response to therapy in two females, 22 and 28 yr of age, and one male 33 yr of age. Baseline liver iron concentrations ranged from 16 to 23 mg/g dry weight. In humans, a liver iron concentration greater than 15 mg/g is considered severe and associated with endocrine and cardiac toxicity. The uakaris were otherwise asymptomatic, generally healthy, nonpregnant, and on a stable, low-iron diet. Quantitative magnetic resonance imaging indicated that dosage escalations up to 100 mg/kg were needed to produce meaningful reductions in iron stores. After 5 yr of therapy, two animals continue at a dosage of 100 mg/kg per day, and the third was transitioned to twice-weekly maintenance dosing because of successful de-ironing. The animals tolerated iron chelation therapy well, having stable hematologic, renal, and hepatic function profiles before, during, and after treatment. Deferasirox monotherapy may represent a therapeutic option in primates with iron storage disease when dietary measures are ineffective and phlebotomy is logistically challenging.

  19. Effects of chelating agents on oral uptake and renal deposition and excretion of cadmium.

    PubMed Central

    Engström, B

    1984-01-01

    The gastrointestinal absorption, transport, tissue deposition and excretion of cadmium was studied in adult male mice given a single oral LD50 dose of 109Cd-labeled CdCl2 alone or in combination with nitrilotriacetic acid (NTA), sodium tripolyphosphate (STPP) or ethylenediaminetetraacetic acid (EDTA). Blood, intestinal mucosa, liver and kidneys were analyzed for 109Cd at different times after exposure and the influence of the chelating agents on Cd binding to metallothionein and other tissue ligands was also studied. Acute toxicity was noted. Complex formation between Cd and EDTA was studied in solutions containing Cd:EDTA at 1:04 and 1:4 molar ratios. Adult male mice were exposed orally or by direct infusion into the stomach to either of the two solutions (containing an LD50 dose of Cd). Body retention and tissue deposition of Cd was recorded after 4 (direct infusion) or 21 days (oral exposure), and the mortality in different exposure groups observed. Adult male were also exposed to a low oral dose of 109Cd-labeled cadmium (0.5 mg/kg), followed by 18 months continuous administration of NTA, (500 ppm) STPP (500 ppm) or EDTA (50 ppm) in the drinking water or the chelating agent in combination with Cd (50 ppm), Cd alone (50 ppm) or deionized water. Whole-body retention of 109Cd, tissue deposition of 109Cd and total Cd and development of proteinuria were observed. When cadmium was given with an excess of EDTA, all Cd ions were bound in a 1:1 Cd-EDTA complex. Decreased acute toxicity was observed which was related to increased body elimination of cadmium. The Cd passes though the body still bound to EDTA and is excreted via the kidneys in this form. Similar results were found in mice exposed to Cd + NTA, while gavage of CD + STPP led to an initially decreased systemic uptake of Cd and thereafter to a prolongation of the biological half-time and thus a comparatively higher body retention of the metal. Cd may form a 2:1 complex with EDTA in the presence of excess cadmium

  20. Improving the efficiency of phytoremediation using electrically charged plant and chelating agents.

    PubMed

    Tahmasbian, Iman; Safari Sinegani, Ali Akbar

    2016-02-01

    The low efficiency of phytoremediation is a considerable problem that limits the application of this environmentally friendly method on heavy metal-polluted soils. The combination of chelate-assisted phytoextraction and electrokinetic remediation could offer new opportunities to improve the effectiveness of phytoextraction. The current experiment aims to investigate the effects of electrical fields and chelating agents on phytoremediation efficiency. In a pot experiment using mine soil, poultry manure extract (PME), cow manure extract (CME), and ethylenediaminetetraacetic acid (EDTA) were applied to soil as chelating agents (2 g kg(-1)) at the beginning of the flowering stage. A week later, Helianthus annuus (sunflower) was negatively charged by inserting a stainless steel needle with 10 and 30 V DC electricity in the lowest part of the stems for 1 h each day for a 14-day period. At the end of the experiment, the shoot and root dry weight, lead (Pb) concentration in plant organs, translocation factor (TF), metal uptake index (UI), and soil available Pb (diethylene triamine pentaacetic acid (DTPA) extractable) were detected. Results indicated that the application of electrical fields had no significant impact on the shoot and root dry weights, while Pb concentration and UI increased in the 10-V EDTA treatment by 500 % compared to control. There was no significant difference between UI in 30- and 10-V EDTA treatments. Soil available Pb significantly increased in the 30-V treated soil. A positive correlation was observed between the available Pb in soil near the root and Pb concentration in shoot, its TF, and UI. In conclusion, a negatively charged plant along with the application of EDTA significantly increased the phytoremediation efficiency.

  1. Improving the efficiency of phytoremediation using electrically charged plant and chelating agents.

    PubMed

    Tahmasbian, Iman; Safari Sinegani, Ali Akbar

    2016-02-01

    The low efficiency of phytoremediation is a considerable problem that limits the application of this environmentally friendly method on heavy metal-polluted soils. The combination of chelate-assisted phytoextraction and electrokinetic remediation could offer new opportunities to improve the effectiveness of phytoextraction. The current experiment aims to investigate the effects of electrical fields and chelating agents on phytoremediation efficiency. In a pot experiment using mine soil, poultry manure extract (PME), cow manure extract (CME), and ethylenediaminetetraacetic acid (EDTA) were applied to soil as chelating agents (2 g kg(-1)) at the beginning of the flowering stage. A week later, Helianthus annuus (sunflower) was negatively charged by inserting a stainless steel needle with 10 and 30 V DC electricity in the lowest part of the stems for 1 h each day for a 14-day period. At the end of the experiment, the shoot and root dry weight, lead (Pb) concentration in plant organs, translocation factor (TF), metal uptake index (UI), and soil available Pb (diethylene triamine pentaacetic acid (DTPA) extractable) were detected. Results indicated that the application of electrical fields had no significant impact on the shoot and root dry weights, while Pb concentration and UI increased in the 10-V EDTA treatment by 500 % compared to control. There was no significant difference between UI in 30- and 10-V EDTA treatments. Soil available Pb significantly increased in the 30-V treated soil. A positive correlation was observed between the available Pb in soil near the root and Pb concentration in shoot, its TF, and UI. In conclusion, a negatively charged plant along with the application of EDTA significantly increased the phytoremediation efficiency. PMID:26423283

  2. Effect of Systemic Iron Overload and a Chelation Therapy in a Mouse Model of the Neurodegenerative Disease Hereditary Ferritinopathy.

    PubMed

    Garringer, Holly J; Irimia, Jose M; Li, Wei; Goodwin, Charles B; Richine, Briana; Acton, Anthony; Chan, Rebecca J; Peacock, Munro; Muhoberac, Barry B; Ghetti, Bernardino; Vidal, Ruben

    2016-01-01

    Mutations in the ferritin light chain (FTL) gene cause the neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF). HF is characterized by a severe movement disorder and by the presence of nuclear and cytoplasmic iron-containing ferritin inclusion bodies (IBs) in glia and neurons throughout the central nervous system (CNS) and in tissues of multiple organ systems. Herein, using primary mouse embryonic fibroblasts from a mouse model of HF, we show significant intracellular accumulation of ferritin and an increase in susceptibility to oxidative damage when cells are exposed to iron. Treatment of the cells with the iron chelator deferiprone (DFP) led to a significant improvement in cell viability and a decrease in iron content. In vivo, iron overload and DFP treatment of the mouse model had remarkable effects on systemic iron homeostasis and ferritin deposition, without significantly affecting CNS pathology. Our study highlights the role of iron in modulating ferritin aggregation in vivo in the disease HF. It also puts emphasis on the potential usefulness of a therapy based on chelators that can target the CNS to remove and redistribute iron and to resolubilize or prevent ferritin aggregation while maintaining normal systemic iron stores. PMID:27574973

  3. Effect of Systemic Iron Overload and a Chelation Therapy in a Mouse Model of the Neurodegenerative Disease Hereditary Ferritinopathy

    PubMed Central

    Li, Wei; Goodwin, Charles B.; Richine, Briana; Acton, Anthony; Chan, Rebecca J.; Peacock, Munro; Muhoberac, Barry B.; Ghetti, Bernardino; Vidal, Ruben

    2016-01-01

    Mutations in the ferritin light chain (FTL) gene cause the neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF). HF is characterized by a severe movement disorder and by the presence of nuclear and cytoplasmic iron-containing ferritin inclusion bodies (IBs) in glia and neurons throughout the central nervous system (CNS) and in tissues of multiple organ systems. Herein, using primary mouse embryonic fibroblasts from a mouse model of HF, we show significant intracellular accumulation of ferritin and an increase in susceptibility to oxidative damage when cells are exposed to iron. Treatment of the cells with the iron chelator deferiprone (DFP) led to a significant improvement in cell viability and a decrease in iron content. In vivo, iron overload and DFP treatment of the mouse model had remarkable effects on systemic iron homeostasis and ferritin deposition, without significantly affecting CNS pathology. Our study highlights the role of iron in modulating ferritin aggregation in vivo in the disease HF. It also puts emphasis on the potential usefulness of a therapy based on chelators that can target the CNS to remove and redistribute iron and to resolubilize or prevent ferritin aggregation while maintaining normal systemic iron stores. PMID:27574973

  4. Effect of a novel chelating agent on defect removal during post-CMP cleaning

    NASA Astrophysics Data System (ADS)

    Hong, Jiao; Niu, Xinhuan; Liu, Yuling; He, Yangang; Zhang, Baoguo; Wang, Juan; Han, Liying; Yan, Chenqi; Zhang, Jin

    2016-08-01

    Chemical mechanical polishing (CMP) has become widely accepted for the planarization of device interconnect structures in deep submicron semiconductor manufacturing. However, during CMP process the foreign particles, metal contaminants, and other chemical components are introduced onto the wafer surface, so CMP process is considered as one of the dirtiest process to wafer surface defects which may damage the GLSI patterns and the metallic impurities can induce many crystal defects in wafers during the following furnace processing. Therefore, the post-CMP cleaning of wafers has become a key step in successful CMP process and the polyvinyl alcohol (PVA) brush cleaning is the most effective method for post-CMP in situ cleaning. In this study, the effect of the chelating agent with different concentrations on defect removal by using PVA brush cleaning was discussed emphatically. It can be seen from the surface images obtained by scanning electron microscopy and KLA digital comparison system analysis confirmed that the chelating agent can effectively act on the defect removal.

  5. Dissolution of metal oxides accumulated in nuclear steam generators: study of solutions containing organic chelating agents

    SciTech Connect

    Gilbert, R.; Ouellet, L.

    1985-03-01

    A study of the reactivity of ethylenediaminetetraacetic acid (EDTA), citric acid, and hydrazine for the dissolution of magnetite particles has allowed some steps of the different mechanisms to be identified. Two mechanisms are suggested: In acidic solutions, the chelating agents are adsorbed at the solid/solution interface followed by desorption of the complexed species FeH /SUB n/ L, where HnL is EDTA or citric acid, whereas in alkaline media, direct dissolution of the oxide particles takes place followed by complexation of the species Fe/sup 3 +//Fe/sup 2 +/ in solution. The hydrazine apparently reduces the Fe/sup 3 +/ ions via a surface complexing reaction involving the N/sub 2/H/sub +//sub 5/ ions, a reaction which is in competition with the protonation of the Fe/sub 3/O/sub 4/ crystal lattice. Finally, regardless of the type of oxide (Fe/sub 3/O/sub 4/, Fe/sub 2/O/sub 3/, FeOOH, CuO, or Cu/sub 2/O) or the composition of the complexing solutions, suspensions of these particles are highly unstable with respect to agglomeration or settling out, more because of the high concentration of chelating agents than their chemical characteristics.

  6. Investigation of stabilization mechanism and size controlling of Fe3O4 nanoparticles using anionic chelating agents

    NASA Astrophysics Data System (ADS)

    Ghazanfari, Mohammad Reza; Kashefi, Mehrdad; Jaafari, Mahmoud Reza

    2016-07-01

    Chelating agents have potential effects on different properties of nanoparticles. Fe3O4 nanoparticles were synthesizes Using coprecipitation technique and oxalic, citric, stearic and lauric acids with concentrations of 0.5, 1, 2, and 5 vol% were utilized as the chelating agents. Subsequently, stability, structural, and magnetic properties of the samples were studied using measurement of zeta potential as well as FT-IR, XRD, DLS, TEM, and VSM analyses. It was found that the lower end of the size range was achieved for all samples utilizing 2 vol% chelating agents. So, in the present study, it was chosen as the optimum volume percentage of the chelating agents. Furthermore, for the nanoparticles treated with oxalic and citric acids, particle sizes were lower and the zeta potentials were larger comparing to those treated with stearic and lauric acids, which is an indication of their higher stabilization ability. Finally, the type of chelating agents had negligible effects on the structural and magnetic properties of the synthesized nanoparticles.

  7. Changes in gene expression with iron loading and chelation in cardiac myocytes and non-myocytic fibroblasts.

    PubMed

    Parkes, J G; Liu, Y; Sirna, J B; Templeton, D M

    2000-02-01

    Iron overload is associated with long-term cardiac iron accumulation and tissue changes such as fibrosis. To determine short-term iron-dependent changes in expression of genes associated with iron homeostasis and fibrosis we measured mRNA on Northern blots prepared from cultured rat neonatal cardiomyocytes and non-myocytes (fibroblasts) as a function of iron loading and chelation. Transferrin receptor mRNA was reduced in myocytes exposed to various concentrations of iron for 3 days and this decline was associated with a 63% decline in iron-response element (IRE) binding of iron regulatory protein-1, indicating that myocytes utilize IRE-dependent mechanisms to modulate gene expression. In myocytes iron caused a dose-dependent decline in mRNAs coding for transforming growth factor- beta(1)(TGF- beta(1)), biglycan, and collagen type I while plasminogen activator inhibitor-1 mRNA was unaffected by iron loading and decorin mRNA doubled. Total TGF- beta bioactivity was also decreased by iron loading. Thus, the effects of iron loading on genes related to cardiac fibrosis are gene-specific. Addition of deferoxamine for 1 day did not have any significant effect on any of these genes. Parallel changes in gene expression were exhibited by non-myocytes (fibroblasts), where chelation also decreased TGF- beta(1)mRNA and activity, and mRNA for collagen type I and biglycan, and collagen synthesis. In addition to these changes in transcripts associated with matrix formation the mRNA of the metabolic enzyme glyceraldehyde-3-phosphate dehydrogenase was unaffected by iron loading but doubled in both cell types upon treatment with deferoxamine. These findings suggest that in both cardiac myocytes and non-myocyte fibroblasts gene expression is coupled to intracellular iron pools by gene-specific and IRE-dependent and idependent mechanisms. This linkage may influence matrix deposition, a significant component of cardiac injury.

  8. Impact of iron chelators on short-term dissolution of basaltic glass

    NASA Astrophysics Data System (ADS)

    Perez, Anne; Rossano, Stéphanie; Trcera, Nicolas; Verney-Carron, Aurélie; Huguenot, David; van Hullebusch, Eric D.; Catillon, Gilles; Razafitianamaharavo, Angelina; Guyot, François

    2015-08-01

    Although microorganisms seem to play an important role in the alteration processes of basaltic glasses in solution, the elementary mechanisms involved remain unclear in particular with regard to the role of organic ligands excreted by the cells. Two glasses, one with Fe and one without Fe were synthesized to model basaltic glass compositions. Fe in the glass was mostly Fe(III) for enhancing interaction with siderophores, yet with small but significant amounts of Fe(II) (between 10% and 30% of iron). The prepared samples were submitted to abiotic alteration experiments in buffered (pH 6.4) diluted solutions of metal-specific ligands, namely oxalic acid (OA, 10 mM), desferrioxamine (DFA, 1 mM) or 2,2‧-bipyridyl (BPI, 1 mM). Element release from the glass into the solution after short term alteration (maximum 1 week) was measured by ICP-OES, and normalized mass losses and relative release ratios (with respect to Si) were evaluated for each element in each experimental condition. The presence of organic ligands had a significant effect on the dissolution of both glasses. Trivalent metals chelators (OA, DFA) impacted on the release of Fe3+ and Al3+, and thus on the global dissolution of both glasses, enhancing all release rates and dissolution stoichiometry (release rates were increased up to 7 times for Al or Fe). As expected, the mostly divalent metal chelator BPI interacted preferentially with Ca2+, Mg2+ and Fe2+. This study thus allows to highlight the central roles of iron and aluminium in interaction with some organic ligands in the alteration processes of basaltic glasses. It thus provides a step toward understanding the biological contribution of this fundamental geological process.

  9. In Vivo Iron-Chelating Activity and Phenolic Profiles of the Angel's Wings Mushroom, Pleurotus porrigens (Higher Basidiomycetes).

    PubMed

    Khalili, Masoumeh; Ebrahimzadeh, Mohammad Ali; Kosaryan, Mehrnoush

    2015-01-01

    Pleurotus porrigens is an culinary-medicinal mushroom. It is locally called sadafi and is found in the northern regions of Iran, especially in Mazandaran. This mushroom is used to prepare a variety of local and specialty foods. Because of the phenol and flavonoid contents and the strong iron-chelating activity of this mushroom, it was selected for an assay of in vivo iron-chelating activity. Methanolic extract was administered intraperitoneally to iron-overloaded mice at two dosages (200 and 400 mg/kg/24 hours) for a total of 20 days, with a frequency of 5 times a week for 4 successive weeks. The total iron content was determined by atomic absorption spectroscopy. Plasma Fe3+ content was determined using a kit. Liver sections were stained by hematoxylin and eosin and Perls stain. A significant decrease in the plasma concentration of iron was observed in mice treated with extracts (P < 0.001). The animals showed a dramatic decrease in plasma Fe3+ content when compared with the control group (P < 0.001). Also, Perls stain improved the smaller amount of deposited iron in the liver of iron-overloaded mice treated with the extract. Liver sections revealed a marked reduction in the extent of necrotic hepatocytes, fibrous tissues, and pseudo-lobules. A high-performance liquid chromatography method was developed to simultaneously separate 7 phenolic acids in extract. Rutin (1.784 ± 0.052 mg g(-1) of extract) and p-coumaric acid (1.026 ± 0.043 mg g(-1) of extract) were detected as the main flavonoid and phenolic acids in extract, respectively. The extract exhibited satisfactory potency to chelate excessive iron in mice, potentially offering new natural alternatives to treat patients with iron overload. More studies are needed to determine which compounds are responsible for these biological activities.

  10. Iron Oxide as an MRI Contrast Agent for Cell Tracking

    PubMed Central

    Korchinski, Daniel J.; Taha, May; Yang, Runze; Nathoo, Nabeela; Dunn, Jeff F.

    2015-01-01

    Iron oxide contrast agents have been combined with magnetic resonance imaging for cell tracking. In this review, we discuss coating properties and provide an overview of ex vivo and in vivo labeling of different cell types, including stem cells, red blood cells, and monocytes/macrophages. Furthermore, we provide examples of applications of cell tracking with iron contrast agents in stroke, multiple sclerosis, cancer, arteriovenous malformations, and aortic and cerebral aneurysms. Attempts at quantifying iron oxide concentrations and other vascular properties are examined. We advise on designing studies using iron contrast agents including methods for validation. PMID:26483609

  11. EFFECT OF CHELATING AGENTS ON THE GROWTH OF ESCHERICHIA COLI IN SEAWATER.

    PubMed

    JONES, G E

    1964-03-01

    Jones, Galen E. (Scripps Institution of Oceanography, University of California, La Jolla). Effect of chelating agents on the growth of Escherichia coli in seawater. J. Bacteriol. 87:483-499. 1964.-Escherichia coli did not grow at 37 C, or grew only after a prolonged lag phase in filter-sterilized basal seawater medium (synthetic or natural seawater supplemented with glucose, NH(4)Cl, and K(2)HPO(4)). When this basal medium was enriched with 0.01% or less organic matter, such as casein hydrolysate, peptone, or yeast extract, growth always occurred after a short lag phase. Adding 10(-5)m cysteine or autoclaving the seawater gave a similar effect. A variety of organic chelating agents (histidine, glycine, methionine, glycylglycine, 8-hydroxyquinoline, thioglycolic acid, o-phenanthroline, disodium ethylenediaminetetraacetic acid, etc.) reversed the toxicity of filter-sterilized basal seawater medium in concentrations predictable from stability constants. Even metal-complexing agents such as Na(2)S(2)O(3), Na(2)S, and NaCN in appropriate concentrations reversed toxicity. The quality of the distilled water and the treatment of glassware had a significant effect on the growth of E. coli in basal seawater medium. It was concluded that iodate is probably not the toxic substance for E. coli in seawater, since relatively high concentrations were stimulatory. The inhibition resulting from the individual salts of synthetic seawater was proportional to their concentration; NaCl was most inhibitory. This toxicity is believed to be derived from trace impurities in the reagent-grade chemicals used to prepare synthetic seawater. Evidence was also found for the toxicity of heavy metals in natural seawater. Heavy metals in seawater appear to inhibit growth but not respiration. PMID:14127563

  12. Determination of ferric iron chelators by high-performance liquid chromatography using luminol chemiluminescence detection.

    PubMed

    Ariga, Tomoko; Imura, Yuki; Suzuki, Michio; Yoshimura, Etsuro

    2016-03-01

    Iron is an essential element for higher plants, and its acquisition and transportation is one of the greatest limiting factors for plant growth because of its low solubility in normal soil pHs. Higher plants biosynthesize ferric iron [Fe(III)] chelator (FIC), which solubilizes the iron and transports it to the rhizosphere. A high-performance liquid chromatography (HPLC) post-column method has been developed for the analysis of FICs using the luminol/H2O2 system for chemiluminescence (CL) detection. A size-exclusion column was the most suited in terms of column efficiency and CL detection efficiency. Mixing of the luminol with H2O2 in a post-column reaction was feasible, and a two-pump system was used to separately deliver the luminol and H2O2 solutions. The luminol and H2O2 concentrations were optimized using Fe(III)-EDTA and Fe(III)-citrate (Cit) solutions as analytes. A strong CL intensity was obtained for Fe(III)-Cit when EDTA was added to the luminol solution, probably because of an exchange of Cit with EDTA after separation on the HPLC column; CL efficiency was much higher for Fe(III)-EDTA than for Fe(III)-Cit with the luminol/H2O2 system. The present method can detect minute levels of Fe(III)-FICs; the detection limits of Fe(III)-EDTA, Fe(III)-Cit and Fe(III)-nicotianamine were 0.77, 2.3 and 1.1pmol, respectively. PMID:26874881

  13. Inhibition of the growth of Neisseria meningitidis by reduced ferritin and other iron-binding agents.

    PubMed Central

    Calver, G A; Kenny, C P; Kushner, D J

    1979-01-01

    Serogroups of N. meningitidis were characterized as virulent or avirulent according to their capacity to establish meningococcal infection in mice. An agar plate diffusion technique demonstrated that iron had a definite growth-supporting role for both of these meningococcal types. The avirulent strains could use ionic or chelated iron as well as the virulent strains. Iron-reversible growth inhibition occurred to the same extent for both bacterial types in the presence of the synthetic iron-chelating agents Desferal and ethylenediamine-di-orthohydroxy phenylacetic acid. A difference in response was demonstrated for these bacterial types when grown in the presence of various iron-binding proteins from animal body fluids and tissues. The growth of the avirulent strain was inhibited to a greater degree by egg white conalbumin. The humoral iron-binding protein transferrin showed a significant inhibitory capacity only when used in conjunction with bicarbonate. Under conditions of increased iron saturation of this protein, the avirulent strain was inhibited to the furthest extent. In the presence of ferritin, the cellular iron-binding protein, which had been reduced, inhibition of the growth of either strain type did not occur on iron-poor media (less than 5 micrograms/100 ml). However, with the incorporation of iron into the media, the inhibitory effect of the protein became evident. As the concentration of iron increased, the inhibition increased to a certain level and subsequently declined. A substantial difference in the ability of the avirulent type to grow in the presence of reduced horse spleen ferritin was observed. For this microorganism, a correlation appears to exist between the capacity to grow by utilizing the available iron in the presence of reduced ferritin and the ability to establish infection. The host protein ferritin, in the reduced state, apart from simply being a storage protein for iron, can prevent the growth of a procaryotic organism. Our

  14. Iron(II) PARACEST MRI contrast agents.

    PubMed

    Dorazio, Sarina J; Tsitovich, Pavel B; Siters, Kevin E; Spernyak, Joseph A; Morrow, Janet R

    2011-09-14

    The first examples of Fe(II) PARACEST magnetic resonance contrast agents are reported (PARACEST = paramagnetic chemical exchange saturation transfer). The iron(II) complexes contain a macrocyclic ligand, either 1,4,7-tris(carbamoylmethyl)-1,4,7-triazacyclononane (L1) or 1,4,7-tris[(5-amino-6-methyl-2-pyridyl)methyl]-1,4,7-triazacyclononane (L2). The macrocycles bind Fe(II) in aqueous solution with formation constants of log K = 13.5 and 19.2, respectively, and maintain the Fe(II) state in the presence of air. These complexes each contain six exchangeable protons for CEST which are amide protons in [Fe(L1)](2+) or amino protons in [Fe(L2)](2+). The CEST peak for the [Fe(L1)](2+) amide protons is at 69 ppm downfield of the bulk water resonance whereas the CEST peak for the [Fe(L2)](2+) amine protons is at 6 ppm downfield of bulk water. CEST imaging using a MRI scanner shows that the CEST effect can be observed in solutions containing low millimolar concentrations of complex at neutral pH, 100 mM NaCl, 20 mM buffer at 25 °C or 37 °C.

  15. Iron overload-related heart failure in a patient with transfusion-dependent myelodysplastic syndrome reversed by intensive combined chelation therapy.

    PubMed

    Pinto, Valeria; Balocco, Manuela; Ambaglio, Ilaria; Derchi, Giorgio; Malcovati, Luca; Forni, Gian Luca

    2015-11-01

    Patients with transfusion-dependent myelodysplastic syndromes (MDS) have an increased risk of cardiac events, due to both chronic anemia and iron overload. Here, we report the recovery of cardiac function after an intensive iron chelation therapy in a MDS patient who had developed heart failure due to iron overload.

  16. Caustic Leaching of SRS Tank 12H Sludge With and Without Chelating Agents

    SciTech Connect

    Spencer, B.B.

    2003-04-30

    The primary objective of this study was to measure the effect of adding triethanolamine (TEA) to caustic leaching solutions to improve the solubility of aluminum in actual tank-waste sludge. High-level radioactive waste sludge that had a high aluminum assay was used for the tests. This waste, which originated with the processing of aluminum-clad/aluminum-alloy fuels, generates high levels of heat because of the high {sup 90}Sr concentration and contains hard-to-dissolve boehmite phases. In concept, a chelating agent, such as TEA, can both improve the dissolution rate and increase the concentration in the liquid phase. For this reason, TEA could also increase the solubility of other sludge components that are potentially problematic to downstream processing. Tests were conducted to determine if this were the case. Because of its relatively high vapor pressure, process design should include methods to minimize losses of the TEA. Sludge was retrieved from tank 12H at the Savannah River Site by on-site personnel, and then shipped to Oak Ridge National Laboratory for the study. The sludge contained a small quantity of rocky debris. One slate-like flat piece, which had approximate dimensions of 1 1/4 x 1/2 x 1/8 in., was recovered. Additional gravel-like fragments with approximate diameters ranging from 1/8 to 1/4 in. were also recovered by sieving the sludge slurry through a 1.4-mm square-pitch stainless steel mesh. These particles ranged from a yellow quartz-like material to grey-colored gravel. Of the 32.50 g of sludge received, the mass of the debris was only 0.89 g, and the finely divided sludge comprised {approx}97% of the mass. The sludge was successfully subdivided into uniform aliquots during hot-cell operations. Analytical measurements confirmed the uniformity of the samples. The smaller sludge samples were then used as needed for leaching experiments conducted in a glove box. Six tests were performed with leachate concentrations ranging from 0.1 to 3.0 m Na

  17. Mechanism of sorption sulpho-derivative organic chelating agents on strong base anion exchanger Amberlite IRA-402 by FT-IR/PAS and DRS methods

    NASA Astrophysics Data System (ADS)

    Wronski, G.; Pasieczna-Patkowska, S.; Hubicki, Z.

    2008-02-01

    In the paper, strong base anion exchanger Amberlite IRA-402 was modified by using sulpho-derivative organic chelating agents as: Brilliant Yellow, Xylenol Orange, Bromophenyl Blue. The investigations exhibited, that anion exchanger Amberlite IRA-402 is modified very simply by organic chelating agents (working capacity 0.25 0.5 g/cm3).

  18. Thumbnail Sketches: EDTA-Type Chelating Agents in Everyday Consumer Products: Some Food, Cleaning, and Photographic Applications.

    ERIC Educational Resources Information Center

    Hart, J. Roger

    1985-01-01

    Discusses the role of chelating agents in (1) mayonnaise and salad dressings; (2) canned legumes; (3) plant foods; (4) liquid dishwashing detergents; (5) toilet soaps; (6) floor wax removers; (7) hard surface cleaners; (8) carpet cleaning; (9) bathtub and tile cleaners; and (10) photography. (JN)

  19. Exploring the "iron shuttle" hypothesis in chelation therapy: effects of combined deferoxamine and deferiprone treatment in hypertransfused rats with labeled iron stores and in iron-loaded rat heart cells in culture.

    PubMed

    Link, G; Konijn, A M; Breuer, W; Cabantchik, Z I; Hershko, C

    2001-08-01

    Although iron chelation therapy results in a significant improvement in well-being and life expectancy of thalassemic patients with transfusional iron overload, failure to achieve these goals in a substantial proportion of patients underlines the need for improved methods of treatment. In the present studies we used selective radioactive iron probes of hepatocellular and reticuloendothelial (RE) iron stores in hypertransfused rats and iron-loaded heart cells to compare the source of iron chelated in vivo by deferoxamine (DFO) or by deferiprone (L1) and its mode of excretion, to examine the ability of DFO and L1 to remove iron directly from iron-loaded myocardial cells, and to examine the mechanism of their combined interaction through a possible additive or synergistic effect. Our results indicate that L1 given orally is 1.6 to 1.9 times more effective in rats, on a weight-per-weight basis, than parenteral DFO in promoting the excretion of storage iron from parenchymal iron stores but shows no advantage over DFO in promoting RE iron excretion. Simultaneous administration of DFO and L1 results in an increase in chelating effect that is additive but not synergistic. The magnitude of this additive effect is identical to an increase in the equivalent (weight or molar) dose of DFO alone rather than the sum of the separate effects of L1 and DFO. This finding is most probably the result of a transfer of chelated iron from L1 to DFO. These observations may have practical implications for current efforts to design better therapeutic strategies for the management of transfusional iron overload.

  20. Plant-derived phenolic compounds prevent the DNA single-strand breakage and cytotoxicity induced by tert-butylhydroperoxide via an iron-chelating mechanism.

    PubMed Central

    Sestili, Piero; Diamantini, Giuseppe; Bedini, Annalida; Cerioni, Liana; Tommasini, Ilaria; Tarzia, Giorgio; Cantoni, Orazio

    2002-01-01

    The protective effects of selected members from a series of caffeic acid esters and flavonoids were tested in various toxicity paradigms using U937 cells, previously shown to be sensitive to either iron chelators or bona fide radical scavengers or to both classes of compounds. It was found that all the protective polyphenols were active at very low concentrations and that their effects were observed only under those conditions in which iron chelators also afforded protection. Consistently, active polyphenolic compounds, unlike the inactive ones, effectively chelated iron in an in vitro system. It follows that, at least under the experimental conditions utilized in the present study, the most prominent activity of these polyphenolic compounds resides in their ability to chelate iron. Further studies revealed that the protective effects afforded by the caffeic acid esters and flavonoids were largely mediated by the catechol moiety and that the relative biological potency of these compounds was a direct function of their lipophilicity. PMID:11988084

  1. Iron chelation attenuates intracranial pressure and improves survival in a swine model of acute liver failure.

    PubMed

    Arkadopoulos, Nikolaos; Vlahakos, Demetrios; Kostopanagiotou, Georgia; Panagopoulos, Dimitrios; Karvouni, Eleni; Routsi, Christina; Kalimeris, Konstantinos; Andreadou, Ioanna; Kouskouni, Evangelia; Smyrniotis, Vassilios

    2008-08-01

    Oxidative mechanisms have been implicated in the pathogenesis of brain edema in acute liver failure (ALF). The aim of this study was to test the hypothesis that inhibition of iron-catalyzed oxidative reactions through iron chelation using deferoxamine could attenuate brain edema in a swine model of ischemic ALF. Following ALF induction (end-to-side portacaval anastomosis and ligation of the hepatoduodenal ligament), 14 animals were randomized to a study group that received an intravenous infusion of 150 mg/kg deferoxamine (group DF; n = 7) or a control group (group C; n = 7). Six sham-operated animals were also assigned to a deferoxamine-treated group (n = 3) or a control group (n = 3). Hemodynamic, neurological, and hematological parameters were monitored postoperatively. All sham animals maintained normal hemodynamics and intracranial pressure. At 18 hours, group DF animals had higher mean arterial pressure (mean +/- standard deviation: 98.0 +/- 15.9 versus 69.9 +/- 15.8 mmHg, P < 0.004), lower intracranial pressure (18.1 +/- 8.6 versus 32.7 +/- 13.4 mmHg, P < 0.032), and higher cerebral perfusion pressure (76.4 +/- 16.4 versus 37.1 +/- 25.6 mmHg, P < 0.006) in comparison with group C. Similar differences were recorded up to the 24th postoperative hour, leading to a significant difference in animal survival (88% in group DF versus 17% in group C, P < 0.001). Furthermore, group DF exhibited an attenuated increase of serum malondialdehyde from the baseline (16% versus 74%, P < 0.05) and lower brain malondialdehyde concentrations (3.7 +/- 1.3 versus 5.7 +/- 2.0 microM/mg of protein, P < 0.05) in comparison with controls. In conclusion, deferoxamine delayed the development of intracranial hypertension and improved survival in pigs with ischemic ALF.

  2. Synthetic and Predictive Approach to Unsymmetrical Biphenols by Iron-Catalyzed Chelated Radical-Anion Oxidative Coupling.

    PubMed

    Libman, Anna; Shalit, Hadas; Vainer, Yulia; Narute, Sachin; Kozuch, Sebastian; Pappo, Doron

    2015-09-01

    An iron-catalyzed oxidative unsymmetrical biphenol coupling in 1,1,1,3,3,3-hexafluoropropan-2-ol that proceeds via a chelated radical-anion coupling mechanism was developed. Based on mechanistic studies, electrochemical methods, and density functional theory calculations, we suggest a general model that enables prediction of the feasibility of cross-coupling for a given pair of phenols. PMID:26287435

  3. Rapid monitoring of iron-chelating therapy in thalassemia major by a new cardiovascular MR measure: the reduced transverse relaxation rate.

    PubMed

    Kim, Daniel; Jensen, Jens H; Wu, Ed X; Feng, Li; Au, Wing-Yan; Cheung, Jerry S; Ha, Shau-Yin; Sheth, Sujit S; Brittenham, Gary M

    2011-08-01

    In iron overload, almost all the excess iron is stored intracellularly as rapidly mobilizable ferritin iron and slowly exchangeable hemosiderin iron. Increases in cytosolic iron may produce oxidative damage that ultimately results in cardiomyocyte dysfunction. Because intracellular ferritin iron is evidently in equilibrium with the low-molecular-weight cytosolic iron pool, measurements of ferritin iron potentially provide a clinically useful indicator of changes in cytosolic iron. The cardiovascular magnetic resonance (CMR) index of cardiac iron used clinically, the effective transverse relaxation rate (R(2)*), is principally influenced by hemosiderin iron and changes only slowly over several months, even with intensive iron-chelating therapy. Another conventional CMR index of cardiac iron, the transverse relaxation rate (R(2)), is sensitive to both hemosiderin iron and ferritin iron. We have developed a new MRI measure, the 'reduced transverse relaxation rate' (RR(2)), and have proposed in previous studies that this measure is primarily sensitive to ferritin iron and largely independent of hemosiderin iron in phantoms mimicking ferritin iron and human liver explants. We hypothesized that RR(2) could detect changes produced by 1 week of iron-chelating therapy in patients with transfusion-dependent thalassemia. We imaged 10 patients with thalassemia major at 1.5 T in mid-ventricular short-axis planes of the heart, initially after suspending iron-chelating therapy for 1 week and subsequently after resuming oral deferasirox. After resuming iron-chelating therapy, significant decreases were observed in the mean myocardial RR(2) (7.8%, p < 0.01) and R(2) (5.5%, p < 0.05), but not in R(2)* (1.7%, p > 0.90). Although the difference between changes in RR(2) and R(2) was not significant (p > 0.3), RR(2) was consistently more sensitive than R(2) (and R(2)*) to the resumption of iron-chelating therapy, as judged by the effect sizes of relaxation rate differences detected

  4. Competitive binding of plutonium and americium with bone mineral and novel chelating agents

    SciTech Connect

    Guilmette, Ray A.; Hakimi, R.; Durbin, P. W.; Xu, J.; Raymond, K. N.

    2002-01-01

    Effective direct removal of actinides such as Pu and Am from bone in vivo has not been accomplished to date, even with the strong chelating agents CaNa{sub 3}DTPA or ZnNa{sub 3}DTPA. This study, using an established in vitro system, compared removal of Pu and Am bound to bone mineral by ZnNa{sub 3}DTPA and 10 chelating agents designed specifically to sequester actinides, including Pu and Am. Ligands tested were tetra-, hexa, and octadentate with linear or branched backbones containing sulfocatechol [CAM(S)], hydroxycatechol [CAM(C)], hydroxipyridinone (1,2-HOPO, Me-3,2-HOPO), or hydroxamate functional groups. The wide range of Pu and Am removal exhibited by the test ligands generally agreed with their metal coordination and chemical properties. The most effective agents for Pu (100 {micro}M concentration, 24-48 h contact) are all octadentate as follows: 3,4,3-LICAM(S) (54% unbound), 3,4,3-LICAM(C) (6.2%), 3,4,3-LI(1,2-HOPO) (3.8%), H(2,2)-(Me-3,2-HOPO) (2.2%) and DFO-(1,2-HOPO) (1.8%). The other ligands removed less than 1% of the bound Pu, and ZnNa{sub 3}DTPA removed only 0.086%. The most effective ligands for Am removal (100 {micro}M, 24-48 h contact) are as follows: octadentate H(2,2)-(Me-3,2-HOPO) (21% unbound), 3,4,3-LI(1,2-HOPO) (14.5%), and 3,4,3-LICAM(C) (5.9%), hexadentate TREN-(Me-3,2-HOPO) and TREN-(1,2-HOPO) (9.6%), and tetradentate 5-LIO(Me-3,2-HOPO) (5.2%). Am removal by ZnNa{sub 3}DTPA was about 1.4%. Among the ligands presently considered for possible human use, only 3,4,3-LI(1,2-HOPO) removed potentially useful amounts of both Pu and Am from bone mineral.

  5. Curcumin derivatives as metal-chelating agents with potential multifunctional activity for pharmaceutical applications.

    PubMed

    Ferrari, Erika; Benassi, Rois; Sacchi, Stefania; Pignedoli, Francesca; Asti, Mattia; Saladini, Monica

    2014-10-01

    Curcuminoids represent new perspectives for the development of novel therapeutics for Alzheimer's disease (AD), one probable mechanism of action is related to their metal complexing ability. In this work we examined the metal complexing ability of substituted curcuminoids to propose new chelating molecules with biological properties comparable with curcumin but with improved stability as new potential AD therapeutic agents. The K2T derivatives originate from the insertion of a -CH2COOC(CH3)3 group on the central atom of the diketonic moiety of curcumin. They retain the diketo-ketoenol tautomerism which is solvent dependent. In aqueous solution the prevalent form is the diketo one but the addition of metal ion (Ga(3+), Cu(2+)) causes the dissociation of the enolic proton creating chelate complexes and shifting the tautomeric equilibrium towards the keto-enol form. The formation of metal complexes is followed by both NMR and UV-vis spectroscopy. The density functional theory (DFT) calculations on K2T21 complexes with Ga(3+) and Cu(2+) are performed and compared with those on curcumin complexes. [Ga(K2T21)2(H2O)2](+) was found more stable than curcumin one. Good agreement is detected between calculated and experimental (1)H and (13)C NMR data. The calculated OH bond dissociation energy (BDE) and the OH proton dissociation enthalpy (PDE), allowed to predict the radical scavenging ability of the metal ion complexed with K2T21, while the calculated electronic affinity (EA) and ionization potential (IP) represent yardsticks of antioxidant properties. Eventually theoretical calculations suggest that the proton-transfer-associated superoxide-scavenging activity is enhanced after binding metal ions, and that Ga(3+) complexes display possible superoxide dismutase (SOD)-like activity.

  6. Cytoprotective role of astaxanthin against glycated protein/iron chelate-induced toxicity in human umbilical vein endothelial cells.

    PubMed

    Nishigaki, Ikuo; Rajendran, Peramaiyan; Venugopal, Ramachandran; Ekambaram, Gnapathy; Sakthisekaran, Dhanapal; Nishigaki, Yutaka

    2010-01-01

    Astaxanthin (ASX), a red carotenoid pigment with no pro-vitamin A activity, is a biological antioxidant that occurs naturally in a wide variety of plants, algae and seafoods. This study investigated whether ASX could inhibit glycated protein/iron chelate-induced toxicity in human umbilical-vein endothelial cells (HUVEC) by interfering with ROS generation in these cells. Glycated fetal bovine serum (GFBS) was prepared by incubating fetal bovine serum (FBS) with high-concentration glucose. Stimulation of cultured HUVECs with 50 mm 1 mL of GFBS significantly enhanced lipid peroxidation and decreased antioxidant enzyme activities and levels of phase II enzymes. However, preincubation of the cultures with ASX resulted in a marked decrease in the level of lipid peroxide (LPO) and an increase in the levels of antioxidant enzymes in an ASX concentration-dependent manner. These results demonstrate that ASX could inhibit LPO formation and enhance the antioxidant enzyme status in GFBS/iron chelate-exposed endothelial cells by suppressing ROS generation, thereby limiting the effects of the AGE-RAGE interaction. The results indicate that ASX could have a beneficial role against glycated protein/iron chelate-induced toxicity by preventing lipid and protein oxidation and increasing the activity of antioxidant enzymes. PMID:19548280

  7. The Exochelins of Pathogenic Mycobacteria: Unique, Highly Potent, Lipid- and Water-Soluble Hexadentate Iron Chelators with Multiple Potential Therapeutic Uses

    PubMed Central

    Horwitz, Lawrence D.

    2014-01-01

    Abstract Significance: Exochelins are lipid- and water-soluble siderophores of Mycobacterium tuberculosis with unique properties that endow them with exceptional pharmacologic utility. Exochelins can be utilized as probes to decipher the role of iron in normal and pathological states, and, since they rapidly cross cell membranes and chelate intracellular iron with little or no toxicity, exochelins are potentially useful for the treatment of a number of iron-dependent pathological phenomena. Recent Advances: In animal models, exochelins have been demonstrated to have promise for the treatment of transfusion-related iron overload, restenosis after coronary artery angioplasty, cancer, and oxidative injury associated with acute myocardial infarction and transplantation. Critical Issues: To be clinically effective, iron chelators should be able to rapidly enter cells and chelate iron at key intracellular sites. Desferri-exochelins, and other lipid-soluble chelators, can readily cross cell membranes and remove intracellular free iron; whereas deferoxamine, which is lipid insoluble, cannot do so. Clinical utility also requires that the chelators be nontoxic, which, we hypothesize, includes the capability to prevent iron from catalyzing free radical reactions which produce •OH or other reactive oxygen species. Lipid-soluble iron chelators currently available for clinical application are bidentate (deferiprone) or tridentate (desferasirox) molecules that do not block all six sites on the iron molecule capable of catalyzing free radical reactions. In contrast, desferri-exochelins are hexadentate molecules, and by forming a one-to-one binding relationship with iron, they prevent free radical reactions. Future Directions: Clinical studies are needed to assess the utility of desferri-exochelins in the treatment of iron-dependent pathological disorders. Antioxid. Redox Signal. 21, 2246–2261. PMID:24684595

  8. Chemical and biological properties of toxic metals and use of chelating agents for the pharmacological treatment of metal poisoning.

    PubMed

    Sinicropi, Maria Stefania; Amantea, Diana; Caruso, Anna; Saturnino, Carmela

    2010-07-01

    Exposure to toxic metals is a well-known problem in industrialized countries. Metals interfere with a number of physiological processes, including central nervous system (CNS), haematopoietic, hepatic and renal functions. In the evaluation of the toxicity of a particular metal it is crucial to consider many parameters: chemical forms (elemental, organic or inorganic), binding capability, presence of specific proteins that selectively bind metals, etc. Medical treatment of acute and chronic metal toxicity is provided by chelating agents, namely organic compounds capable of interacting with metal ions to form structures called chelates. The present review attempts to provide updated information about the mechanisms, the cellular targets and the effects of toxic metals.

  9. Iron chelation and a free radical scavenger suppress angiotensin II-induced upregulation of TGF-beta1 in the heart.

    PubMed

    Saito, Kan; Ishizaka, Nobukazu; Aizawa, Toru; Sata, Masataka; Iso-o, Naoyuki; Noiri, Eisei; Mori, Ichiro; Ohno, Minoru; Nagai, Ryozo

    2005-04-01

    Long-term administration of angiotensin II causes myocardial loss and cardiac fibrosis. We previously found iron deposition in the heart of the angiotensin II-infused rat, which may promote angiotensin II-induced cardiac damage. In the present study, we have investigated whether an iron chelator (deferoxamine) and a free radical scavenger (T-0970) affect the angiotensin II-induced upregulation of transforming growth factor-beta1 (TGF-beta1). Angiotensin II infusion for 7 days caused a robust increase in TGF-beta1 mRNA expression in vascular smooth muscle cells, myofibroblast-like cells, and migrated monocytes/macrophages. T-0970 and deferoxamine suppressed the upregulation of TGF-beta1 mRNA and reduced the extent of cardiac fibrosis in the heart of rats treated with angiotensin II. These agents blocked the angiotensin II-induced upregulation of heme oxygenase-1, a potent oxidative and cellular stress-responsive gene, but they did not significantly affect systolic blood pressure or plasma levels of aldosterone. In addition, T-0970 and deferoxamine suppressed the angiotensin II-induced upregulation of monocyte chemoattractant protein-1 in the heart. These results collectively suggest that iron and the iron-mediated generation of reactive oxygen species may contribute to angiotensin II-induced upregulation of profibrotic and proinflammatory genes, such as TGF-beta1 and monocyte chemoattractant protein-1.

  10. The Copper Sulfide Coating on Polyacrylonitrile with Chelating Agents by an Electroless Deposition Method and its EMI Shielding Effectiveness

    NASA Astrophysics Data System (ADS)

    Roan, Ming-Lih; Chen, Yen-Hung; Huang, Chi-Yuan

    2008-08-01

    In this study, a variety of concentrations of chelating agents were added to obtain the anchoring effect and chelating effect in the electroless plating bath. The mechanism of the Cux(x = 1,2)S growth and the electromagnetic interference shielding effectiveness (EMI SE) of the composite were studied. It was found that the vinyl acetate residued in PAN substrate would be purged due to the swelling effect by chelating agents solution. And then, the anchoring effect occurred due to the hydrogen bonding between the pits of PAN substrate and the chelating agent. Consequently, the copper sulfide layer deposited by the electroless plating reaction with EDTA and TEA. The swelling degree (Sd) was proposed and evaluated from the FT-IR spectra. The relationship between swelling degree of the PAN films and EDTA (C) is expressed as: Sd = 0.13+0.90×e∧(-15.15C). And TEA series is expressed as: Sd = 0.07+1.00×e∧(-15.15C). On the other hand, the FESEM micrograph showed that the average thickness of copper sulfide increased from 76 nm to 383 nm when the concentration of EDTA increased from 0.00M to 0.20M. Consequently, the EMI SE of the composites increased from 10˜12 dB to 25˜27 dB. The GIA-XRD analyze indicated that the deposited layer consisted of CuS and Cu2S.

  11. Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias

    PubMed Central

    Cappellini, Maria Domenica; Porter, John; El-Beshlawy, Amal; Li, Chi-Kong; Seymour, John F.; Elalfy, Mohsen; Gattermann, Norbert; Giraudier, Stéphane; Lee, Jong-Wook; Chan, Lee Lee; Lin, Kai-Hsin; Rose, Christian; Taher, Ali; Thein, Swee Lay; Viprakasit, Vip; Habr, Dany; Domokos, Gabor; Roubert, Bernard; Kattamis, Antonis

    2010-01-01

    Background Following a clinical evaluation of deferasirox (Exjade®) it was concluded that, in addition to baseline body iron burden, ongoing transfusional iron intake should be considered when selecting doses. The 1-year EPIC study, the largest ever investigation conducted for an iron chelator, is the first to evaluate whether fixed starting doses of deferasirox, based on transfusional iron intake, with dose titration guided by serum ferritin trends and safety markers, provides clinically acceptable chelation in patients (aged ≥2 years) with transfusional hemosiderosis from various types of anemia. Design and Methods The recommended initial dose was 20 mg/kg/day for patients receiving 2–4 packed red blood cell units/month and 10 or 30 mg/kg/day was recommended for patients receiving less or more frequent transfusions, respectively. Dose adjustments were based on 3-month serum ferritin trends and continuous assessment of safety markers. The primary efficacy end-point was change in serum ferritin after 52 weeks compared with baseline. Results The 1744 patients enrolled had the following conditions; thalassemia (n=1115), myelodysplastic syndromes (n=341), aplastic anemia (n=116), sickle cell disease (n=80), rare anemias (n=43) and other transfused anemias (n=49). Overall, there was a significant reduction in serum ferritin from baseline (−264 ng/mL; P<0.0001), reflecting dosage adjustments and ongoing iron intake. The most common (>5%) adverse events were gastrointestinal disturbances (28%) and skin rash (10%). Conclusions Analysis of this large, prospectively collected data set confirms the response to chelation therapy across various anemias, supporting initial deferasirox doses based on transfusional iron intake, with subsequent dose titration guided by trends in serum ferritin and safety markers (clinicaltrials.gov identifier: NCT00171821). PMID:19951979

  12. Structure-Activity Relationships of Novel Salicylaldehyde Isonicotinoyl Hydrazone (SIH) Analogs: Iron Chelation, Anti-Oxidant and Cytotoxic Properties

    PubMed Central

    Potůčková, Eliška; Hrušková, Kateřina; Bureš, Jan; Kovaříková, Petra; Špirková, Iva A.; Pravdíková, Kateřina; Kolbabová, Lucie; Hergeselová, Tereza; Hašková, Pavlína; Jansová, Hana; Macháček, Miloslav; Jirkovská, Anna; Richardson, Vera; Lane, Darius J. R.; Kalinowski, Danuta S.; Richardson, Des R.; Vávrová, Kateřina; Šimůnek, Tomáš

    2014-01-01

    Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, tridentate iron chelator with marked anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic ketones with improved hydrolytic stability). Their structure-activity relationships were assessed with respect to their stability in plasma, iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these chelators and their ability to afford protection against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity. The introduction of a bromine substituent increased ligand-induced cytotoxicity to both cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects. PMID:25393531

  13. Nitrosothiol formation and protection against Fenton chemistry by nitric oxide-induced dinitrosyliron complex formation from anoxia-initiated cellular chelatable iron increase.

    PubMed

    Li, Qian; Li, Chuanyu; Mahtani, Harry K; Du, Jian; Patel, Aashka R; Lancaster, Jack R

    2014-07-18

    Dinitrosyliron complexes (DNIC) have been found in a variety of pathological settings associated with (•)NO. However, the iron source of cellular DNIC is unknown. Previous studies on this question using prolonged (•)NO exposure could be misleading due to the movement of intracellular iron among different sources. We here report that brief (•)NO exposure results in only barely detectable DNIC, but levels increase dramatically after 1-2 h of anoxia. This increase is similar quantitatively and temporally with increases in the chelatable iron, and brief (•)NO treatment prevents detection of this anoxia-induced increased chelatable iron by deferoxamine. DNIC formation is so rapid that it is limited by the availability of (•)NO and chelatable iron. We utilize this ability to selectively manipulate cellular chelatable iron levels and provide evidence for two cellular functions of endogenous DNIC formation, protection against anoxia-induced reactive oxygen chemistry from the Fenton reaction and formation by transnitrosation of protein nitrosothiols (RSNO). The levels of RSNO under these high chelatable iron levels are comparable with DNIC levels and suggest that under these conditions, both DNIC and RSNO are the most abundant cellular adducts of (•)NO.

  14. Time-dependent leaching of coal fly ash by chelating agents

    SciTech Connect

    Harris, W.R.; Silberman, D.

    1983-03-01

    The rates of leaching of several transition-metal ions from coal fly ash by pH 7.4 solutions of the chelating agents citric acid, EDTA, Listidine and glycine have been measured as part of an investigation of the potential health effects of inhaled fly ash. The results are compared to leaching of the same fly ash by 0.5M HCl, 0.10 M pH 7.4 Tris buffer, 0.5 M NH/sub 4/OH, and canine serum. For the trace elements, Zn, Mn, G, Ni, and Cu, the initial leaching rates with 0.5 M HCl range from 350 to 850 ppm/d. The rates drop by 1-2 orders of magnitude within 24 h and then level off at 1-10 ppm/d. The initial rates with EDTA and citric acid are also high, 100-400 ppm/d, but they fall off even more rapidly than the HCl leaching rates. The leaching of vanadium is exceptionally rapid, with initial rates of 1000-3000 ppm/d.

  15. [Oxidation of nicotine and chelating agent by mercury(II)-compounds].

    PubMed

    Möhrle, H; Berlitz, J

    2008-01-01

    The dehydrogenation of (S)-nicotine (1) with mercuric acetate in diluted acetic acid yields no cotinine (3), but reacts only to the iminium stage, resulting far predominant the 5'-iminium structure without affecting the chiral center at 2', therefore the reduction with borohydride nearly quantitatively gives rise to (S)-nicotine (1). For the preparation of cotinine (3) the best method proves the oxidation of (S)-1 with the equimolecular complex Hg(II)-EDTA in pure water. With preliminary alkalization of the preparation an oxidation also of the liberated EDTA to iminodiacetic acid (10) and oxalic acid (15) occurs. This side reaction increase with an excess of chelating agent, which makes the precipitation of mercury as measuring system for control of the dehydrogenation invalid. Surprising is the nearly complete failure of the dehydrogenation to the tertiary carbenium ion and the consecutive reaction of the secondary carbenium ion 5, which in equilibrium with its carbinolamine 5a is again dehydrogenated with Hg(II)-EDTA to the lactam 3 with retention of the configuration. PMID:18271295

  16. Biomolecule conjugation strategy using novel water-soluble phosphine-based chelating agents

    DOEpatents

    Katti, Kattesh V.; Gali, Hariprasad; Volkert, Wynn A.

    2004-08-24

    This invention describes a novel strategy to produce phosphine-functionalized biomolecules (e.g. peptides or proteins) for potential use in the design and development of site-specific radiopharmaceuticals for diagnosis or therapy of specific cancers. Hydrophilic alkyl phosphines, in general, tend to be oxidatively unstable. Therefore, incorporation of such phosphine functionalities on peptide (and other biomolecule) backbones, without oxidizing the P.sup.III centers, is difficult. In this context this discovery reports on a new technology by which phosphines, in the form of bifunctional chelating agents, can be directly incorporated on biomolecular backbones using manual synthetic or solid phase peptide synthesis methodologies. The superior ligating abilities of phosphine ligands, with various diagnostically (e.g. TC-99m) or therapeutically (e.g. Re186/188, Rh-105, Au-199) useful radiometals, coupled with the findings that the resulting complexes demonstrate high in vivo stability makes this approach useful in the development of radiolabeled biomolecules for applications in the design of tumor-specific radiopharmaceuticals.

  17. Optimization of isolation of cellulose from orange peel using sodium hydroxide and chelating agents.

    PubMed

    Bicu, Ioan; Mustata, Fanica

    2013-10-15

    Response surface methodology was used to optimize cellulose recovery from orange peel using sodium hydroxide (NaOH) as isolation reagent, and to minimize its ash content using ethylenediaminetetraacetic acid (EDTA) as chelating agent. The independent variables were NaOH charge, EDTA charge and cooking time. Other two constant parameters were cooking temperature (98 °C) and liquid-to-solid ratio (7.5). The dependent variables were cellulose yield and ash content. A second-order polynomial model was used for plotting response surfaces and for determining optimum cooking conditions. The analysis of coefficient values for independent variables in the regression equation showed that NaOH and EDTA charges were major factors influencing the cellulose yield and ash content, respectively. Optimum conditions were defined by: NaOH charge 38.2%, EDTA charge 9.56%, and cooking time 317 min. The predicted cellulose yield was 24.06% and ash content 0.69%. A good agreement between the experimental values and the predicted was observed.

  18. Universal dispersing agent for electrophoretic deposition of inorganic materials with improved adsorption, triggered by chelating monomers.

    PubMed

    Liu, Yangshuai; Luo, Dan; Ata, Mustafa S; Zhang, Tianshi; Wallar, Cameron J; Zhitomirsky, Igor

    2016-01-15

    Poly[1-[4-(3-carboxy-4-hydroxyphenylazo)benzenesulfonamido]-1,2-ethanediyl, sodium salt] (PAZO) is a polymeric functional material with a number of unique physical properties, which attracted significant interest of different scientific communities. Films of PAZO were deposited by anodic electrophoretic deposition (EPD) under constant current and constant voltage conditions. The deposition kinetics was analyzed under different conditions and the deposition mechanism was discussed. New strategy was developed for the EPD of different inorganic materials and composites using PAZO as a dispersing, charging, binding and film forming agent. It was found that PAZO exhibits remarkable adsorption on various inorganic materials due to the presence of chelating salicylate ligands in its molecular structure. The salicylate ligands of PAZO monomers provide multiple adsorption sites by complexation of metal atoms on particle surfaces and allow for efficient electrosteric stabilization of particle suspensions. The remarkable performance of PAZO in its application in EPD have been exemplified by deposition of a wide variety of inorganic materials including the single element oxides (NiO, ZnO, Fe2O3) the complex oxides (Al2TiO5, BaTiO3, ZrSiO4, CoFe2O4) different nitrides (TiN, Si3N4, BN) as well as pure Ni metal and hydrotalcite clay. The use of PAZO can avoid limitation of other dispersing agents in deposition and co-deposition of different materials. Composite films were obtained using PAZO as a co-dispersant for different inorganic materials. The deposit composition, microstructure and deposition yield can be varied. The EPD method offers the advantages of simplicity, high deposition rate, and ability to deposit thin or thick films. PMID:26433084

  19. Removal of Fe3+ and Zn2+ from plasma metalloproteins by iron chelating therapeutics depicted with SEC-ICP-AES.

    PubMed

    Sooriyaarachchi, Melani; Gailer, Jürgen

    2010-08-28

    The iron chelation therapy drugs desferrioxamine B (DFO) and deferiprone (DFP) are used to treat iron overload patients, but not much is known about their adverse effects on other essential metals in vivo. After the addition of a clinically relevant dose of DFP or an equimolar dose of DFO to human plasma in vitro, the mixtures were analyzed by size exclusion chromatography (SEC) coupled to an inductively coupled plasma atomic emission spectrometer (ICP-AES). Simultaneous detection of the emission lines of copper, iron and zinc allowed the visualization of changes that these drugs exerted at the metalloprotein level. After the addition of DFP, a <10 kDa novel Fe-peak was detected and identified as (DFP)(3)Fe, whereas DFO resulted in the elution of a much smaller amount of Fe in this elution range. In fact, DFP was approximately 8-times more efficient than DFO regarding the removal of Fe from plasma proteins. The addition of both iron chelators also resulted in the elution of a <10 kDa novel Zn-peak. DFP abstracted twice as much Zn from plasma proteins compared to DFO. The identification of one of these peaks as (DFP)(2)Zn establishes a feasible biomolecular basis for the etiology of Zn-deficiency in patients that undergo long-term treatment with these drugs. Our results demonstrate that the analysis of plasma by SEC-ICP-AES can simultaneously provide insight into the efficacy of chelation therapy drugs and their adverse health effects at the metalloprotein level. Thus, SEC-ICP-AES emerges as a useful analytical tool to visualize health-relevant bioinorganic chemistry-related reactions of medicinal drugs in blood plasma in vitro.

  20. Anti-plasmodial activity of aroylhydrazone and thiosemicarbazone iron chelators: effect on erythrocyte membrane integrity, parasite development and the intracellular labile iron pool.

    PubMed

    Walcourt, Asikiya; Kurantsin-Mills, Joseph; Kwagyan, John; Adenuga, Babafemi B; Kalinowski, Danuta S; Lovejoy, David B; Lane, Darius J R; Richardson, Des R

    2013-12-01

    Iron chelators inhibit the growth of the malaria parasite, Plasmodium falciparum, in culture and in animal and human studies. We previously reported the anti-plasmodial activity of the chelators, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), 2-hydroxy-1-naphthylaldehyde 4-methyl-3-thiosemicarbazone (N4mT), and 2-hydroxy-1-naphthylaldehyde 4-phenyl-3-thiosemicarbazone (N4pT). In fact, these ligands showed greater growth inhibition of chloroquine-sensitive (3D7) and chloroquine-resistant (7G8) strains of P. falciparum in culture compared to desferrioxamine (DFO). The present study examined the effects of 311, N4mT and N4pT on erythrocyte membrane integrity and asexual parasite development. While the characteristic biconcave disk shape of the erythrocytes was unaffected, the chelators caused very slight hemolysis at IC50 values that inhibited parasite growth. The chelators 311, N4mT and N4pT affected all stages of the intra-erythrocytic development cycle (IDC) of P. falciparum in culture. However, while these ligands primarily affected the ring-stage, DFO inhibited primarily trophozoite and schizont-stages. Ring, trophozoite and schizont-stages of the IDC were inhibited by significantly lower concentrations of 311, N4mT, and N4pT (IC50=4.45±1.70, 10.30±4.40, and 3.64±2.00μM, respectively) than DFO (IC50=23.43±3.40μM). Complexation of 311, N4mT and N4pT with iron reduced their anti-plasmodial activity. Estimation of the intracellular labile iron pool (LIP) in erythrocytes showed that the chelation efficacy of 311, N4mT and N4pT corresponded to their anti-plasmodial activities, suggesting that the LIP may be a potential source of non-heme iron for parasite metabolism within the erythrocyte. This study has implications for malaria chemotherapy that specifically disrupts parasite iron utilization.

  1. Rapid screening of different chelating agents in the lead extraction from cathode ray tube (CRT) funnel glass.

    PubMed

    Barbieri, Luisa; Lancellotti, Isabella; Ponzoni, Chiara

    2014-12-01

    The cathode ray tube (CRT) glass is one of the most important problem that afflicts the electronic waste disposal whose solution lies in the identification of efficient and ecofriendly processes to detoxify and reutilize lead-contained funnel glass. This study is focused on a rapid screening of different chemical and mechanochemical processes to reduce lead content in waste CRT glass downgrading the risk correlated to it. In particular, as a possibility to clean waste CRT glass, treatments of lead-containing glass with different chelating agents (EDTA, NTA, ATMP, EDTMP and HEDP) were performed to evaluate their extractive capabilities. Furthermore, the influence of the grinding, the chelating agent functional groups (polyamino-carboxylic acid, carboxylic acid, and polyamino phosphonic acid), and the time and the temperature on lead content reduction were analyzed. ESEM and EDS analysis were performed on all the samples to evaluate the lead amount before and after the treatments.

  2. Heterogeneity of myocardial iron distribution in response to chelation therapy in patients with transfusion-dependent anemias.

    PubMed

    Hanneman, Kate; Raju, Vikram M; Moshonov, Hadas; Ward, Richard; Wintersperger, Bernd J; Crean, Andrew M; Ross, Heather; Nguyen, Elsie T

    2013-10-01

    The purpose of this study is to examine the effect of different iron chelation regimens on the distribution of myocardial iron in patients with transfusion-dependent anemias. Institutional review board approval was obtained. Patients treated with iron chelation therapy who had undergone baseline and 1-year follow-up cardiac T2* MR studies in a four-year period were identified retrospectively. One hundred and eight patients (44 % male, mean age 31.6 ± 9.7 years) were included. The interventricular septum on three short-axis slices (basal, mid and apical) was divided into anterior and inferior regions of interest for T2* analysis. Cardiac iron concentration (CIC) was calculated from T2* values. Statistical analysis included analysis of variance and paired t-test, using Bonferroni adjustment in all pairwise comparisons. At baseline, T2* measurements varied significantly across all six regions (p < 0.001): lowest in the mid anteroseptum (mean 22.3 ± 10.1 ms) and highest in the apical inferoseptum (mean 26.2 ± 12.8 ms). At follow-up, T2* and CIC values improved significantly in all segments [mean change of 3.78 ms (95 % CI (2.93, 4.62), p < 0.001) and 0.23 mg/g (95 % CI (0.16, 0.29), p < 0.001), respectively]. Change in T2* values varied significantly between segments (p < 0.001) with greatest improvement in the apical inferoseptum [4.26 ms, 95 % CI (2.42, 6.11)] and least improvement in the basal anteroseptum [2.95 ms, 95 % CI (1.37, 4.54)]. The largest improvement in T2* values was noted in patients treated with deferiprone [4.96 ms, 95 % CI (2.34, 7.58)]. There was a statistically significant difference in improvement in CIC values between chelation regimens (p = 0.016). This is the first study to report heterogeneity in response to iron chelating drugs with variable segmental changes in T2* values.

  3. Longitudinal MRI and Ferritin Monitoring of Iron Overload in Chronically Transfused and Chelated Children With Sickle Cell Anemia and Thalassemia Major.

    PubMed

    Aubart, Mélodie; Ou, Phalla; Elie, Caroline; Canniffe, Carla; Kutty, Shelby; Delos, Vincent; Graffigne, Christine; de Montalembert, Mariane; Brousse, Valentine

    2016-10-01

    Iron overload is an ineluctable complication in chronically transfused children warranting accurate assessment to avoid related morbidity. We investigated longitudinally the relationships between ferritin levels and hepatic and cardiac T2* magnetic resonance imaging (MRI) in a cohort of chronically transfused children receiving chelation therapy. Thirty children with sickle cell anemia (SCA) and 7 with thalassemia major (TM) chelated similarly by deferasirox were analyzed. Sex ratio, age, median duration of transfusion programs (5 y; range, 2 to 14 y), median transfusion iron intake 0.54 mg/kg/d (range, 0.27 to 0.74 mg/kg/d), and median ferritin level (1550 mg/L; range, 184 to 6204 mg/L) were comparable in TM and SCA. A significant relation was found between ferritin level and transfusion iron intake (P<0.001) despite chelation therapy. Analysis of 73 hepatic T2* MRI performed yearly demonstrated severe hepatic iron overload (≥14 mg/g) in 38.3% cases and a strong relationship between serum ferritin level and liver iron content both in SCA and TM (P<0.001). Analysis of 55 cardiac T2* MRI measurements found no cardiac overload in patients with SCA. Cardiac iron overload was moderate in 4 cases and severe in 1 case of TM. In almost half the cases, ferritin trend correctly predicted hepatic iron trend, both in patients with SCA and TM but failed to predict cardiac iron trend, notably in TM patients. Despite chelation therapy, iron burden in chronically transfused patients remains a threat. Ferritin levels are associated with liver iron overload in chelated children with SCA and TM, but iron burden should be best monitored with MRI whenever the setting allows it. PMID:27548334

  4. A new kind of chelating agent with low pH value applied in the TSV CMP slurry

    NASA Astrophysics Data System (ADS)

    Jiao, Hong; Yuling, Liu; Baoguo, Zhang; Xinhuan, Niu; Liying, Han

    2015-12-01

    TSV (through silicon via) is an emerging technology, which can realize micromation compared with the conventional packaging and extend Moore's law. Chemical mechanical polishing (CMP) is one of the most important steps in the process of TSV manufacture, and it is an enabling technology to extend Moore's law in the past two decades. Low pressure, low abrasive and low pH value are the main requirements for copper interconnection. In this paper, the effect of different kinds of TSV slurry with FA/O II or FA/O IV type chelating agent on CMP are studied. All kinds of slurry used in this study are alkaline with no added inhibitors. From the experiment results, it can be seen that the copper removal rate and surface roughness achieved by using the FA/O IV type chelating agent with a low pH value is superior to using the FA/O II type chelating agent. Project supported by the Major National Science and Technology Special Projects (No. 2009ZX02308), the Fund Project of Hebei Provincial Department of Education, China (No. QN2014208), the Natural Science Foundation of Hebei Province, China (No. E2013202247), and the Colleges and Universities Scientific Research Project of Hebei Province, China (No. Z2014088).

  5. Effect of chelating agent concentration in alkaline Cu CMP process under the condition of different applied pressures

    NASA Astrophysics Data System (ADS)

    Haobo, Yuan; Yuling, Liu; Mengting, Jiang; Weijuan, Liu; Guodong, Chen

    2014-11-01

    We propose the action mechanism of Cu chemical mechanical planarization (CMP) in an alkaline solution. Meanwhile, the effect of abrasive mass fraction on the copper removal rate and within wafer non-uniformity (WIWNU) have been researched. In addition, we have also investigated the synergistic effect between the applied pressure and the FA/O chelating agent on the copper removal rate and WIWNU in the CMP process. Based on the experimental results, we chose several concentrations of the FA/O chelating agent, which added in the slurry can obtain a relatively high removal rate and a low WIWNU after polishing, to investigate the planarization performance of the copper slurry under different applied pressure conditions. The results demonstrate that the copper removal rate can reach 6125 Å/min when the abrasive concentration is 3 wt.%. From the planarization experimental results, we can see that the residual step height is 562 Å after excessive copper of the wafer surface is eliminated. It denotes that a good polishing result is acquired when the FA/O chelating agent concentration and applied pressure are fixed at 3 vol% and 1 psi, respectively. All the results set forth here are very valuable for the research and development of alkaline slurry.

  6. Headgroup interactions and ion flotation efficiency in mixtures of a chelating surfactant, different foaming agents, and divalent metal ions.

    PubMed

    Svanedal, Ida; Boija, Susanne; Norgren, Magnus; Edlund, Håkan

    2014-06-10

    The correlation between interaction parameters and ion flotation efficiency in mixtures of chelating surfactant metal complexes and different foaming agents was investigated. We have recently shown that chelating surfactant 2-dodecyldiethylenetriaminepentaacetic acid (4-C12-DTPA) forms strong coordination complexes with divalent metal ions, and this can be utilized in ion flotation. Interaction parameters for mixed micelles and mixed monolayer formation for Mg(2+) and Ni(2+) complexes with the chelating surfactant 4-C12-DTPA and different foaming agents were calculated by Rubingh's regular solution theory. Parameters for the calculations were extracted from surface tension measurements and NMR diffusometry. The effects of metal ion coordination on the interactions between 4-C12-DTPA and the foaming agents could be linked to a previously established difference in coordination chemistry between the examined metal ions. As can be expected from mixtures of amphoteric surfactants, the interactions were strongly pH-dependent. Strong correlation was found between interaction parameter β(σ) for mixed monolayer formation and the phase-transfer efficiency of Ni(2+) complexes with 4-C12-DTPA during flotation in a customized flotation cell. In a mixture of Cu(2+) and Zn(2+), the significant difference in conditional stability constants (log K) between the metal complexes was utilized to selectively recover the metal complex with the highest log K (Cu(2+)) by ion flotation. Flotation experiments in an excess concentration of metal ions confirmed the coordination of more than one metal ion to the headgroup of 4-C12-DTPA.

  7. Headgroup interactions and ion flotation efficiency in mixtures of a chelating surfactant, different foaming agents, and divalent metal ions.

    PubMed

    Svanedal, Ida; Boija, Susanne; Norgren, Magnus; Edlund, Håkan

    2014-06-10

    The correlation between interaction parameters and ion flotation efficiency in mixtures of chelating surfactant metal complexes and different foaming agents was investigated. We have recently shown that chelating surfactant 2-dodecyldiethylenetriaminepentaacetic acid (4-C12-DTPA) forms strong coordination complexes with divalent metal ions, and this can be utilized in ion flotation. Interaction parameters for mixed micelles and mixed monolayer formation for Mg(2+) and Ni(2+) complexes with the chelating surfactant 4-C12-DTPA and different foaming agents were calculated by Rubingh's regular solution theory. Parameters for the calculations were extracted from surface tension measurements and NMR diffusometry. The effects of metal ion coordination on the interactions between 4-C12-DTPA and the foaming agents could be linked to a previously established difference in coordination chemistry between the examined metal ions. As can be expected from mixtures of amphoteric surfactants, the interactions were strongly pH-dependent. Strong correlation was found between interaction parameter β(σ) for mixed monolayer formation and the phase-transfer efficiency of Ni(2+) complexes with 4-C12-DTPA during flotation in a customized flotation cell. In a mixture of Cu(2+) and Zn(2+), the significant difference in conditional stability constants (log K) between the metal complexes was utilized to selectively recover the metal complex with the highest log K (Cu(2+)) by ion flotation. Flotation experiments in an excess concentration of metal ions confirmed the coordination of more than one metal ion to the headgroup of 4-C12-DTPA. PMID:24824327

  8. Deferoxamine alleviates chronic hydrocephalus after intraventricular hemorrhage through iron chelation and Wnt1/Wnt3a inhibition.

    PubMed

    Meng, Hui; Li, Fei; Hu, Rong; Yuan, Yikai; Gong, Guoqi; Hu, Shengli; Feng, Hua

    2015-03-30

    Post-hemorrhagic chronic hydrocephalus (PHCH) is a common complication after intraventricular hemorrhage (IVH). The mechanism of PHCH is not fully understood, and its treatment is relatively difficult. In the present study, a rat model of PHCH was used to elucidate the role of iron in the pathogenesis of PHCH. The action of deferoxamine (DFX) in IVH-induced PHCH, the expression of brain ferritin, the concentration of iron in cerebrospinal fluid (CSF), and changes in Wnt1/Wnt3a gene expression were determined. Results indicate that iron plays an important role in the occurrence of hydrocephalus after IVH. The iron chelator, DFX, can decrease the concentrations of iron and ferritin after cerebral hemorrhage and can thereby decrease the incidence of hydrocephalus. In addition, after IVH, the gene expression of Wnt1 and Wnt3a was enhanced, with protein expression also upregulated; DFX was able to suppress both gene and protein expression of Wnt1 and Wnt3a in brain tissue. This indicates that iron may be the key stimulus that activates the Wnt signaling pathway and regulates subarachnoid fibrosis after cerebral hemorrhage, and that DFX may be a candidate for preventing PHCH in patients with IVH.

  9. Effects of combined chelation treatment with pyridoxal isonicotinoyl hydrazone analogs and deferoxamine in hypertransfused rats and in iron-loaded rat heart cells.

    PubMed

    Link, Gabriela; Ponka, Prem; Konijn, Abraham M; Breuer, William; Cabantchik, Z Ioav; Hershko, Chaim

    2003-05-15

    Although iron chelation therapy with deferoxamine (DFO) results in improved life expectancy of patients with thalassemia, compliance with parenteral DFO treatment is unsatisfactory, underlining the need for alternative drugs and innovative ways of drug administration. We examined the chelating potential of pyridoxal isonicotinoyl hydrazone (PIH) analogs, alone or in combination with DFO, using hypertransfused rats with labeled hepatocellular iron stores and cultured iron-loaded rat heart cells. Our in vivo studies using 2 representative PIH analogs, 108-o and 109-o, have shown that PIH analogs given orally are 2.6 to 2.8 times more effective in mobilizing hepatocellular iron in rats, on a weight-per-weight basis, than parenteral DFO administered intraperitoneally. The combined effect of DFO and 108-o on hepatocellular iron excretion was additive, and response at a dose range of 25 to 200 mg/kg was linear. In vitro studies in heart cells showed that DFO was more effective in heart cell iron mobilization than all PIH analogs studied. Response to joint chelation with DFO and PIH analogs was similar to an increase in the equivalent molar dose of DFO alone, rather than the sum of the separate effects of the PIH analog and DFO. This finding was most likely the result of iron transfer from PIH analogs to DFO, a conclusion supported directly by iron-shuttle experiments using fluorescent DFO. These findings provide a rationale for the combined, simultaneous use of iron-chelating drugs and may have useful, practical implications for designing novel strategies of iron chelation therapy.

  10. Bifunctional chelates of RH-105 and AU199 as potential radiotherapeutic agents

    SciTech Connect

    Droege, P.

    1997-03-01

    Research is presented on new bifunctional chelating ligand systems with stability on the macroscopic and radiochemical levels. The synthesis of the following complexes are described: rhodium 105, palladium 109, and gold 198.

  11. A combination of an iron chelator with an antioxidant effectively diminishes the dendritic loss, tau-hyperphosphorylation, amyloids-β accumulation and brain mitochondrial dynamic disruption in rats with chronic iron-overload.

    PubMed

    Sripetchwandee, Jirapas; Wongjaikam, Suwakon; Krintratun, Warunsorn; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2016-09-22

    Iron-overload can cause cognitive impairment due to blood-brain barrier (BBB) breakdown and brain mitochondrial dysfunction. Although deferiprone (DFP) has been shown to exert neuroprotection, the head-to-head comparison among iron chelators used clinically on brain iron-overload has not been investigated. Moreover, since antioxidant has been shown to be beneficial in iron-overload condition, its combined effect with iron chelator has not been tested. Therefore, the hypothesis is that all chelators provide neuroprotection under iron-overload condition, and that a combination of an iron chelator with an antioxidant has greater efficacy than monotherapy. Male Wistar rats (n=42) were assigned to receive a normal diet (ND) or a high-iron diet (HFe) for 4months. At the 2nd month, HFe-fed rats were treated with a vehicle, deferoxamine (DFO), DFP, deferasirox (DFX), n-acetyl cysteine (NAC) or a combination of DFP with NAC, while ND-fed rats received vehicle. At the end of the experiment, rats were decapitated and brains were removed to determine brain iron level and deposition, brain mitochondrial function, BBB protein expression, brain mitochondrial dynamic, brain apoptosis, tau-hyperphosphorylation, amyloid-β (Aβ) accumulation and dendritic spine density. The results showed that iron-overload induced BBB breakdown, brain iron accumulation, brain mitochondrial dysfunction, impaired brain mitochondrial dynamics, tau-hyperphosphorylation, Aβ accumulation and dendritic spine reduction. All treatments, except DFX, attenuated these impairments. Moreover, combined therapy provided a greater efficacy than monotherapy. These findings suggested that iron-overload induced brain iron toxicity and a combination of an iron chelator with an antioxidant provided a greatest efficacy for neuroprotection than monotherapy.

  12. A combination of an iron chelator with an antioxidant effectively diminishes the dendritic loss, tau-hyperphosphorylation, amyloids-β accumulation and brain mitochondrial dynamic disruption in rats with chronic iron-overload.

    PubMed

    Sripetchwandee, Jirapas; Wongjaikam, Suwakon; Krintratun, Warunsorn; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2016-09-22

    Iron-overload can cause cognitive impairment due to blood-brain barrier (BBB) breakdown and brain mitochondrial dysfunction. Although deferiprone (DFP) has been shown to exert neuroprotection, the head-to-head comparison among iron chelators used clinically on brain iron-overload has not been investigated. Moreover, since antioxidant has been shown to be beneficial in iron-overload condition, its combined effect with iron chelator has not been tested. Therefore, the hypothesis is that all chelators provide neuroprotection under iron-overload condition, and that a combination of an iron chelator with an antioxidant has greater efficacy than monotherapy. Male Wistar rats (n=42) were assigned to receive a normal diet (ND) or a high-iron diet (HFe) for 4months. At the 2nd month, HFe-fed rats were treated with a vehicle, deferoxamine (DFO), DFP, deferasirox (DFX), n-acetyl cysteine (NAC) or a combination of DFP with NAC, while ND-fed rats received vehicle. At the end of the experiment, rats were decapitated and brains were removed to determine brain iron level and deposition, brain mitochondrial function, BBB protein expression, brain mitochondrial dynamic, brain apoptosis, tau-hyperphosphorylation, amyloid-β (Aβ) accumulation and dendritic spine density. The results showed that iron-overload induced BBB breakdown, brain iron accumulation, brain mitochondrial dysfunction, impaired brain mitochondrial dynamics, tau-hyperphosphorylation, Aβ accumulation and dendritic spine reduction. All treatments, except DFX, attenuated these impairments. Moreover, combined therapy provided a greater efficacy than monotherapy. These findings suggested that iron-overload induced brain iron toxicity and a combination of an iron chelator with an antioxidant provided a greatest efficacy for neuroprotection than monotherapy. PMID:27403880

  13. Inhibition of Xanthomonas fragariae, Causative Agent of Angular Leaf Spot of Strawberry, through Iron Deprivation

    PubMed Central

    Henry, Peter M.; Gebben, Samantha J.; Tech, Jan J.; Yip, Jennifer L.; Leveau, Johan H. J.

    2016-01-01

    In commercial production settings, few options exist to prevent or treat angular leaf spot (ALS) of strawberry, a disease of economic importance and caused by the bacterial pathogen Xanthomonas fragariae. In the process of isolating and identifying X. fragariae bacteria from symptomatic plants, we observed growth inhibition of X. fragariae by bacterial isolates from the same leaf macerates. Identified as species of Pseudomonas and Rhizobium, these isolates were confirmed to suppress growth of X. fragariae in agar overlay plates and in microtiter plate cultures, as did our reference strain Pseudomonas putida KT2440. Screening of a transposon mutant library of KT2440 revealed that disruption of the biosynthetic pathway for the siderophore pyoverdine resulted in complete loss of X. fragariae antagonism, suggesting iron competition as a mode of action. Antagonism could be replicated on plate and in culture by addition of purified pyoverdine or by addition of the chelating agents tannic acid and dipyridyl, while supplementing the medium with iron negated the inhibitory effects of pyoverdine, tannic acid and dipyridyl. When co-inoculated with tannic acid onto strawberry plants, X. fragariae’s ability to cause foliar symptoms was greatly reduced, suggesting a possible opportunity for iron-based management of ALS. We discuss our findings in the context of ‘nutritional immunity,’ the idea that plant hosts restrict pathogen access to iron, either directly, or indirectly through their associated microbiota. PMID:27790193

  14. Production of chelating agents through the enzymatic oxidation of acetosolv sugarcane bagasse lignin.

    PubMed

    Gonçalves, Adilson R; Soto-Oviedo, Mauro A

    2002-01-01

    Oxidation of lignin obtained from Acetosolv pulping of sugarcane bagasse was performed by polyphenoloxidase (PPO) using glycerol or polyethyleneglycol to increase the number of carbonyl and hydroxyl groups in lignin, and to improve its chelating capacity. Increase in the absorption in UV-spectrum related to alpha-carbonylphenolic and alpha,beta-unsaturated structures was observed in all the experiments. The chelating properties of the original and oxidized lignins were compared by monitoring the amount of Cu2+ bound to lignin by gel permeation chromatography. The chelating capacity of original Acetosolv lignin was 354 mg Cu2+/g lignin. On the other hand, lignin oxidized with PPO/O2 showed an increase of 73% in chelating capacity in relation to the original lignin. The chelating capacity of lignin oxidized with PPO/O2/glycerol was 110% higher than that of the original lignin. Glycerol stabilizes PPO, increasing its half-life. Average molecular weight (MW), measured by size-exclusion chromatography, was smaller for the oxidized lignins than for the original Acetosolv lignin. This result suggests that quinones can eventually be formed through the action of PPO, but are not polymerized. The chelating capacity of oxidized lignins increases with the incorporation of vicinal hydroxyl groups. PMID:12018263

  15. The Copper Sulfide Coating on Polyacrylonitrile with Chelating Agents by an Electroless Deposition Method and its EMI Shielding Effectiveness

    SciTech Connect

    Roan, M.-L.; Chen, Y.-H.; Huang, C.-Y.

    2008-08-28

    In this study, a variety of concentrations of chelating agents were added to obtain the anchoring effect and chelating effect in the electroless plating bath. The mechanism of the Cu{sub x(x=1,2)}S growth and the electromagnetic interference shielding effectiveness (EMI SE) of the composite were studied. It was found that the vinyl acetate residued in PAN substrate would be purged due to the swelling effect by chelating agents solution. And then, the anchoring effect occurred due to the hydrogen bonding between the pits of PAN substrate and the chelating agent. Consequently, the copper sulfide layer deposited by the electroless plating reaction with EDTA and TEA. The swelling degree (S{sub d}) was proposed and evaluated from the FT-IR spectra. The relationship between swelling degree of the PAN films and EDTA (C) is expressed as: S{sub d} = 0.13+0.90xe and (-15.15C). And TEA series is expressed as: S{sub d} = 0.07+1.00xe and (-15.15C). On the other hand, the FESEM micrograph showed that the average thickness of copper sulfide increased from 76 nm to 383 nm when the concentration of EDTA increased from 0.00M to 0.20M. Consequently, the EMI SE of the composites increased from 10{approx}12 dB to 25{approx}27 dB. The GIA-XRD analyze indicated that the deposited layer consisted of CuS and Cu{sub 2}S.

  16. Iron chelation with deferasirox for the treatment of secondary hemosiderosis in pediatric oncology patients: a single-center experience.

    PubMed

    Ktena, Yiouli P; Athanasiadou, Anastasia; Lambrou, George; Adamaki, Maria; Moschovi, Maria

    2013-08-01

    Pediatric oncology patients are often iron overloaded, due to the multiple blood transfusions necessary during the course of chemotherapy. Our aim is to report the efficacy and safety of deferasirox, an oral iron chelator, in this patient group. Deferasirox was administered to 13 children with malignancies in remission and iron overload. Ferritin, blood urea nitrogen, creatinine, transaminases, and bilirubin were recorded at 4- to 8-week intervals, and hepatic and cardiac iron overload were assessed with magnetic resonance imaging before initiation of treatment. Deferasirox was administered for an average of 6 months (SD=4.5; range, 0.3 to 18.2). Two children presented with skin rash, 1 with gastrointestinal disturbances, and 1 with fully reversible acute renal failure. The mean monthly rate of change in ferritin levels was -10.8 μg/L before initiation of treatment (95% confidence interval [CI], -19.8 to -1.8; P=0.02) and -93.6 μg/L during deferasirox treatment (95% CI, -118.1 to -69.1; P<0.001). The difference in the monthly rate of change in ferritin levels before and after treatment initiation was -82.8 μg/L (95% CI, -111.6 to -53.9; P<0.001). Deferasirox was effective in reducing the iron burden. The adverse effects were easily monitored and managed. Further studies are warranted to investigate the effect of deferasirox on mortality and morbidity in this population.

  17. The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.

    PubMed

    Yoshii, J; Yoshiji, H; Kuriyama, S; Ikenaka, Y; Noguchi, R; Okuda, H; Tsujinoue, H; Nakatani, T; Kishida, H; Nakae, D; Gomez, D E; De Lorenzo, M S; Tejera, A M; Fukui, H

    2001-12-15

    Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy.

  18. The Influence of Chelating Agent on the Structural and Magnetic Properties of CoFe2O4, Nanoparticles.

    PubMed

    Pedra, P P; Silva Filho, J L; Lima, R J S; Sharma, S K; Moura, K O; Duque, J G S; Meneses, C T

    2016-05-01

    We have studied the influence of chelating agents (glycerin and sucrose) on the structural and magnetic properties of cobalt ferrite (CoFe2O4) nanoparticles synthesized via co-precipitation method. The Rietveld refinements from X-ray diffraction patterns confirm that all samples are single phase identified in a cubic crystalline system belonging to the space group Fd-3m. Besides, we have verified that the addition of chelating agents produces a decreasing in the particles average size from 14(2) to 5(1) nm. Magnetization measurements as a function of temperature show a decrease in the blocking temperature (T(B)) to sample obtained with addition of sucrose. A superparamagnetic behavior at room temperature was observed by magnetic measurements as function of field in the sample with 0.020 mol/L of sucrose. The results show that character chelating of sucrose reduces the coalescence effect and magnetic interaction in the CoFe2O4 nanoparticles. These results suggest that sucrose could be an alternative to control the structural and magnetic properties of other oxides nanoparticles. PMID:27483850

  19. Effect of pH on the release of radionuclides and chelating agents from cement-solidified decontamination ion-exchange resins collected from operating nuclear power stations

    SciTech Connect

    McIsaac, C.V.; Akers, D.W.; McConnell, J.W. )

    1991-06-01

    Data are presented on the physical stability and leachability of radionuclides and chelating agents from cement-solidified decontamination ion-exchange resin wastes collected from two operating commercial light water reactors. Small-scale waste--form specimens collected during solidifications performed at the Brunswick Steam Electric Plant Unit 1 and at the James A. FitzPatrick Nuclear Power Station were leach-tested and subjected to compressive strength testing in accordance with the Nuclear Regulatory Commission's Technical Position on Waste Form'' (Revision 1). Samples of untreated resin waste collected from each solidification vessel before the solidification process were analyzed for concentrations of radionuclides, selected transition metals, and chelating agents to determine the quantities of these chemicals in the waste-form specimens. The chelating agents included oxalic, citric, and picolinic acids. In order to determine the effect of leachant chemical composition and pH on the stability and leachability of the waste forms, waste-form specimens were leached in various leachants. Results of this study indicate that differences in pH do not affect releases from cement-solidified decontamination ion-exchange resin waste forms, but that differences in leachant chemistry and the presence of chelating agents may affect the releases of radionuclides and chelating agents. Also, this study indicates that the cumulative releases of radionuclides and chelating agents are similar for waste- form specimens that decomposed and those that retained their general physical form. 36 refs., 60 figs., 28 tabs.

  20. Durable Red Blood Cell Transfusion Independence in a Patient with an MDS/MPN Overlap Syndrome Following Discontinuation of Iron Chelation Therapy.

    PubMed

    Kochhar, Harpreet; Leger, Chantal S; Leitch, Heather A

    2015-01-01

    Background. Hematologic improvement (HI) occurs in some patients with acquired anemias and transfusional iron overload receiving iron chelation therapy (ICT) but there is little information on transfusion status after stopping chelation. Case Report. A patient with low IPSS risk RARS-T evolved to myelofibrosis developed a regular red blood cell (RBC) transfusion requirement. There was no response to a six-month course of study medication or to erythropoietin for three months. At 27 months of transfusion dependence, she started deferasirox and within 6 weeks became RBC transfusion independent, with the hemoglobin normalizing by 10 weeks of chelation. After 12 months of chelation, deferasirox was stopped; she remains RBC transfusion independent with a normal hemoglobin 17 months later. We report the patient's course in detail and review the literature on HI with chelation. Discussion. There are reports of transfusion independence with ICT, but that transfusion independence may be sustained long term after stopping chelation deserves emphasis. This observation suggests that reduction of iron overload may have a lasting favorable effect on bone marrow failure in at least some patients with acquired anemias.

  1. Effects of additional iron-chelators on Fe(2+)-initiated lipid peroxidation: evidence to support the Fe2+ ... Fe3+ complex as the initiator.

    PubMed

    Tang, L X; Yang, J L; Shen, X

    1997-12-01

    The addition of chelated Fe2+ ions in a liposomal system often results in a short lag period before peroxidation starts. The addition of a second chelator at the end of the lag period results in an inhibition of the lipid peroxidation. The degree of inhibition depends on the stability constants of the chelator in ligating Fe2+ and/or Fe3+. A more striking inhibitory effect was observed for the chelators with higher stability constant for either or both Fe(2+)- and Fe(3+)-complex, but much less inhibition was found for those with lower stability constants for both complexes. Assuming that the "initiator" for iron-dependent lipid peroxidation is formed through the redox process of iron ion and finally emerged at the end of the latent period, the inhibitory effect of the second chelator may be explained as the abstraction of either Fe2+ or Fe3+ from the initiator by an additional free chelator, which results in the decomposition of the initiator. This study supports the hypothesis that a Fe2+ ... Fe3+ complex is responsible for iron-initiated lipid peroxidation. PMID:9397574

  2. Complete hematopoietic recovery after continuous iron chelation therapy in a patient with severe aplastic anemia with secondary hemochromatosis.

    PubMed

    Park, Soo-Jeong; Han, Chi-Wha

    2008-04-01

    A 16-yr-old male patient with hemochromatosis due to multiple packed red blood cell transfusions was referred to our emergency center for the treatment of severe aplastic anemia and dyspnea. He was diagnosed with aplastic anemia at 11-yr of age. He had received continuous transfusions because an HLA-matched marrow donor was unavailable. Following a continuous, approximately 5-yr transfusion, he was noted to develop hemochromatosis. He had a dilated cardiomyopathy and required diuretics and digitalis, multiple endocrine and liver dysfunction, generalized bleeding, and skin pigmentation. A total volume of red blood cell transfusion before deferoxamine therapy was about 96,000 mL. He received a regular iron chelation therapy (continuous intravenous infusion of deferoxamine, 50 mg/kg/day for 5 days q 3-4 weeks) for approximately seven years after the onset of multiple organ failures. His cytopenia and organ dysfunctions began to be gradually recovered since about 2002, following a 4-yr deferoxamine treatment. He showed completely normal ranges of peripheral blood cell counts, heart size, and liver function two years ago. He has not received any transfusions for the last four years. This finding suggests that a continuous deferoxamine infusion may play a role in the immune regulation in addition to iron chelation effect.

  3. Lead(II) binding to the chelating agent D-penicillamine in aqueous solution.

    PubMed

    Sisombath, Natalie S; Jalilehvand, Farideh; Schell, Adam C; Wu, Qiao

    2014-12-01

    A spectroscopic investigation of the complexes formed between the Pb(II) ion and D-penicillamine (H2Pen), a chelating agent used in the treatment of lead poisoning, was carried out on two sets of alkaline aqueous solutions with CPb(II) ≈ 10 and 100 mM, varying the H2Pen/Pb(II) molar ratio (2.0, 3.0, 4.0, 10.0). Ultraviolet-visible (UV-vis) spectra of the 10 mM Pb(II) solutions consistently showed an absorption peak at 298 nm for S(-) → Pb(II) ligand-to-metal charge-transfer. The downfield (13)C NMR chemical shift for the penicillamine COO(-) group confirmed Pb(II) coordination. The (207)Pb NMR chemical shifts were confined to a narrow range between 1806 ppm and 1873 ppm for all Pb(II)-penicillamine solutions, indicating only small variations in the speciation, even in large penicillamine excess. Those chemical shifts are considerably deshielded, relative to the solid-state (207)Pb NMR isotropic chemical shift of 909 ppm obtained for crystalline penicillaminatolead(II) with Pb(S,N,O-Pen) coordination. The Pb LIII-edge extended X-ray absorption fine structure (EXAFS) spectra obtained for these solutions were well-modeled with two Pb-S and two Pb-(N/O) bonds with mean distances 2.64 ± 0.04 Å and 2.45 ± 0.04 Å, respectively. The combined spectroscopic results, reporting δ((207)Pb) ≈ 1870 ppm and λmax ≈ 298 nm for a Pb(II)S2NO site, are consistent with a dominating 1:2 lead(II):penicillamine complex with [Pb(S,N,O-Pen)(S-HnPen)](2-n) (n = 0-1) coordination in alkaline solutions, and provide useful structural information on how penicillamine can function as an antidote against lead toxicity in vivo. PMID:25385465

  4. Lead(II) Binding to the Chelating Agent d-Penicillamine in Aqueous Solution

    PubMed Central

    2015-01-01

    A spectroscopic investigation of the complexes formed between the Pb(II) ion and d-penicillamine (H2Pen), a chelating agent used in the treatment of lead poisoning, was carried out on two sets of alkaline aqueous solutions with CPb(II) ≈ 10 and 100 mM, varying the H2Pen/Pb(II) molar ratio (2.0, 3.0, 4.0, 10.0). Ultraviolet–visible (UV-vis) spectra of the 10 mM Pb(II) solutions consistently showed an absorption peak at 298 nm for S– → Pb(II) ligand-to-metal charge-transfer. The downfield 13C NMR chemical shift for the penicillamine COO– group confirmed Pb(II) coordination. The 207Pb NMR chemical shifts were confined to a narrow range between 1806 ppm and 1873 ppm for all Pb(II)-penicillamine solutions, indicating only small variations in the speciation, even in large penicillamine excess. Those chemical shifts are considerably deshielded, relative to the solid-state 207Pb NMR isotropic chemical shift of 909 ppm obtained for crystalline penicillaminatolead(II) with Pb(S,N,O-Pen) coordination. The Pb LIII-edge extended X-ray absorption fine structure (EXAFS) spectra obtained for these solutions were well-modeled with two Pb–S and two Pb-(N/O) bonds with mean distances 2.64 ± 0.04 Å and 2.45 ± 0.04 Å, respectively. The combined spectroscopic results, reporting δ(207Pb) ≈ 1870 ppm and λmax ≈ 298 nm for a PbIIS2NO site, are consistent with a dominating 1:2 lead(II):penicillamine complex with [Pb(S,N,O-Pen)(S-HnPen)]2–n (n = 0–1) coordination in alkaline solutions, and provide useful structural information on how penicillamine can function as an antidote against lead toxicity in vivo. PMID:25385465

  5. Obtainment of chelating agents through the enzymatic oxidation of lignins by phenol oxidase.

    PubMed

    Calabria, Gabriela M M; Gonçalves, Adilson R

    2006-01-01

    Oxidation of lignin obtained from acetosolv and ethanol/water pulping of sugarcane bagasse was performed by phenol oxidases: tyrosinase (TYR) and laccase (LAC), to increase the number of carbonyl and hydroxyl groups in lignin, and to improve its chelating capacity. The chelating properties of the original and oxidized lignins were compared by monitoring the amount of Cu2+ bound to lignin by gel permeation chromatography. The Acetosolv lignin oxidized with TYR was 16.8% and with LAC 21% higher than that of the original lignin. For ethanol/water lignin oxidized with TYR was 17.2% and with LAC 18% higher than that of the original lignin. PMID:16915650

  6. Effect of supplementation with ferrous sulfate or iron bis-glycinate chelate on ferritin concentration in Mexican schoolchildren: a randomized controlled trial

    PubMed Central

    2014-01-01

    Background Iron deficiency is one of the most common nutritional deficiencies worldwide. It is more prevalent when iron requirements are increased during pregnancy and during growth spurts of infancy and adolescence. The last stage in the process of iron depletion is characterized by a decrease in hemoglobin concentration, resulting in iron deficiency anemia. Iron deficiency, even before it is clinically identified as anemia, compromises the immune response, physical capacity for work, and intellectual functions such as attention level. Therefore, interventions addressing iron deficiency should be based on prevention rather than on treatment of anemia. The aim of this study was to compare short- and medium-term effects on ferritin concentration of daily supplementation with ferrous sulfate or iron bis-glycinate chelate in schoolchildren with iron deficiency but without anemia. Methods Two hundred schoolchildren from public boarding schools in Mexico City who had low iron stores as assessed by serum ferritin concentration but without anemia were randomly assigned to a daily supplement of 30 mg/day of elemental iron as ferrous sulfate or iron bis-glycinate chelate for 12 weeks. Iron status was evaluated at baseline, one week post-supplementation (short term), and 6 months (medium term) after supplementation. Results Ferritin concentration increased significantly between baseline and post-supplementation as well as between baseline and 6 months after supplementation. One week post-supplementation no difference was found in ferritin concentration between iron compounds, but 6 months after supplementation ferritin concentration was higher in the group that received bis-glycinate chelate iron. However, there is no difference in the odds for low iron storage between 6 months after supplementation versus the odds after supplementation; nor were these odds different by type of supplement. Hemoglobin concentration did not change significantly in either group after

  7. Determination of o,oEDDHA - a xenobiotic chelating agent used in Fe fertilizers - in plant tissues by liquid chromatography/electrospray mass spectrometry: overcoming matrix effects.

    PubMed

    Orera, Irene; Abadía, Anunciación; Abadía, Javier; Alvarez-Fernández, Ana

    2009-06-01

    The Fe(III)-chelate of ethylenediamine-N,N'-bis(o-hydroxyphenylacetic) acid (o,oEDDHA) is generally considered as the most efficient and widespread Fe fertilizer for fruit crops and intensive horticulture. The determination of the xenobiotic chelating agent o,oEDDHA inside the plant is a key issue in the study of this fertilizer. Both the low concentrations of o,oEDDHA expected and the complexity of plant matrices have been important drawbacks in the development of analytical methods for the determination of o,oEDDHA in plant tissues. The determination of o,oEDDHA in plant materials has been tackled in this study by liquid chromatography coupled to mass spectrometry using several plant species and tissues. Two types of internal standards have been tested: Iron stable isotope labeled compounds and a structural analogue compound, the Fe(III) chelate of ethylenediamine-N,N'-bis(2-hydroxy-4-methylphenylacetic) acid (o,oEDDHMA). Iron stable isotope labeled internal standards did not appear to be suitable because of the occurrence of isobaric endogenous compounds and/or isotope exchange reactions between plant native Fe pools and the Fe stable isotope of the internal standard. However, the structural analogue Fe(III)-o,oEDDHMA is an adequate internal standard for the determination of both isomers of o,oEDDHA (racemic and meso) in plant tissues. The method was highly sensitive, with limits of detection and quantification in the range of 3-49 and 11-162 pmol g(-1) fresh weight, respectively, and analyte recoveries were in the range of 74-116%. Using this methodology, both o,oEDDHA isomers were found in all tissues of sugar beet and tomato plants treated with 90 microM Fe(III)-o,oEDDHA for 24 h, including leaves, roots and xylem sap. This methodology constitutes a useful tool for studies on o,oEDDHA plant uptake, transport and allocation. PMID:19412919

  8. Using a dual-stable isotope tracer method to study the uptake, xylem transport and distribution of Fe and its chelating agent from stereoisomers of an Fe(III)-chelate used as fertilizer in Fe-deficient Strategy I plants.

    PubMed

    Orera, Irene; Rodríguez-Castrillón, José A; Moldovan, Mariella; García-Alonso, José I; Abadía, Anunciación; Abadía, Javier; Alvarez-Fernández, Ana

    2010-09-01

    A dual-stable isotope tracer experiment was carried out with Fe-deficient sugar beet plants grown hydroponically and resupplied with differentially Fe labeled racemic and meso Fe(iii)-chelates of the ethylendiamine di(o-hydroxyphenylacetic) acid (o,oEDDHA). No short-term Fe isotope exchange reactions occurred in the nutrient solution and plants did not discriminate between (54)Fe and (57)Fe. After 3-6 h, stable Fe isotopes, chelating agents and chelates were analyzed in roots, xylem sap and leaves by ICP-MS and HPLC-ESI/TOFMS. Ferric chelate reductase rates, xylem transport and total uptake were 2-fold higher with the meso isomer than with the racemic one. Both chelating agent isomers were incorporated and distributed by plants at similar rates, in amounts one order of magnitude lower than those of Fe. After 6 h of Fe resupply, most of the Fe acquired was localized in roots, whereas most of the chelating agent was in leaves. In a separate experiment, Fe-deficient sugar beet and tomato plants were treated with different concentrations of Fe(iii)-o,oEDDHA (with a meso/racemic ratio of 1). The xylem sap Fe concentration at 24 h was unaffected by the chelate concentration, with xylem Fe(iii)-o,oEDDHA accounting for 1-18% of total Fe and xylem meso/racemic ratio close to 1. Although most of the Fe coming from Fe(iii)-o,oEDDHA was taken up through a reductive dissociative mechanism, a small part of the Fe may be taken up via non-dissociative mechanisms. PMID:21072356

  9. Comparison of the antibacterial activity of chelating agents using the agar diffusion method

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The agar diffusion assay was used to examine antibacterial activity of 2 metal chelators. Concentrations of 0 to 40 mM of ethylenediaminetetraacetic acid (EDTA) and ethylenediamine-N,N’-disuccinic acid (EDDS) were prepared in 1.0 M potassium hydroxide (KOH). The pH of the solutions was adjusted to 1...

  10. Topical efficacy of dimercapto-chelating agents against lewisite-induced skin lesions in SKH-1 hairless mice

    SciTech Connect

    Mouret, Stéphane; Wartelle, Julien; Emorine, Sandy; Bertoni, Marine; Nguon, Nina; Cléry-Barraud, Cécile; Dorandeu, Frédéric; Boudry, Isabelle

    2013-10-15

    Lewisite is a potent chemical warfare arsenical vesicant that can cause severe skin lesions. Today, lewisite exposure remains possible during demilitarization of old ammunitions and as a result of deliberate use. Although its cutaneous toxicity is not fully elucidated, a specific antidote exists, the British anti-lewisite (BAL, dimercaprol) but it is not without untoward effects. Analogs of BAL, less toxic, have been developed such as meso-2,3-dimercaptosuccinic acid (DMSA) and have been employed for the treatment of heavy metal poisoning. However, efficacy of DMSA against lewisite-induced skin lesions remains to be determined in comparison with BAL. We have thus evaluated in this study the therapeutic efficacy of BAL and DMSA in two administration modes against skin lesions induced by lewisite vapor on SKH-1 hairless mice. Our data demonstrate a strong protective efficacy of topical application of dimercapto-chelating agents in contrast to a subcutaneous administration 1 h after lewisite exposure, with attenuation of wound size, necrosis and impairment of skin barrier function. The histological evaluation also confirms the efficacy of topical application by showing that treatments were effective in reversing lewisite-induced neutrophil infiltration. This protective effect was associated with an epidermal hyperplasia. However, for all the parameters studied, BAL was more effective than DMSA in reducing lewisite-induced skin injury. Together, these findings support the use of a topical form of dimercaprol-chelating agent against lewisite-induced skin lesion within the first hour after exposure to increase the therapeutic management and that BAL, despite its side-effects, should not be abandoned. - Highlights: • Topically applied dimercapto-chelating agents reduce lewisite-induced skin damage. • One topical application of BAL or DMSA is sufficient to reverse lewisite effects. • Topical BAL is more effective than DMSA to counteract lewisite-induced skin damage.

  11. Optimising iron chelation therapy with deferasirox for non-transfusion-dependent thalassaemia patients: 1-year results from the THETIS study.

    PubMed

    Taher, Ali T; Cappellini, M Domenica; Aydinok, Yesim; Porter, John B; Karakas, Zeynep; Viprakasit, Vip; Siritanaratkul, Noppadol; Kattamis, Antonis; Wang, Candace; Zhu, Zewen; Joaquin, Victor; Uwamahoro, Marie José; Lai, Yong-Rong

    2016-03-01

    Efficacy and safety of iron chelation therapy with deferasirox in iron-overloaded non-transfusion-dependent thalassaemia (NTDT) patients were established in the THALASSA study. THETIS, an open-label, single-arm, multicentre, Phase IV study, added to this evidence by investigating earlier dose escalation by baseline liver iron concentration (LIC) (week 4: escalation according to baseline LIC; week 24: adjustment according to LIC response, maximum 30mg/kg/day). The primary efficacy endpoint was absolute change in LIC from baseline to week 52. 134 iron-overloaded non-transfusion-dependent anaemia patients were enrolled and received deferasirox starting at 10mg/kg/day. Mean actual dose±SD over 1year was 14.70±5.48mg/kg/day. At week 52, mean LIC±SD decreased significantly from 15.13±10.72mg Fe/g dw at baseline to 8.46±6.25mg Fe/g dw (absolute change from baseline, -6.68±7.02mg Fe/g dw [95% CI: -7.91, -5.45]; P<0.0001). Most common drug-related adverse events were gastrointestinal: abdominal discomfort, diarrhoea and nausea (n=6 each). There was one death (pneumonia, not considered drug related). With significant and clinically relevant reductions in iron burden alongside a safety profile similar to that in THALASSA, these data support earlier escalation with higher deferasirox doses in iron-overloaded non-transfusion-dependent anaemia patients.

  12. Optimising iron chelation therapy with deferasirox for non-transfusion-dependent thalassaemia patients: 1-year results from the THETIS study.

    PubMed

    Taher, Ali T; Cappellini, M Domenica; Aydinok, Yesim; Porter, John B; Karakas, Zeynep; Viprakasit, Vip; Siritanaratkul, Noppadol; Kattamis, Antonis; Wang, Candace; Zhu, Zewen; Joaquin, Victor; Uwamahoro, Marie José; Lai, Yong-Rong

    2016-03-01

    Efficacy and safety of iron chelation therapy with deferasirox in iron-overloaded non-transfusion-dependent thalassaemia (NTDT) patients were established in the THALASSA study. THETIS, an open-label, single-arm, multicentre, Phase IV study, added to this evidence by investigating earlier dose escalation by baseline liver iron concentration (LIC) (week 4: escalation according to baseline LIC; week 24: adjustment according to LIC response, maximum 30mg/kg/day). The primary efficacy endpoint was absolute change in LIC from baseline to week 52. 134 iron-overloaded non-transfusion-dependent anaemia patients were enrolled and received deferasirox starting at 10mg/kg/day. Mean actual dose±SD over 1year was 14.70±5.48mg/kg/day. At week 52, mean LIC±SD decreased significantly from 15.13±10.72mg Fe/g dw at baseline to 8.46±6.25mg Fe/g dw (absolute change from baseline, -6.68±7.02mg Fe/g dw [95% CI: -7.91, -5.45]; P<0.0001). Most common drug-related adverse events were gastrointestinal: abdominal discomfort, diarrhoea and nausea (n=6 each). There was one death (pneumonia, not considered drug related). With significant and clinically relevant reductions in iron burden alongside a safety profile similar to that in THALASSA, these data support earlier escalation with higher deferasirox doses in iron-overloaded non-transfusion-dependent anaemia patients. PMID:26852651

  13. Chelating agents for uranium(IV): 2. Efficacy and toxicity of tetradentate catecholate and hydroxypyridinonate ligands in mice

    SciTech Connect

    Durbin, P.W.; Kullgren, B.; Ebbe, S.N.; Xu, J.; Raymond, K.N.

    2000-05-01

    Uranium(VI) (UO{sub 2}{sup 2+}, uranyl) is nephrotoxic. Depending on isotopic composition and dosage, U(VI) is also chemically toxic and carcinogenic in bone. Several ligands containing two, three, or four bidentate catecholate or hydroxypyridinonate metal binding groups, developed for in vivo chelation of other actinides, were found, on evaluation in mice, to be effective for in vivo chelation of U(VI). The most promising ligands contained two bidentate groups per chelator molecule (tetradentate) attached to linear 4- or 5-carbon backbones (4-LI, butylene; 5-LI, pentylene; 5-LIO, diethyl ether). New ligands were then prepared to optimize ligand affinity for U(VI) in vivo and low acute toxicity. Five bidentate binding groups--sulfocatechol [CAM(S)], carboxycatechol [CAM(C)], methylterephthalamide (MeTAM), 1,2-hydroxypyridinone (1,2-HOPO), or 3,2-hydroxypyridinone (Me-3,2-HOPO)--were each attached to two linear backbones (4-LI and 5-LI or 5-LIO). Those ten tetradentate ligands and octadentate 3,4,3-LI(1,2-HOPO), an effective actinide chelator, were evaluated in mice for in vivo chelation of {sup 233}U(VI) (injection at 3 min, 1 h, or 24 h or oral administration at 3 min after intravenous injection of {sup 233}UO{sub 2}Cl{sub 2}) and for acute toxicity (100 {micro}mol kg{sup {minus}1} injected daily for 10 d). The combined efficacy and toxicity screening identified 5-LIO(Me-3,2-HOPO) and 5-LICAM(S) as the most effective low-toxicity agents. They chelate circulating U(VI) efficiently at ligand:uranium molar ratios {ge} 20, remove useful amounts of newly deposited U(VI) from kidney and bone at molar ratios {ge} 100, and reduce kidney U(VI) levels significantly when given orally at molar ratios {ge} 100. 5-LIO(Me-3,2-HOPO) has greater affinity for kidney U(VI) while 5-LICAM(S) has greater affinity for bone U(VI), and a 1:1 mixture (total molar ratio = 91) reduced kidney and bone U(VI) to 15 and 58% of control, respectively--more than an equimolar amount of either ligand

  14. The copper-chelating agent, trientine, attenuates liver enzyme-altered preneoplastic lesions in rats by angiogenesis suppression.

    PubMed

    Yoshiji, Hitoshi; Kuriyama, Shigeki; Yoshii, Junichi; Ikenaka, Yasuhide; Noguchi, Ryuichi; Yanase, Koji; Namisaki, Tadashi; Yamazaki, Masaharu; Tsujinoue, Hirohisa; Imazu, Hiroo; Fukui, Hiroshi

    2003-01-01

    It has been shown that angiogenesis plays an important role not only in tumor growth, but also in carcinogenesis. We previously reported that the copper-chelating agent, trientine dihydrochloride (trientine), exerted strong anti-angiogenic activity and inhibited hepatocellular carcinoma (HCC) tumor growth. The aim of the current study was to elucidate the effect of trientine on liver enzyme-altered preneoplastic lesions in rats, especially in conjunction with angiogenesis alteration in the liver. In a diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis model, trientine treatment, even at a clinically comparable low dose, significantly suppressed glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions associated with a decrease in copper content in the liver. Trientine also markedly suppressed neovascularization in the liver to a similar level as that of development of the preneoplastic lesions. On the contrary, the proliferative cell nuclear antigen (PCNA)-positive cells were not altered with or without trientine treatment. These results suggested that the copper-chelating agent, trientine, exerted chemopreventive effects against rat liver carcinogenesis due to the suppression of angiogenesis, and suggest that it might be useful clinically as a chemopreventive agent of HCC.

  15. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

    PubMed Central

    Kell, Douglas B

    2009-01-01

    Background The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. Review We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, since in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox

  16. Effect of Chelating Agents on the Stability of Nano-TiO2 Sol Particles for Sol-Gel Coating.

    PubMed

    Maeng, Wan Young; Yoo, Mi

    2015-11-01

    Agglomeration of sol particles in a titanium alkoxide (tetrabutyl orthotitanate (TBOT), > 97%) solution during the hydrolysis and condensation steps makes the sol solution difficult to use for synthesizing homogeneous sol-gel coating. Here, we have investigated the effect of stabilizing agents (acetic acid and ethyl acetoacetate (EAcAc)) on the agglomeration of Ti alkoxide particles during hydrolysis and condensation in order to determine the optimized conditions for controlling the precipitation of TiO2 particles. The study was conducted at R(AC) ([acetic acid]/[TBOT]) = 0.1-5 and R(EAcAc)([EAcAc]/[TBOT]) = 0.05-0.65. We also studied the effects of a basic catalyst ethanolamine (ETA), water, and HCl on sol stability. The chelating ligands in the precursor sol were analyzed with FT-IR. The coating properties were examined by focused ion beam. The stabilizing agents (acetic acid and EAcAc) significantly influenced the agglomeration and precipitation of TBOT precursor particles during hydrolysis. As R(AC) and R(EAcAc) increased, the agglomeration remarkably decreased. The stability of the sol with acetic acid and EAcAc arises from the coordination of the chelating ligand to TBOT that hinders hydrolysis and condensation. A uniform fine coating (thickness: 30 nm) on stainless steel was obtained by using an optimized sol with R(AC) = 0.5 and R(EAcAc) = 0.65.

  17. Synergetic effect of chelating agent and nonionic surfactant for benzotriazole removal on post Cu-CMP cleaning

    NASA Astrophysics Data System (ADS)

    Yanlei, Li; Yuling, Liu; Chenwei, Wang; Yue, Li

    2016-08-01

    The cleaning of copper interconnects after chemical mechanical planarization (CMP) process is a critical step in integrated circuits (ICs) fabrication. Benzotriazole (BTA), which is used as corrosion inhibitor in the copper CMP slurry, is the primary source for the formation of organic contaminants. The presence of BTA can degrade the electrical properties and reliability of ICs which needs to be removed by using an effective cleaning solution. In this paper, an alkaline cleaning solution was proposed. The alkaline cleaning solution studied in this work consists of a chelating agent and a nonionic surfactant. The removal of BTA was characterized by contact angle measurements and potentiodynamic polarization studies. The cleaning properties of the proposed cleaning solution on a 300 mm copper patterned wafer were also quantified, total defect counts after cleaning was studied, scanning electron microscopy (SEM) review was used to identify types of BTA to confirm the ability of cleaning solution for BTA removal. All the results reveal that the chelating agent can effectively remove the BTA residual, nonionic surfactant can further improve the performance. Project supported by the Natural Science Foundation of Hebei Province, China (No. F2015202267) and the Scientific Innovation Grant for Excellent Young Scientists of Hebei University of Technology (No. 2015007).

  18. Nitric oxide suppresses tumor cell migration through N-Myc downstream-regulated gene-1 (NDRG1) expression: role of chelatable iron.

    PubMed

    Hickok, Jason R; Sahni, Sumit; Mikhed, Yuliya; Bonini, Marcelo G; Thomas, Douglas D

    2011-12-01

    N-Myc downstream-regulated gene 1 (NDRG1) is a ubiquitous cellular protein that is up-regulated under a multitude of stress and growth-regulatory conditions. Although the exact cellular functions of this protein have not been elucidated, mutations in this gene or aberrant expression of this protein have been linked to both tumor suppressive and oncogenic phenotypes. Previous reports have demonstrated that NDRG1 is strongly up-regulated by chemical iron chelators and hypoxia, yet its regulation by the free radical nitric oxide ((•)NO) has never been demonstrated. Herein, we examine the chemical biology that confers NDRG1 responsiveness at the mRNA and protein levels to (•)NO. We demonstrate that the interaction of (•)NO with the chelatable iron pool (CIP) and the appearance of dinitrosyliron complexes (DNIC) are key determinants. Using HCC 1806 triple negative breast cancer cells, we find that NDRG1 is up-regulated by physiological (•)NO concentrations in a dose- and time-dependant manner. Tumor cell migration was suppressed by NDRG1 expression and we excluded the involvement of HIF-1α, sGC, N-Myc, and c-Myc as upstream regulatory targets of (•)NO. Augmenting the chelatable iron pool abolished (•)NO-mediated NDRG1 expression and the associated phenotypic effects. These data, in summary, reveal a link between (•)NO, chelatable iron, and regulation of NDRG1 expression and signaling in tumor cells.

  19. Effect of chelating agent acetylacetone on corrosion protection properties of silane-zirconium sol-gel coatings

    NASA Astrophysics Data System (ADS)

    Yu, Mei; Liang, Min; Liu, Jianhua; Li, Songmei; Xue, Bing; Zhao, Hao

    2016-02-01

    The hybrid sol-gel coatings on AA2024-T3 were prepared with a silane coupling agent 3-glycidoxypropyltrimethoxysilane (GPTMS) and a metal alkoxide tetra-n-propoxyzirconium (TPOZ) as precursors. The effect of acetylacetone (AcAc) as a chelating agent on the corrosion protection properties of sol-gel coatings were evaluated and the optimal AcAc/TPOZ molar ratio was obtained. The sol-gel coatings were characterized by atomic force microscopy (AFM), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). The corrosion protection properties of the coatings were evaluated by means of potentiodynamic polarization study (PDS) and electrochemical impedance spectroscopy (EIS). It is demonstrated that AcAc avoids fast hydrolysis of TPOZ and benefits to form stable sols. The coating with AcAc/TPOZ molar ratio of 3 shows the best corrosion protection performance in 0.05 M NaCl solution.

  20. A promising approach for improving the recovery of heart transplants. Prevention of free radical injury through iron chelation by deferoxamine.

    PubMed

    Menasché, P; Grousset, C; Mouas, C; Piwnica, A

    1990-07-01

    Iron catalysis is involved in the generation of the highly cytotoxic hydroxyl radical and in the chain reactions of subsequent lipid peroxidation that lead to irreversible membrane damage. Assuming that ischemically stored heart transplants may incur free radical injury at the time of reoxygenation, we assessed the effects of the iron chelator deferoxamine in 70 isolated isovolumic buffer-perfused rat hearts subjected to the following protocol: cardioplegic arrest; cold (2 degrees C) storage for 5 hours; global ischemia at 15 degrees C for 1 hour, intended to simulate the implantation procedure; and normothermic reperfusion for 1 additional hour. During poststorage ischemic arrest, the following techniques of myocardial protection were evaluated: hypothermia alone; high-pressure (60 cm H2O) cardioplegia given at 0, 30, and 55 minutes of arrest; low-pressure (30 cm H2O) cardioplegia given at 0 and 55 minutes of arrest; and low-pressure (30 cm H2O) cardioplegia only given at 55 minutes of arrest. Treated hearts had deferoxamine (6 mumol) added to the cardioplegic solution used throughout the experimental time course. Further, in the treated group subjected to the protocol of single cardioplegic delivery at end ischemia, deferoxamine was given both in the cardioplegic reperfusate and in the Krebs buffer over the 15 initial minutes of reflow. Based on comparisons of postreperfusion ventricular pressure development, maximal rate of rise of ventricular pressure, left ventricular compliance, and coronary flow, the best myocardial protection was afforded by deferoxamine given as an additive to single-dose cardioplegic solution at the end of arrest and to the reperfusate during the initial phase of reoxygenation. As the drug has no inotropic effect, its protective action is most likely related to a decrease in catalytic iron available for free radical production and lipid peroxidation. These results support the hypothesis that oxidative damage may contribute to donor heart

  1. Combination of copper-chelating agent, trientine, and methotrexate attenuates colorectal carcinoma development and angiogenesis in mice.

    PubMed

    Yoshiji, Hitoshi; Yoshii, Junichi; Kuriyama, Shigeki; Ikenaka, Yasuhide; Noguchi, Ryuichi; Yanase, Koji; Namisaki, Tadashi; Kitade, Mitsuteru; Yamazaki, Masaharu; Fukui, Hiroshi

    2005-07-01

    Recent studies have suggested that an anti-angiogenic agent could improve the inhibitory effects of standard chemotherapeutic drugs against tumor development. We previously reported that the clinically used copper-chelating agent, trientine dihydrochloride (trientine), exerted strong anti-angiogenic activity and inhibited tumor growth. The aim of the current study was to examine the combined effect of trientine and methotrexate on the development and angiogenesis of xenograft human colorectal carcinoma (CRC) cells at clinically comparable low doses. When used individually, both trientine and methotrexate significantly suppressed CRC development along with inhibition of neovascularization in the tumor. A combination regimen of trientine and methotrexate exerted the most potent tumoricidal effect and led to 'tumor dormancy.' The combination of these agents also resulted in a marked suppression of the angiogenic factors, in particular the vascular endothelial growth factor and interleukin-8, and an increase of apoptosis in the tumor. In vitro studies revealed that neither trientine nor methotrexate was cytotoxic for tumor cells. On the other hand, the endothelial cell proliferation and tubular formation were significantly suppressed by these agents. The combined treatment of trientine and methotrexate at clinically comparable low doses could inhibit CRC development and angiogenesis, as well as suppress the angiogenic factors. Because both agents are widely used in clinical practice, the combination regimen may represent a potential new strategy for CRC therapy in the future.

  2. In vitro and in vivo biological activities of iron chelators and gallium nitrate against Acinetobacter baumannii.

    PubMed

    de Léséleuc, Louis; Harris, Greg; KuoLee, Rhonda; Chen, Wangxue

    2012-10-01

    We investigated the ability of compounds interfering with iron metabolism to inhibit the growth of Acinetobacter baumannii. Iron restriction with transferrin or 2,2-bipyridyl significantly inhibited A. baumannii growth in vitro. Gallium nitrate alone was moderately effective at reducing A. baumannii growth but became bacteriostatic in the presence of serum or transferrin. More importantly, gallium nitrate treatment reduced lung bacterial burdens in mice. The use of gallium-based therapies shows promise for the control of multidrug-resistant A. baumannii.

  3. Longitudinal changes of endocrine and bone disease in adults with β-thalassemia major receiving different iron chelators over 5 years.

    PubMed

    Poggi, Maurizio; Sorrentino, Francesco; Pugliese, Pellegrina; Smacchia, Maria Paola; Daniele, Carmine; Equitani, Francesco; Terlizzi, Filomena; Guitarrini, Maria Rita; Monti, Salvatore; Maffei, Laura; Losardo, Anna; Pasin, Methap; Toscano, Vincenzo

    2016-04-01

    In this study, we compared the long-term effects of different iron chelation regimens (deferoxamine, deferiprone, deferoxamine + deferiprone, and deferasirox) in preventing or reversing endocrinopathy (diabetes mellitus, hypothyroidism, or hypogonadism) and bone disease (measured through DEXA) in 165 adults with β-thalassemia major (TM) (mean age 39.9 ± 8.3 years, 43 % males). After five consecutive years of therapy, patients on deferasirox had the highest decrease in the prevalence of any endocrinopathy compared to other chelators which either had no change (deferiprone and deferoxamine) or had an increase (deferoxamine + deferiprone), p = 0.015. This was attributed to a lower proportion of patients on deferasirox developing new-onset endocrinopathy and higher proportion showing reversal of disease, compared to other chelators. A serum ferritin level of >1300 ng/mL predicted the development of new endocrinopathy (p = 0.025) while a level of <200 ng/mL predicted reversal of existing endocrinopathy (p = 0.147). A significant increase in mean BMD T-score (p < 0.001) and a considerable decrease in osteoporosis prevalence were observed in patients receiving deferasirox but not other chelators. Iron chelation therapy with deferasirox has a role in the prevention of endocrinopathy and reversal of existing disease. PMID:26957357

  4. Impact of two iron(III) chelators on the iron, cadmium, lead and nickel accumulation in poplar grown under heavy metal stress in hydroponics.

    PubMed

    Mihucz, Victor G; Csog, Árpád; Fodor, Ferenc; Tatár, Enikő; Szoboszlai, Norbert; Silaghi-Dumitrescu, Luminiţa; Záray, Gyula

    2012-04-15

    Poplar (Populus jacquemontiana var. glauca cv. Kopeczkii) was grown in hydroponics containing 10 μM Cd(II), Ni(II) or Pb(II), and Fe as Fe(III) EDTA or Fe(III) citrate in identical concentrations. The present study was designed to compare the accumulation and distribution of Fe, Cd, Ni and Pb within the different plant compartments. Generally, Fe and heavy-metal accumulation were higher by factor 2-7 and 1.6-3.3, respectively, when Fe(III) citrate was used. Iron transport towards the shoot depended on the Fe(III) chelate and, generally, on the heavy metal used. Lead was accumulated only in the root. The amounts of Fe and heavy metals accumulated by poplar were very similar to those of cucumber grown in an identical way, indicating strong Fe uptake regulation of these two Strategy I plants: a cultivar and a woody plant. The Strategy I Fe uptake mechanism (i.e. reducing Fe(III) followed by Fe(II) uptake), together with the Fe(III) chelate form in the nutrient solution had significant effects on Fe and heavy metal uptake. Poplar appears to show phytoremediation potential for Cd and Ni, as their transport towards the shoot was characterized by 51-54% and 26-48% depending on the Fe(III) supply in the nutrient solution.

  5. Effects of feed supplementation with glycine chelate and iron sulfate on selected parameters of cell-mediated immune response in broiler chickens.

    PubMed

    Jarosz, Łukasz; Kwiecień, Małgorzata; Marek, Agnieszka; Grądzki, Zbigniew; Winiarska-Mieczan, Anna; Kalinowski, Marcin; Laskowska, Ewa

    2016-08-01

    Because little is known about the impact of chelated (Fe-Gly, Fe-Gly+F) and inorganic (FeSO4, FeSO4+F) iron products on immune response parameters in broiler chickens, the objective of the study was to determine the effects of inorganic and organic forms of iron on selected parameters of the cell-mediated immune response in broiler chickens by assessing the percentage of CD3(+)CD4(+), CD3(+)CD8(+), CD25(+), and MHC Class II lymphocytes, as well as the CD4(+)/CD8(+) ratio and IL-2 concentration in the peripheral blood. The experiments were conducted using 50day-old Ross 308 roosters. The test material was peripheral blood. Flow cytometry was used to determine selected cell-mediated immune response parameters. The results obtained indicate that the use of iron chelates in the diet of broiler chickens may stimulate cellular defense mechanisms. As a result of the experiment an increase was observed in the percentage of Th1, mainly T CD4(+) and T CD8(+). It was also noted that application of chelated iron can increase production of T CD8(+) cytotoxic cells and IL-2, which promotes the body's natural response to developing inflammation. There were no changes in T CD4(+), T CD8(+), T CD25(+) or MHC II lymphocyte subpopulations in the chickens following application of the inorganic form of iron. PMID:27473977

  6. Effects of feed supplementation with glycine chelate and iron sulfate on selected parameters of cell-mediated immune response in broiler chickens.

    PubMed

    Jarosz, Łukasz; Kwiecień, Małgorzata; Marek, Agnieszka; Grądzki, Zbigniew; Winiarska-Mieczan, Anna; Kalinowski, Marcin; Laskowska, Ewa

    2016-08-01

    Because little is known about the impact of chelated (Fe-Gly, Fe-Gly+F) and inorganic (FeSO4, FeSO4+F) iron products on immune response parameters in broiler chickens, the objective of the study was to determine the effects of inorganic and organic forms of iron on selected parameters of the cell-mediated immune response in broiler chickens by assessing the percentage of CD3(+)CD4(+), CD3(+)CD8(+), CD25(+), and MHC Class II lymphocytes, as well as the CD4(+)/CD8(+) ratio and IL-2 concentration in the peripheral blood. The experiments were conducted using 50day-old Ross 308 roosters. The test material was peripheral blood. Flow cytometry was used to determine selected cell-mediated immune response parameters. The results obtained indicate that the use of iron chelates in the diet of broiler chickens may stimulate cellular defense mechanisms. As a result of the experiment an increase was observed in the percentage of Th1, mainly T CD4(+) and T CD8(+). It was also noted that application of chelated iron can increase production of T CD8(+) cytotoxic cells and IL-2, which promotes the body's natural response to developing inflammation. There were no changes in T CD4(+), T CD8(+), T CD25(+) or MHC II lymphocyte subpopulations in the chickens following application of the inorganic form of iron.

  7. Amyloid β25-35 induced ROS-burst through NADPH oxidase is sensitive to iron chelation in microglial Bv2 cells.

    PubMed

    Part, Kristin; Künnis-Beres, Kai; Poska, Helen; Land, Tiit; Shimmo, Ruth; Zetterström Fernaeus, Sandra

    2015-12-10

    Iron chelation therapy and inhibition of glial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can both represent possible routes for Alzheimer's disease modifying therapies. The metal hypothesis is largely focused on direct binding of metals to the N-terminal hydrophilic 1-16 domain peptides of Amyloid beta (Aβ) and how they jointly give rise to reactive oxygen species (ROS) production. The cytotoxic effects of Aβ through ROS and metals are mainly studied in neuronal cells using full-length Aβ1-40/42 peptides. Here we study cellularly-derived ROS during 2-60min in response to non-metal associated mid domain Aβ25-35 in microglial Bv2 cells by fluorescence based spectroscopy. We analyze if Aβ25-35 induce ROS production through NADPH oxidase and if the production is sensitive to iron chelation. NADPH oxidase inhibitor diphenyliodonium (DPI) is used to confirm the production of ROS through NADPH oxidase. We modulate cellular iron homeostasis by applying cell permeable iron chelators desferrioxamine (DFO) and deferiprone (DFP). NADPH oxidase subunit gp91-phox level was analyzed by Western blotting. Our results show that Aβ25-35 induces strong ROS production through NADPH oxidase in Bv2 microglial cells. Intracellular iron depletion resulted in restrained Aβ25-35 induced ROS.

  8. Phytoremediation of Cr(VI) by Spirodela polyrrhiza (L.) Schleiden employing reducing and chelating agents.

    PubMed

    Bala, Rajni; Thukral, Ashwani K

    2011-01-01

    Phytoremediation of Cr(VI) by Spirodela polyrrhiza in binary combinations with low molecular weight organic compounds (LMWOCs) with a reducing or chelating potential, viz., ascorbic acid, citric acid, tartaric acid, oxalic acid, lactic acid, and glycerol was studied in Cr(VI) containing hydroponic media. Significant increase in the relative dry weight of plants with respect to Cr(VI) treated controls was observed with ascorbic acid and glycerol. The uptake of chromium by S. polyrrhiza followed Michaelis-Menten kinetics of active ion uptake. Interaction between Cr and ascorbic acid, oxalic acid, and lactic acid decreased Cr uptake, whereas citric acid, glycerol, and tartaric acid increased it. Supplementation of LMWOCs to Cr(VI) containing media decreased the MDA content of the plants. Multiple regression models revealed that LMWOCs decrease lipid peroxidation independently, as well as that induced by Cr(VI). It was found that superoxide dismutase (SOD), guaiacol peroxidase (GPX), and catalase (CAT) activities were increased significantly in plants growing in media containing Cr(VI). The study established that lactic acid, citric acid, ascorbic acid, and glycerol were most effective in increasing the Cr(VI) phytoremediating potential of S. polyrrhiza and LMWOCs with reducing or chelating properties decrease Cr(VI) stress in S. polyrrhiza.

  9. Phytoremediation of Cr(VI) by Spirodela polyrrhiza (L.) Schleiden employing reducing and chelating agents.

    PubMed

    Bala, Rajni; Thukral, Ashwani K

    2011-01-01

    Phytoremediation of Cr(VI) by Spirodela polyrrhiza in binary combinations with low molecular weight organic compounds (LMWOCs) with a reducing or chelating potential, viz., ascorbic acid, citric acid, tartaric acid, oxalic acid, lactic acid, and glycerol was studied in Cr(VI) containing hydroponic media. Significant increase in the relative dry weight of plants with respect to Cr(VI) treated controls was observed with ascorbic acid and glycerol. The uptake of chromium by S. polyrrhiza followed Michaelis-Menten kinetics of active ion uptake. Interaction between Cr and ascorbic acid, oxalic acid, and lactic acid decreased Cr uptake, whereas citric acid, glycerol, and tartaric acid increased it. Supplementation of LMWOCs to Cr(VI) containing media decreased the MDA content of the plants. Multiple regression models revealed that LMWOCs decrease lipid peroxidation independently, as well as that induced by Cr(VI). It was found that superoxide dismutase (SOD), guaiacol peroxidase (GPX), and catalase (CAT) activities were increased significantly in plants growing in media containing Cr(VI). The study established that lactic acid, citric acid, ascorbic acid, and glycerol were most effective in increasing the Cr(VI) phytoremediating potential of S. polyrrhiza and LMWOCs with reducing or chelating properties decrease Cr(VI) stress in S. polyrrhiza. PMID:21598777

  10. Preservation of glutamic acid-iron chelate into montmorillonite to efficiently degrade Reactive Blue 19 in a Fenton system under sunlight irradiation at neutral pH

    NASA Astrophysics Data System (ADS)

    Huang, Zhujian; Wu, Pingxiao; Gong, Beini; Yang, Shanshan; Li, Hailing; Zhu, Ziao; Cui, Lihua

    2016-05-01

    To further enhance the visible light responsive property and the chemical stability of Fe/clay mineral catalysts, glutamic acid-iron chelate intercalated montmorillonite (G-Fe-Mt) was developed. The physiochemical properties of G-Fe-Mt were investigated by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), UV-vis diffuse reflectance spectroscopy (DRS), etc. The results showed that glutamic acid-iron chelates were successfully intercalated into the gallery of montmorillonite and the intercalated glutamic acid-iron chelate molecules were well preserved. The product G-Fe-Mt displayed excellent catalytic performance in heterogeneous photo-Fenton reaction under sunlight irradiation at acidic and neutral pH values. The chelation and the visible light responsiveness of glutamic acid produce a synergistic effect leading to greatly enhanced sunlight-Fenton reaction catalyzed by the heterogeneous G-Fe-Mt under neutral pH. G-Fe-Mt is a promising catalyst for advanced oxidation processes.

  11. Medical complications, resource utilization and costs in patients with myelofibrosis by frequency of blood transfusion and iron chelation therapy.

    PubMed

    Vekeman, Francis; Cheng, Wendy Y; Sasane, Medha; Huynh, Lynn; Duh, Mei Sheng; Paley, Carole; Mesa, Ruben A

    2015-01-01

    Iron chelation therapies (ICTs) can help eliminate iron surplus in erythrocyte transfusion-dependent (TD) patients with myelofibrosis (MF). The study assessed adjusted incidence rate ratios (aIRRs) of MF-related complications and resource utilization (RU) and adjusted mean monthly inpatient cost differences in patients with TD MF treated with versus without ICT (ICT+ vs. ICT-) using data from two healthcare claims databases. Patients with ≥ 2 MF International Classification of Diseases, 9th Revision (ICD-9) diagnosis codes ≥ 30 days apart were included. Among 571 patients with TD MF, 103 (18%) were ICT+ and 468 (82%) were ICT-. ICT+ patients had lower rates of thrombocytopenia (aIRR: 0.55; p < 0.001), pancytopenia (0.53; p < 0.001), emergency room visits (0.84 [95% confidence interval: 0.74-0.96]) and inpatient stays (0.75 [0.64-0.87]), but higher rates of outpatient visits (1.21 [1.18-1.23]). Adjusted mean complication-related inpatient cost difference per month was lower in ICT+ patients (-$1804 [$570]; p = 0.004). ICT+ patients had significantly lower rates of acute care, but higher rates of outpatient care.

  12. Inhibition of Fe(2+)- and Fe(3+)- induced hydroxyl radical production by the iron-chelating drug deferiprone.

    PubMed

    Timoshnikov, V A; Kobzeva, T V; Polyakov, N E; Kontoghiorghes, G J

    2015-01-01

    Deferiprone (L1) is an effective iron-chelating drug that is widely used for the treatment of iron-overload diseases. It is known that in aqueous solutions Fe(2+) and Fe(3+) ions can produce hydroxyl radicals via Fenton and photo-Fenton reactions. Although previous studies with Fe(2+) have reported ferroxidase activity by L1 followed by the formation of Fe(3+) chelate complexes and potential inhibition of Fenton reaction, no detailed data are available on the molecular antioxidant mechanisms involved. Similarly, in vitro studies have also shown that L1-Fe(3+) complexes exhibit intense absorption bands up to 800nm and might be potential sources of phototoxicity. In this study we have applied an EPR spin trapping technique to answer two questions: (1) does L1 inhibit the Fenton reaction catalyzed by Fe(2+) and Fe(3+) ions and (2) does UV-Vis irradiation of the L1-Fe(3+) complex result in the formation of reactive oxygen species. PBN and TMIO spin traps were used for detection of oxygen free radicals, and TEMP was used to trap singlet oxygen if it was formed via energy transfer from L1 in the triplet excited state. It was demonstrated that irradiation of Fe(3+) aqua complexes by UV and visible light in the presence of spin traps results in the appearance of an EPR signal of the OH spin adduct (TMIO-OH, a(N)=14.15G, a(H)=16.25G; PBN-OH, a(N)=16.0G, a(H)=2.7G). The presence of L1 completely inhibited the OH radical production. The mechanism of OH spin adduct formation was confirmed by the detection of methyl radicals in the presence of dimethyl sulfoxide. No formation of singlet oxygen was detected under irradiation of L1 or its iron complexes. Furthermore, the interaction of L1 with Fe(2+) ions completely inhibited hydroxyl radical production in the presence of hydrogen peroxide. These findings confirm an antioxidant targeting potential of L1 in diseases related to oxidative damage. PMID:25451643

  13. Inhibition of Fe(2+)- and Fe(3+)- induced hydroxyl radical production by the iron-chelating drug deferiprone.

    PubMed

    Timoshnikov, V A; Kobzeva, T V; Polyakov, N E; Kontoghiorghes, G J

    2015-01-01

    Deferiprone (L1) is an effective iron-chelating drug that is widely used for the treatment of iron-overload diseases. It is known that in aqueous solutions Fe(2+) and Fe(3+) ions can produce hydroxyl radicals via Fenton and photo-Fenton reactions. Although previous studies with Fe(2+) have reported ferroxidase activity by L1 followed by the formation of Fe(3+) chelate complexes and potential inhibition of Fenton reaction, no detailed data are available on the molecular antioxidant mechanisms involved. Similarly, in vitro studies have also shown that L1-Fe(3+) complexes exhibit intense absorption bands up to 800nm and might be potential sources of phototoxicity. In this study we have applied an EPR spin trapping technique to answer two questions: (1) does L1 inhibit the Fenton reaction catalyzed by Fe(2+) and Fe(3+) ions and (2) does UV-Vis irradiation of the L1-Fe(3+) complex result in the formation of reactive oxygen species. PBN and TMIO spin traps were used for detection of oxygen free radicals, and TEMP was used to trap singlet oxygen if it was formed via energy transfer from L1 in the triplet excited state. It was demonstrated that irradiation of Fe(3+) aqua complexes by UV and visible light in the presence of spin traps results in the appearance of an EPR signal of the OH spin adduct (TMIO-OH, a(N)=14.15G, a(H)=16.25G; PBN-OH, a(N)=16.0G, a(H)=2.7G). The presence of L1 completely inhibited the OH radical production. The mechanism of OH spin adduct formation was confirmed by the detection of methyl radicals in the presence of dimethyl sulfoxide. No formation of singlet oxygen was detected under irradiation of L1 or its iron complexes. Furthermore, the interaction of L1 with Fe(2+) ions completely inhibited hydroxyl radical production in the presence of hydrogen peroxide. These findings confirm an antioxidant targeting potential of L1 in diseases related to oxidative damage.

  14. Complex inhibition of tyrosinase by thiol-composed Cu2+ chelators: a clue for designing whitening agents.

    PubMed

    Park, Yong-Doo; Lyou, You-Jeong; Hahn, Hwa-Sun; Hahn, Myong-Joon; Yang, Jun-Mo

    2006-10-01

    The inhibition of tyrosinase has attracted considerable attention for potential medicinal and cosmetic applications, as well as in agriculture. This study investigated the inhibition effects of thiol-associated Cu(2+) chelators and deduced a strategy for designing and/or selecting tyrosinase inhibitors. Among the several compounds tested, dithioglycerine (DTGC) was selected for further experiments on the inhibition kinetics on tyrosinase. Different types of tyrosinases derived from mushroom and from the transient overexpression in HEK293 cells were tested individually. The results showed that DTGC significantly inhibited human tyrosinase in a complex manner (slope-parabolic mixed-type inhibition), which was comparable to mushroom tyrosinase. The affinity of DTGC affinity to human tyrosinase was evaluated by setting up a K(i slope) equation. The results suggest that a Cu(2+) chelator modified with thiol groups has potential as a whitening agent. In addition, a strategy for designing and/or selecting tyrosinase inhibitors that target the active enzyme site was also suggested. PMID:16928136

  15. On modeling of chemical stimulation of an enhanced geothermal system using a high pH solution with chelating agent

    SciTech Connect

    Xu, T.; Rose, P.; Fayer, S.; Pruess, K.

    2009-05-01

    Dissolution of silica and calcite in the presence of a chelating agent (NTA) at a high pH was successfully demonstrated in laboratory experiments using a high-temperature flow reactor. (Note that the term 'silica' used here includes amorphous silica, quartz, and silicate glass bead). The mineral dissolution and associated porosity enhancement in the experiments were reproduced by reactive transport modeling using TOUGHREACT. The chemical stimulation method was applied by numerical modeling to a field geothermal injection well system to investigate its effectiveness. Parameters applicable to the quartz monzodiorite unit at the Enhanced Geothermal Systems (EGS) site at Desert Peak (Nevada) were used. Results indicate that the injection of a high pH chelating solution results in dissolution of both calcite and plagioclase, while avoiding precipitation of calcite at high temperature conditions. Consequently reservoir porosity and permeability can be enhanced especially near the injection well. Injection at a lower temperature of 120 C (over 160 C in the base-case) results in a porosity increase that is smaller close to the injection point, but extends to a larger radial distance. A slower kinetic rate results in less aggressive mineral dissolution close to the injection point and larger extent along the flow path, which is favorable for chemical stimulation.

  16. Biodegradable chelating agent ethylenediaminedisuccinic acid reduces uptake of copper through alleviation of copper toxicity in hydroponically grown Chrysanthemum coronarium L.

    PubMed

    Wei, Lan; Luo, Chunling; Wang, Chunchun; Li, Xiangdong; Shen, Zhenguo

    2007-04-01

    Hydroponic cultures were conducted to investigate the effects of the biodegradable chelating agent S,S-ethylenediaminedisuccinic acid (EDDS) on the growth and copper uptake by garland chrysanthemum (Chrysanthemum coronarium L.), a plant species sensitive to soil chelate amendment. In the presence of 50 micromol/L Cu, the addition of EDDS increased shoot and root biomass and the vitality of cells in root tips and decreased the relative electrolyte leakage of root cells and the concentration of Cu in shoots. When the roots were pretreated with 65 degrees C hot water for 0.5 to 2 h or with 0.001 to 0.1 mol/L HCl for 24 h before the exposure to 50 micromol/L Cu + 100 micromol/L EDDS, the concentration of Cu in shoots increased considerably compared with the plants without any pretreatment. A statistically significant correlation was found between the Cu concentrations in shoots and the relative electrolyte leakage of root cells. These results indicated that Cu-EDDS might be a less bioavailable form to plants and that some physiological damage to the roots led to enhanced accumulation of Cu in plant shoots.

  17. Development of a new radiolabel (lead-203) and new chelating agents for labeling monoclonal anntibodies for imaging

    SciTech Connect

    Srivastava, S.C.; Mease, R.C.; Meinken, G.E.; Mausner, L.F.; Steplewski, Z.

    1988-01-01

    High liver uptake and slow body clearance presently limit the usefulness of /sup 111/In labeled antibodies for tumor imaging. We have investigated /sup 203/Pb as an alternate and better antibody label. The DTPA and cyclohexyl EDTA (CDTA) conjugates of an anticolon carcinoma antibody, 17-1A were labeled (bicyclic anhydride method) with /sup 203/Pb and /sup 111/In with 60 and 90% labeling yields, respectively. The biodistribution of /sup 203/Pb-17-1A conjugates was compared with the corresponding /sup 111/In-labeled preparations and with /sup 203/Pb-DTPA, /sup 203/Pb-nitrate and nonrelevant antibody controls in normal and human tumor (SW948) xenografted nude mice at 24, and 96 hr. Lead-203-labeled CDTA and DTPA antibody conjugates gave similar in vivo distributions. Even though the lead bound to these chelate-antibody conjugates was more labile in serum and in vivo, compared to indium, it cleared much faster from the liver and the whole body. A new series of chelating agents based on the incorporation of a trans-1,2- diaminocyclohexane moiety into the carbon backbone of polyaminocarboxylates is being synthesized. These are expected to provide stronger complexing ability for lead and produce greater in vivo stability. These ligands are also expected to be superior to EDTA and DTPA for labeling antibodies with other radiometals, including indium. 32 refs., 3 tabs.

  18. Hydroxamate-based iron chelators: combinatorial syntheses of desferrioxamine B analogues and evaluation of binding affinities.

    PubMed

    Poreddy, Amruta R; Schall, Otto F; Osiek, Todd A; Wheatley, James R; Beusen, Denise D; Marshall, Garland R; Slomczynska, Urszula

    2004-01-01

    This article describes the solid-phase combinatorial methods developed for the synthesis of polyhydroxamate-based siderophores. This strategy was applied to generate several libraries of structural DFO (1a) analogues that include DFO variants, non-amide analogues, C-terminal modified analogues, reverse-amide analogues, and hybrid analogues. To assess the relative iron-binding affinities of these compounds, a high-throughput spectrophotometric screening method based on competition with 8-hydroxyquinoline-5-sulfonic acid was developed. Some of the promising candidates containing various terminal functional groups were identified and prepared on large scale to enable future studies in animal models for iron-overload diseases.

  19. Chelation in Metal Intoxication

    PubMed Central

    Flora, Swaran J.S.; Pachauri, Vidhu

    2010-01-01

    Chelation therapy is the preferred medical treatment for reducing the toxic effects of metals. Chelating agents are capable of binding to toxic metal ions to form complex structures which are easily excreted from the body removing them from intracellular or extracellular spaces. 2,3-Dimercaprol has long been the mainstay of chelation therapy for lead or arsenic poisoning, however its serious side effects have led researchers to develop less toxic analogues. Hydrophilic chelators like meso-2,3-dimercaptosuccinic acid effectively promote renal metal excretion, but their ability to access intracellular metals is weak. Newer strategies to address these drawbacks like combination therapy (use of structurally different chelating agents) or co-administration of antioxidants have been reported recently. In this review we provide an update of the existing chelating agents and the various strategies available for the treatment of heavy metals and metalloid intoxications. PMID:20717537

  20. The effects of repeated parenteral administration of chelating agents on the distribution and excretion of uranium

    SciTech Connect

    Domingo, J.L.; Ortega, A.; Llobet, J.M.; Paternain, J.L.; Corbella, J.

    1989-04-01

    The effects of repeated ip administration of gallic acid, 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron), diethylenetriaminepentaacetic acid (DTPA), and 5-aminosalicylic acid (5-AS) on the distribution and excretion of uranium were assessed in male Swiss mice. Only Tiron significantly increased the amount of uranium excreted into urine and feces. A significant decrease in the concentration of uranium in liver, spleen and bone was observed after administration of Tiron, whereas injection of gallic acid or DTPA resulted in a significant decrease in the concentration of the metal in the liver. The results show that Tiron was consistently the most effective chelator of those tested in the treatment of uranium poisoning after repeated daily administration of the metal.

  1. Trientine, a copper-chelating agent, induced apoptosis in murine fibrosarcoma cells by activation of the p38 MAPK pathway.

    PubMed

    KADOWAKI, Shingo; ENDOH, Daiji; OKUI, Toyo; HAYASHI, Masanobu

    2009-11-01

    We have reported that treatment with trientine, Cu-chelating agent, inhibits tumor growth in a murine transplantation model using fibrosarcoma and induces apoptosis in tumor cells in vivo and in vitro. When fibrosarcoma cells were treated with 10 mM trientine, the activities of p38 MAPK in treated cells were approximately 3-4 times higher than those in untreated cells. Proportions of cells in which apoptosis was induced by trientine increased in an incubation time-dependent manner from days 2 to 6. The proportions of apoptotic cells in the cells treated with trientine and SB203580, an inhibitor of p38 MAPK, were approximately 50% in those of cells treated with trientine alone. The present results showed that the p38 MAPK pathway may play an important role in induction of apoptosis in fibrosarcoma cells by trientine.

  2. Effect of Surface Modification by Chelating Agents on Fischer- Tropsch Performance of Co/SiO{sub 2} Catalysts

    SciTech Connect

    Bambal, Ashish S.; Kugler, Edwin L.; Gardner, Todd H.; Dadyburjor, Dady B.

    2013-11-14

    The silica support of a Co-based catalyst for Fischer-Tropsch (FT) synthesis was modified by the chelating agents (CAs) nitrilotriacetic acid (NTA) and ethylenediaminetetraacetic acid (EDTA). After the modification, characterization of the fresh and spent catalysts show reduced crystallite sizes, a better-dispersed Co₃O₄ phase on the calcined samples, and increased metal dispersions for the reduced samples. The CA-modified catalysts display higher CO conversions, product yields, reaction rates and rate constants. The improved FT performance of CA-modified catalysts is attributed to the formation of stable complexes with Co. The superior performance of the EDTA-modified catalyst in comparison to the NTA-modified catalyst is due to the higher affinity of the former for complex formation with Co ions.

  3. Detoxifying polyhalogenated catechols through a copper-chelating agent by forming stable and redox-inactive hydrogen-bonded complexes with an unusual perpendicular structure.

    PubMed

    Li, Yan; Huang, Chun-Hua; Liu, Yu-Xiang; Mao, Li; Zhu, Ben-Zhan

    2014-09-26

    The use of selective metal chelating agents with preference for binding of a specific metal ion to investigate its biological role is becoming increasingly common. We found recently that a well-known copper-specific chelator 2,9-dimethyl-1,10-phenanthroline (2,9-Me2OP) could completely inhibit the synergistic toxicity induced by tetrachlorocatechol (TCC) and sodium azide (NaN3). However, its underlying molecular mechanism is still not clear. Here, we show that the protection by 2,9-Me2OP is not due to its classic copper-chelating property, but rather due to formation of a multiple hydrogen-bonded complex between 2,9-Me2OP and TCC, featuring an unusual perpendicular arrangement of the two binding partners. The two methyl groups at the 2,9 positions in 2,9-Me2OP were found to be critical to stabilize the 2,9-Me2OP/TCC complex due to steric hindrance, and therefore completely prevents the generation of the reactive and toxic semiquinone radicals by TCC/NaN3. This represents the first report showing that an unexpected new protective mode of action for the copper "specific" chelating agent 2,9-Me2OP by using its steric hindrance effect of the two CH3 groups not only to chelate copper, but also to "chelate" a catechol through multiple H-bonding. These findings may have broad biological implications for future research of this widely used copper-chelating agent and the ubiquitous catecholic compounds.

  4. Topical efficacy of dimercapto-chelating agents against lewisite-induced skin lesions in SKH-1 hairless mice.

    PubMed

    Mouret, Stéphane; Wartelle, Julien; Emorine, Sandy; Bertoni, Marine; Nguon, Nina; Cléry-Barraud, Cécile; Dorandeu, Frédéric; Boudry, Isabelle

    2013-10-15

    Lewisite is a potent chemical warfare arsenical vesicant that can cause severe skin lesions. Today, lewisite exposure remains possible during demilitarization of old ammunitions and as a result of deliberate use. Although its cutaneous toxicity is not fully elucidated, a specific antidote exists, the British anti-lewisite (BAL, dimercaprol) but it is not without untoward effects. Analogs of BAL, less toxic, have been developed such as meso-2,3-dimercaptosuccinic acid (DMSA) and have been employed for the treatment of heavy metal poisoning. However, efficacy of DMSA against lewisite-induced skin lesions remains to be determined in comparison with BAL. We have thus evaluated in this study the therapeutic efficacy of BAL and DMSA in two administration modes against skin lesions induced by lewisite vapor on SKH-1 hairless mice. Our data demonstrate a strong protective efficacy of topical application of dimercapto-chelating agents in contrast to a subcutaneous administration 1h after lewisite exposure, with attenuation of wound size, necrosis and impairment of skin barrier function. The histological evaluation also confirms the efficacy of topical application by showing that treatments were effective in reversing lewisite-induced neutrophil infiltration. This protective effect was associated with an epidermal hyperplasia. However, for all the parameters studied, BAL was more effective than DMSA in reducing lewisite-induced skin injury. Together, these findings support the use of a topical form of dimercaprol-chelating agent against lewisite-induced skin lesion within the first hour after exposure to increase the therapeutic management and that BAL, despite its side-effects, should not be abandoned.

  5. Topical efficacy of dimercapto-chelating agents against lewisite-induced skin lesions in SKH-1 hairless mice.

    PubMed

    Mouret, Stéphane; Wartelle, Julien; Emorine, Sandy; Bertoni, Marine; Nguon, Nina; Cléry-Barraud, Cécile; Dorandeu, Frédéric; Boudry, Isabelle

    2013-10-15

    Lewisite is a potent chemical warfare arsenical vesicant that can cause severe skin lesions. Today, lewisite exposure remains possible during demilitarization of old ammunitions and as a result of deliberate use. Although its cutaneous toxicity is not fully elucidated, a specific antidote exists, the British anti-lewisite (BAL, dimercaprol) but it is not without untoward effects. Analogs of BAL, less toxic, have been developed such as meso-2,3-dimercaptosuccinic acid (DMSA) and have been employed for the treatment of heavy metal poisoning. However, efficacy of DMSA against lewisite-induced skin lesions remains to be determined in comparison with BAL. We have thus evaluated in this study the therapeutic efficacy of BAL and DMSA in two administration modes against skin lesions induced by lewisite vapor on SKH-1 hairless mice. Our data demonstrate a strong protective efficacy of topical application of dimercapto-chelating agents in contrast to a subcutaneous administration 1h after lewisite exposure, with attenuation of wound size, necrosis and impairment of skin barrier function. The histological evaluation also confirms the efficacy of topical application by showing that treatments were effective in reversing lewisite-induced neutrophil infiltration. This protective effect was associated with an epidermal hyperplasia. However, for all the parameters studied, BAL was more effective than DMSA in reducing lewisite-induced skin injury. Together, these findings support the use of a topical form of dimercaprol-chelating agent against lewisite-induced skin lesion within the first hour after exposure to increase the therapeutic management and that BAL, despite its side-effects, should not be abandoned. PMID:23806213

  6. Differential effects of the type of iron chelator on the absolute number of hematopoietic peripheral progenitors in patients with β-thalassemia major

    PubMed Central

    Forni, Gian Luca; Podestà, Marina; Musso, Marco; Piaggio, Giovanna; Musallam, Khaled M.; Balocco, Manuela; Pozzi, Sarah; Rosa, Alessandra; Frassoni, Francesco

    2013-01-01

    Several studies have established an association between iron chelation therapy with deferasirox and hematopoietic improvement in patients with myelodysplastic syndromes. There are no data from patients with β-thalassemia major. In a cross-sectional study, we evaluated the absolute number of several hematopoietic peripheral progenitors (colony-forming unit-granulocyte/macrophage, erythroid burst-forming units, colony-forming unit-granulocyte/erythrocyte/macrophage/megakaryocyte, and long-term culture-initiating cells) in 30 patients with β-thalassemia major (median age 29.5 years, 40% males) and 12 age-matched controls. For the β-thalassemia major patients, data on splenectomy status, the type of iron chelator used, and serum ferritin levels reflecting changes in iron status on the chelator were also retrieved. All patients had to be using the same iron chelator for at least 6 months with >80% compliance. The absolute number of all hematopoietic peripheral progenitors was higher in β-thalassemia major patients than in controls, and varied between splenectomized and non-splenectomized patients (lower number of erythroid burst-forming units and higher numbers of colony-forming unit-granulocyte/macrophage, colony-forming unit-granulocyte/erythrocyte/macrophage/megakaryocyte, and long-term culture-initiating cells). The number of erythroid burst-forming units was significantly higher in patients taking deferasirox (n=10) than in those taking either deferoxamine (n=10) or deferiprone (n=10) (P<0.05). After adjusting for age, sex, splenectomy status, and serum ferritin changes, the association between a higher absolute number of erythroid burst-forming units in deferasirox-treated patients than in patients taking deferoxamine or deferiprone remained statistically significant (P=0.011). In conclusion, in β-thalassemia major patients, compared with other iron chelators, deferasirox therapy is associated with higher levels of circulating erythroid burst-forming units

  7. Expression of SFT (stimulator of Fe transport) is enhanced by iron chelation in HeLa cells and by hemochromatosis in liver.

    PubMed

    Yu, J; Yu, Z K; Wessling-Resnick, M

    1998-12-25

    SFT (stimulator of Fe transport) is a novel transport protein that has been found to facilitate uptake of iron presented to cells as either Fe(II) or Fe(III). When HeLa cells are exposed to the iron chelator desferrioxamine, levels of SFT mRNA increase in an actinomycin D-sensitive manner. In contrast, cells exposed to high levels of iron down-regulate SFT expression in a time-dependent and reversible fashion. Thus, homeostatic regulation of SFT expression not only ensures that sufficient levels of iron are maintained but also limits excessive assimilation to prevent potentially harmful effects of this toxic metal. The unexpected observation that SFT transcript levels are up-regulated in hemochromatosis patients therefore suggests that enhanced SFT expression contributes to the etiology of this iron overload disorder.

  8. Proximal muscular atrophy and weakness: An unusual adverse effect of deferasirox iron chelation therapy.

    PubMed

    Vill, K; Müller-Felber, W; Teusch, V; Blaschek, A; Gerstl, L; Huetker, S; Albert, M H

    2016-01-01

    Deferasirox is a standard treatment for chronic transfusional iron overload. Adverse effects of deferasirox have been reported in large prospective studies. We report two cases of monozygotic twins manifesting with proximal muscular atrophy and weakness under deferasirox. Discontinuation of deferasirox resulted in symptom improvement and ultimately in complete remission five months after successful haematopoietic stem cell transplantation. Broad diagnostic work-up could not bring evidence of another aetiology of muscular weakness. Iron overload or beta thalassemia itself as a cause is considered unlikely in our patients because the chronological coincidence of muscular symptoms was contra-directional to serum ferritin levels and significant clinical improvement was observed promptly after cessation of deferasirox even before transplantation. These observations suggest that the development of muscular weakness in patients on deferasirox should be recognised as a possible adverse effect of the drug.

  9. Impact of iron, chelators, and free fatty acids on lipid oxidation in low-moisture crackers.

    PubMed

    Barden, Leann; Vollmer, Daniel; Johnson, David; Decker, Eric

    2015-02-18

    This research strove to understand the relationship between physical structure and oxidative stability in crackers since mechanisms of lipid oxidation are poorly understood in low-moisture foods. Confocal microscopy showed that lipids formed a continuous matrix surrounding starch granules, and starch-lipid, lipid-air, and protein-lipid interfaces were observed. Unlike bulk oils, meats, and emulsions, lipid hydroperoxides exhibited greater stability in low-moisture crackers as hexanal formation was delayed >20 d. Iron, added at 10 times the concentrations normally found in enriched flour, did not increase oxidation rates compared to the control. EDTA may reduce endogenous iron activity but not as greatly as in other matrices. Addition of fatty acids up to 1.0% of total lipid weight did not statistically affect lipid oxidation lag phases. The unique structure of low-moisture foods clearly affects their resistance to metal-promoted lipid oxidation. PMID:25641252

  10. Impact of iron, chelators, and free fatty acids on lipid oxidation in low-moisture crackers.

    PubMed

    Barden, Leann; Vollmer, Daniel; Johnson, David; Decker, Eric

    2015-02-18

    This research strove to understand the relationship between physical structure and oxidative stability in crackers since mechanisms of lipid oxidation are poorly understood in low-moisture foods. Confocal microscopy showed that lipids formed a continuous matrix surrounding starch granules, and starch-lipid, lipid-air, and protein-lipid interfaces were observed. Unlike bulk oils, meats, and emulsions, lipid hydroperoxides exhibited greater stability in low-moisture crackers as hexanal formation was delayed >20 d. Iron, added at 10 times the concentrations normally found in enriched flour, did not increase oxidation rates compared to the control. EDTA may reduce endogenous iron activity but not as greatly as in other matrices. Addition of fatty acids up to 1.0% of total lipid weight did not statistically affect lipid oxidation lag phases. The unique structure of low-moisture foods clearly affects their resistance to metal-promoted lipid oxidation.

  11. Iron chelation therapy of transfusion-dependent β-thalassemia during pregnancy in the era of novel drugs: is deferasirox toxic?

    PubMed

    Diamantidis, Michael D; Neokleous, Nikolaos; Agapidou, Aleka; Vetsiou, Evaggelia; Manafas, Achilles; Fotiou, Paraskevi; Vlachaki, Efthymia

    2016-05-01

    The life expectancy of thalassemic patients has increased, and now approaches that of healthy individuals, thanks to improved treatment regimens. However, pregnancy in women with β-Thalassemia Μajor remains a challenging condition. Recent advances in managing this haemoglobinopathy offer the potential for safe pregnancies with favorable outcome. However, clinical data regarding the use of chelation therapy during pregnancy are limited, and it is unclear whether these agents impose any risk to the developing fetus. Successful pregnancies following unintentional treatment with deferoxamine or deferasirox have rarely been reported. Generally, chelators are not recommended during pregnancy. Regarding the new oral chelators, data on fetotoxicity are lacking. In the present study, we describe the evolution and successful outcome of nine pregnancies in six Greek thalassemic women who received deferasirox inadvertently during early pregnancy, and review the literature regarding fetal anomalies due to chelators. Use of chelation before embarking upon a non-programmed pregnancy remains a difficult and unresolved question. In our study, chelation treatment during pregnancy did not prevent the delivery of healthy children. Nonetheless, the use of deferasirox is contraindicated in pregnant women, based on the product label. Deferasirox should only be used during pregnancy if the potential benefit outweighs the potential fetal risk.

  12. Microbial degradation of chelating agents used in detergents with special reference to nitrilotriacetic acid (NTA).

    PubMed

    Egli, T; Bally, M; Uetz, T

    1990-01-01

    The extensive use of phosphate-based detergents and agricultural fertilizers is one of the main causes of the world-wide eutrophication of rivers and lakes. To ameliorate such problems partial or total substitution of phosphates in laundry detergents by synthetic, non-phosphorus containing complexing agents is practiced in several countries. The physiological, biochemical and ecological aspects of the microbial degradation of the complexing agents most frequently used, such as polyphosphates, aminopolycarboxylates (especially of nitrilotriacetic acid), and phosphonates are reviewed.

  13. Regeneration of Three-Way Automobile Catalysts using Biodegradable Metal Chelating Agent – S, S-Ethylenediamine Disuccinic Acid (S, S-EDDS)

    EPA Science Inventory

    Regeneration of the activity of three-way catalytic converters (TWCs) was tested for the first time using a biodegradable metal chelating agent (S, S. Ethylenediamine disuccinic acid (S, S-EDDS). The efficiency of this novel environmentally friendly solvent in removing various c...

  14. High performance liquid chromatography profiling of health-promoting phytochemicals and evaluation of antioxidant, anti-lipoxygenase, iron chelating and anti-glucosidase activities of wetland macrophytes

    PubMed Central

    Ooh, Keng-Fei; Ong, Hean-Chooi; Wong, Fai-Chu; Sit, Nam-Weng; Chai, Tsun-Thai

    2014-01-01

    Background: The phytochemistry and bioactivity of wetland macrophytes are underexplored. Plants are known as the natural sources of phytochemical beneficial to health. Objective: The objective of this study is to analyze the phytochemical profiles and bioactivities of 10 extracts prepared from different plant parts of wetland macrophytes Hanguana malayana, Ludwigia adscendens and Monochoria hastata. Materials and Methods: High performance liquid chromatography (HPLC) was used to analyze the phytochemical profile of the extracts. Antioxidant assay such as 2,2-diphenyl-1-picrylhydrazyl, nitric oxide (NO) radical scavenging activity and ferric reducing antioxidant power were performed. Bioactivity assays carried out were anti-lipoxygenase, anti-glucosidase, and iron chelating. Results: Leaf extract of L. adscendens had the highest 2,2-diphenyl-1-picrylhydrazyl (half of maximal effective concentration [EC50] =0.97 mg/mL) and NO (EC50 = 0.31 mg/mL) scavenging activities. The extract also exhibited the highest iron chelating (EC50 = 3.24 mg/mL) and anti-glucosidase (EC50 = 27.5 μg/mL) activities. The anti-glucosidase activity of L. adscendens leaf extract was comparable or superior to those of acarbose, myricetin and quercetin. Correlation between iron chelating and radical scavenging activities among the extracts implies the presence of dual-function phytoconstituents with concurrent iron chelating and radical scavenging activities. HPLC analysis revealed the presence of p-coumaric acid (p-CA), gallic acid (GA) and myricetin in all or most extracts. M. hastata fruit and leaf extracts had the highest p-hydroxybenzoic acid content. Antioxidant and anti-glucosidase activities of the extracts were correlated with p-CA, GA, and myricetin contents. Conclusion: Our study demonstrated that wetland macrophytes H. malayana, L. adscendens and M. hastata are potential sources of health-promoting phytochemicals with potent therapeutically-relevant bioactivities. PMID:25298659

  15. Predicting the kinetics of chelating agents in man from animal data

    SciTech Connect

    Durbin, P.W.; Schmidt, C.T. )

    1989-01-01

    Published data were collected on clearance of 82Br, 24Na, inulin, and the ligands CaNa2-EDTA and CaNa3-DTPA from plasma of rats, dogs, and adult men. Data were restructured to a common base and reanalyzed using a two-compartment open-system kinetic model with an outlet from plasma to urinary excretion or from interstitial fluid to deposition in tissues. This was used to obtain transfer rates, distribution volumes, renal clearance, tracer content of interstitial fluid, and cumulative urinary excretion. The validity of the approach was demonstrated by good agreement of the calculated distribution volumes and renal clearances of the selected tracers with published values obtained by other analytical methods. The values of the parameters of the plasma curves and the transfer rates for EDTA and DTPA in the animals were combined with physiological data to evaluate the kinetic parameters of those substances in man. The human kinetic parameters of the ligands predicted from rat or dog data differed, on the average, from the values calculated from human data by +/- 13 and +/- 38%, respectively. The effective concentration of EDTA or DTPA in body fluids from time of injection to complete excretion and the mean concentration for the first 360 min after injection was calculated to be about four times greater in man than in rats and 3.5 times greater than in dogs for equimolar amounts injected. Based on the pharmacokinetics of DTPA, chelation therapy immediately after an actinide accident involving inhalation or extensive skin damage will be more efficient and more effective if a fraction of the standard clinical ZnNa3-DTPA dosage is administered every few hours instead of as a single daily injection.

  16. Two cell cycle blocks caused by iron chelation of neuroblastoma cells: separating cell cycle events associated with each block

    PubMed Central

    Siriwardana, Gamini; Seligman, Paul A.

    2013-01-01

    Abstract Studies have presented evidence that besides the well described S phase block, treatment of cancer cell lines with the iron chelator deferrioxamine (DFO) also results in an earlier block in G1 phase. In this article, measurements of cell cycle regulatory proteins define this block at a very specific point in G1. DFO treatment results in markedly decreased cyclin A protein levels. Cyclin E levels that accumulate in early to mid‐G1 are increased in cells treated with DFO as compared to the resting cells. The DFO S phase block is shown after cells are arrested at G1/S by (aphidicolin) then released into DFO. The same S phase block occurs with DFO treatment of a neuroblastoma cell line relatively resistant to the G1 DFO block. These experiments clearly differentiate the S phase DFO block from the earlier block pinpointed to a point in mid‐G1, before G1/S when cyclin E protein increases but before increased cyclin A synthesis. Apoptosis was observed in cells inhibited by DFO at both cell cycle arrest points. PMID:24744856

  17. Two cell cycle blocks caused by iron chelation of neuroblastoma cells: separating cell cycle events associated with each block.

    PubMed

    Siriwardana, Gamini; Seligman, Paul A

    2013-12-01

    Studies have presented evidence that besides the well described S phase block, treatment of cancer cell lines with the iron chelator deferrioxamine (DFO) also results in an earlier block in G1 phase. In this article, measurements of cell cycle regulatory proteins define this block at a very specific point in G1. DFO treatment results in markedly decreased cyclin A protein levels. Cyclin E levels that accumulate in early to mid-G1 are increased in cells treated with DFO as compared to the resting cells. The DFO S phase block is shown after cells are arrested at G1/S by (aphidicolin) then released into DFO. The same S phase block occurs with DFO treatment of a neuroblastoma cell line relatively resistant to the G1 DFO block. These experiments clearly differentiate the S phase DFO block from the earlier block pinpointed to a point in mid-G1, before G1/S when cyclin E protein increases but before increased cyclin A synthesis. Apoptosis was observed in cells inhibited by DFO at both cell cycle arrest points.

  18. Removal effectiveness and mechanisms of naphthalene and heavy metals from artificially contaminated soil by iron chelate-activated persulfate.

    PubMed

    Yan, Dickson Y S; Lo, Irene M C

    2013-07-01

    The effectiveness and mechanisms of naphthalene and metal removal from artificially contaminated soil by FeEDTA/FeEDDS-activated persulfate were investigated through batch experiments. Using FeEDTA-activated persulfate, higher naphthalene removal from the soil at 7 h was achieved (89%), compared with FeEDDS-activated persulfate (75%). The removal was mainly via the dissolution of naphthalene partitioned on mineral surfaces, followed by activated persulfate oxidation. Although EDDS is advantageous over EDTA in terms of biodegradability, it is not preferable for iron chelate-activated persulfate oxidation since persulfate was consumed to oxidize EDDS, resulting in persulfate inadequacy for naphthalene oxidation. Besides, 55 and 40% of naphthalene were removed by FeEDTA and FeEDDS alone, respectively. Particularly, 21 and 9% of naphthalene were degraded in the presence of FeEDTA and FeEDDS alone, respectively, which caused by electrons transfer among dissolved organic matter, Fe(2+)/Fe(3+) and naphthalene. Over 35, 36 and 45% of Cu, Pb and Zn were removed using FeEDTA/FeEDDS-activated persulfate.

  19. Lanthanide Oleates: Chelation, Self-assembly, and Exemplification of Ordered Nanostructured Colloidal Contrast Agents for Medical Imaging

    SciTech Connect

    Liu, Guozhen; Conn, Charlotte E.; Drummond, Calum J.

    2010-01-12

    Eight lanthanide(III) oleates have been prepared and characterized. The chelation and self-assembly structures of these rare-earth oleates have been studied by elemental analysis, Fourier transfer infrared spectroscopy (FTIR), and X-ray powder diffraction (XRD) analysis. Elemental analysis and FTIR results indicate that three oleate anions are complexed with one lanthanide cation and, with the exception of anhydrous cerium(III) oleate, form either a mono- or a hemihydrate. The X-ray analysis showed that the neat lanthanide soaps have a lamellar bilayer structure at room temperature. The thermal behavior has been investigated by cross-polarized optical microscopy (POM), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). POM scans showed that all the lanthanide oleates form a lamellar phase in the presence of excess water. Small-angle X-ray scattering (SAXS) and XRD were used to investigate the internal structure of the bulk lanthanide oleates in excess water, and these X-ray results confirmed that the lanthanide oleates do not swell in water. Select lanthanide oleates were dispersed in water to form nonswelling lamellar submicrometer particles, confirmed by dynamic light scattering (DLS) and synchrotron SAXS measurements. NMR results indicated that colloidal dispersions of lanthanide oleates containing paramagnetic ions, such as gadolinium(III), terbium(III), and dysprosium(III), have a significant effect on the longitudinal (T{sub 1}) and transverse (T{sub 2}) relaxation times of protons in water. Time-resolved fluorescence measurements have demonstrated that colloidal dispersions of europium(III) oleate exhibit strong luminescence. The rare earth metal soaps exemplify the potential of self-assembled chelating amphiphiles as contrast agents in medical imaging modalities such as magnetic resonance imaging (MRI) and fluorescence imaging.

  20. Highly stabilized gadolinium chelates functionalized on metal nanoparticles as magnetic resonance imaging contrast agent

    NASA Astrophysics Data System (ADS)

    Siddiqui, Talha S.

    Magnetic resonance imaging (MRI) is a non-invasive method for imaging and diagnosing tissue damage, organ function and the vascular system. Magnevist(TM) a complex of diethylenetriaminepentaacetic acid (DTPA) and Gd3+ is a clinically approved contrast agent for MRI. A derivative of DTPA was formed by the addition of two cysteine groups (DTPA-L-Cys) through amide linkage. The Gd complex of this ligand bonds with the silver surfaces through the cysteine thiols. GdDTPA-L-Cys was bound to ˜10nm diameter Ag nanoparticles for use as a multifunctional MRI contrast agent. The ligand and complex were characterized by 1H and 13C NMR, ESI-MS and IR spectroscopy. The silver construct was characterized by TEM, TGA and UV-Vis absorption spectra. The per metal complex r1 relaxivity of GdDTPA-L-Cys{Ag} greater than that of Magnavist(TM) with the same molarity for both compounds. The synthesis of a DTPA derivative is described that allows it to bind to silver or gold nanoparticles through a single thiol linkage (DTPASH). The resulting Gd complex, GdDTPASH, was bound to Ag nanoparticles to create a single monolayer on the surface. The construct was further stabilized in buffered solution with the addition of a thiolated PEG chain. The highly stabilized nanoparticle construct delivers a high payload of Gd compelex and is an effective T1 brightening agent. The production of this type of construct opens the way for engineered multimodal MRI contrast agents.

  1. Yerba mate (Ilex paraguariensis St. Hill.)-based beverages: How successive extraction influences the extract composition and its capacity to chelate iron and scavenge free radicals.

    PubMed

    Colpo, Ana C; Rosa, Hemerson; Lima, Maria Eduarda; Pazzini, Camila Eliza F; de Camargo, Vanessa B; Bassante, Felipa E M; Puntel, Robson; Ávila, Daiana Silva; Mendez, Andreas; Folmer, Vanderlei

    2016-10-15

    Chimarrão or mate is a popular beverage from South America that is drank with successive infusions. Although yerba mate extracts have been widely studied, few studies have described the extract contents in beverages. Using yerba mate samples from Brazil, Argentina, and Uruguay, we examined the extract chromatographic profiles, total polyphenol content and their capacities to chelate iron. In addition, we analyzed antioxidant activity by examining the ability of the extracts to scavenge DPPH and NO. Our results showed that the amount of extracted compound was highest in yerba mate extract from Uruguay, followed by Argentina, then Brazil. Herbs from all three areas had a significant capacity to inhibit DPPH and NO free radicals. The Brazilian and Uruguayan herbs had an 80% iron chelation capacity (p<0.001), while the iron chelation capacity of the Argentinean herb was lower but still significant (p⩽0.05). We conclude that the compound concentration decreases with successive extractions, while the antioxidant capacity is maintained at significant levels.

  2. Yerba mate (Ilex paraguariensis St. Hill.)-based beverages: How successive extraction influences the extract composition and its capacity to chelate iron and scavenge free radicals.

    PubMed

    Colpo, Ana C; Rosa, Hemerson; Lima, Maria Eduarda; Pazzini, Camila Eliza F; de Camargo, Vanessa B; Bassante, Felipa E M; Puntel, Robson; Ávila, Daiana Silva; Mendez, Andreas; Folmer, Vanderlei

    2016-10-15

    Chimarrão or mate is a popular beverage from South America that is drank with successive infusions. Although yerba mate extracts have been widely studied, few studies have described the extract contents in beverages. Using yerba mate samples from Brazil, Argentina, and Uruguay, we examined the extract chromatographic profiles, total polyphenol content and their capacities to chelate iron. In addition, we analyzed antioxidant activity by examining the ability of the extracts to scavenge DPPH and NO. Our results showed that the amount of extracted compound was highest in yerba mate extract from Uruguay, followed by Argentina, then Brazil. Herbs from all three areas had a significant capacity to inhibit DPPH and NO free radicals. The Brazilian and Uruguayan herbs had an 80% iron chelation capacity (p<0.001), while the iron chelation capacity of the Argentinean herb was lower but still significant (p⩽0.05). We conclude that the compound concentration decreases with successive extractions, while the antioxidant capacity is maintained at significant levels. PMID:27173551

  3. Reversible immobilization of BSA on Cu-chelated PAMAM dendrimer modified iron oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Demir, M.; Şenel, M.; Baykal, A.

    2014-09-01

    In this study, polyamidoamine (PAMAM) dendrimer coated superparamagnetite nanoparticles were synthesized by growing of PAMAM on amino-silane coated iron oxide nanoparticles. The PAMAM modified superparamagnetite nanoparticles were used as reversible protein immobilization host materials. During the reversible immobilization studies the effect of different metal ions such as; Cu+2, Zn+2, Co+2, Ni+2 on immobilization efficiency of BSA were evaluated. The maximum BSA adsorption capacity of the PAMAM-MNP- Cu+2 beads was observed to be 52.84 mg/g (BSA/PAMAM-MNP) at pH 7.0. Various characteristics of immobilized BSA such as; effect of generation, effect of pH, BSA concentration, temperature, salt concentration and reusability of PAMAM-MNP were evaluated.

  4. Hexadentate bispidine derivatives as versatile bifunctional chelate agents for copper(II) radioisotopes.

    PubMed

    Juran, Stefanie; Walther, Martin; Stephan, Holger; Bergmann, Ralf; Steinbach, Jörg; Kraus, Werner; Emmerling, Franziska; Comba, Peter

    2009-02-01

    The preparation and use of bispidine derivatives (3,7-diazabicyclo[3.3.1]nonane) as chelate ligands for radioactive copper isotopes for diagnosis (64Cu) or therapy (67Cu) are reported. Starting from the hexadentate bispidine-based bis(amine)tetrakis(pyridine) ligand 1 with a keto and two ester substituents, the corresponding mono-ol 2 and two dicarboxylic acid derivatives 3 and 5 have been synthesized. A range of techniques, including single-crystal X-ray structure analysis, UV/vis spectroscopy, cyclic voltammetry, thin-layer- (TLC), and high-performance liquid chromatography (HPLC), have been used to characterize the structure and stability of the copper(II)-bispidine complexes. A rapid formation (within 1 min) of stable copper(II)-bispidine complexes under mild conditions (ambient temperature, aqueous solution) has been observed. Challenge experiments of these complexes in the presence of a high excess of competing ligands, such as glutathione, cyclam, or superoxide dismutase (SOD), as well as in rat plasma, gave no evidence of demetalation or transchelation. The bifunctional bispidine derivative 5 can be readily functionalized with biologically active molecules at the pendant carboxylate groups. The coupling of a bombesin analogue betahomo-Glu-betaAla-betaAla-[Cha(13),Nle(14)]BBN(7-14), by condensation of a carboxylate of the bispidine backbone with the N-terminus of the peptide produced the bifunctional ligand 6. The radiocopper(II) complex of this bombesin-bispidine conjugate has a considerable hydrophilicity (log D(o/w) < -2.4), and this leads to a very fast blood clearance (blood: 0.28 +/- 0.02 SUV, 1 h p.i.), low liver tissue accumulation (liver: 1.20 +/- 0.27 SUV, 1 h p.i.), and rapid renal-urinary excretion (kidneys: 6.06 +/- 2.96 SUV, 1 h p.i.) as shown by biodistribution studies of 64Cu-6 in Wistar rats. Preliminary in vivo studies of 64Cu-6 in NMRI nu/nu mice, bearing the human prostate tumor PC-3 showed an accumulation of the conjugate in the tumor (2

  5. Multidentate terephthalamidate and hydroxypyridonate ligands: towards new orally active chelators.

    PubMed

    Abergel, Rebecca J; Raymond, Kenneth N

    2011-01-01

    The limitations of current therapies for the treatment of iron overload or radioisotope contamination have stimulated efforts to develop new orally bioavailable iron and actinide chelators. Siderophore-inspired tetradentate, hexadentate and octadentate terephthalamidate and hydroxypyridonate ligands were evaluated in vivo as selective and efficacious iron or actinide chelating agents, with several metal loading and ligand assessment procedures, using (59)Fe, (238)Pu, and (241)Am as radioactive tracers. The compounds presented in this study were compared to commercially available therapeutic sequestering agents [deferoxamine (DFO) for iron and diethylenetriaminepentaacetic acid (DPTA) for actinides] and are unrivaled in terms of affinity, selectivity and decorporation efficacy, which attests to the fact that high metal affinity may overcome the low bioavailability properties commonly associated to multidenticity. PMID:21599440

  6. MULTIDENTATE TEREPHTHALAMIDATE AND HYDROXYPYRIDONATE LIGANDS: TOWARDS NEW ORALLY ACTIVE CHELATORS

    SciTech Connect

    Abergel, Rebecca J.; Raymond, Kenneth N.

    2011-07-13

    The limitations of current therapies for the treatment of iron overload or radioisotope contamination have stimulated efforts to develop new orally bioavailable iron and actinide chelators. Siderophore-inspired tetradentate, hexadentate and octadentate terephthalamidate and hydroxypyridonate ligands were evaluated in vivo as selective and efficacious iron or actinide chelating agents, with several metal loading and ligand assessment procedures, using {sup 59}Fe, {sup 238}Pu, and {sup 241}Am as radioactive tracers. The compounds presented in this study were compared to commercially available therapeutic sequestering agents [deferoxamine (DFO) for iron and diethylenetriaminepentaacetic acid (DPTA) for actinides] and are unrivaled in terms of affinity, selectivity and decorporation efficacy, which attests to the fact that high metal affinity may overcome the low bioavailability properties commonly associated to multidenticity.

  7. Additive Neuroprotective Effects of the Multifunctional Iron Chelator M30 with Enriched Diet in a Mouse Model of Amyotrophic Lateral Sclerosis.

    PubMed

    Golko-Perez, Sagit; Mandel, Silvia; Amit, Tamar; Kupershmidt, Lana; Youdim, Moussa B H; Weinreb, Orly

    2016-02-01

    Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motoneuron system, involving various abnormalities, such as mitochondrial dysfunction, oxidative stress, transitional metal accumulation, neuroinflammation, glutamate excitotoxicity, apoptosis, decreased supply of trophic factors, cytoskeletal abnormalities, and extracellular superoxide dismutase (SOD)-1 toxicity. These multiple disease etiologies implicated in ALS gave rise to the perception that future therapeutic approaches for the disease should be aimed at targeting multiple pathological pathways. In line with this view, we have evaluated in the current study the therapeutic effects of low doses of the novel multifunctional monoamine oxidase (MAO) inhibitor/iron-chelating compound, M30 in combination with high Calorie Energy supplemented Diet (CED) in the SOD1-G93A transgenic mouse model of ALS. Our results demonstrated that the combined administration of M30 with CED produced additive neuroprotective effects on motor performance and increased survival of SOD1-G93A mice. We also found that both M30 and M30/CED regimens caused a significant inhibition of MAO-A and -B activities and decreased the turnover of dopamine in the brain of SOD1-G93A mice. In addition, M30/CED combined treatment resulted in a significant increase in mRNA expression levels of various mitochondrial biogenesis and metabolism regulators, such as peroxisome proliferator-activated receptor-γ (PPARγ)-co activator 1 alpha (PGC-1α), PPARγ, uncoupling protein 1, and insulin receptor in the gastrocnemius muscle of SOD1-G93A mice. These results suggest that a combination of drug/agents with different, but complementary mechanisms may be beneficial in the treatment of ALS.

  8. Development of Iron Doped Silicon Nanoparticles as Bimodal Imaging Agents

    PubMed Central

    Singh, Mani P.; Atkins, Tonya M.; Muthuswamy, Elayaraja; Kamali, Saeed; Tu, Chuqiao; Louie, Angelique Y.; Kauzlarich, Susan M.

    2012-01-01

    We demonstrate the synthesis of water-soluble allylamine terminated Fe doped Si (SixFe) nanoparticles as bimodal agents for optical and magnetic imaging. The preparation involves the synthesis of a single source iron containing precursor, Na4Si4 with x% Fe (x = 1, 5, 10), and its subsequent reaction with NH4Br to produce hydrogen terminated SixFe nanoparticles. The hydrogen-capped nanoparticles are further terminated with allylamine via thermal hydrosilylation. Transmission electron microscopy (TEM) indicates that the average particle diameter is ~3.0±1.0 nm. The Si5Fe nanoparticles show strong photoluminescence quantum yield in water (~ 10 %) with significant T2 contrast (r2/r1value of 4.31). Electron paramagnetic resonance (EPR) and Mössbauer spectroscopies indicate that iron in the nanoparticles is in the +3 oxidation state. Analysis of cytotoxicity using the resazurin assay on HepG2 liver cells indicates that the particles have minimal toxicity. PMID:22616623

  9. Combined treatment of Pseudomonas aeruginosa biofilm with lactoferrin and xylitol inhibits the ability of bacteria to respond to damage resulting from lactoferrin iron chelation.

    PubMed

    Ammons, Mary Cloud B; Ward, Loren S; Dowd, Scot; James, Garth A

    2011-04-01

    With an ageing and ever more obese population, chronic wounds such as diabetic ulcers, pressure ulcers and venous leg ulcers are an increasingly relevant medical concern. Identification of bacterial biofilm contamination as a major contributor to non-healing wounds demands biofilm-targeted strategies to manage chronic wounds. Pseudomonas aeruginosa has been identified as a principal biofilm-forming opportunistic pathogen in chronic wounds. The innate immune molecule lactoferrin and the rare sugar alcohol xylitol have been demonstrated to be co-operatively efficacious against P. aeruginosa biofilms in vitro. Data presented here propose a model for the molecular mechanism behind this co-operative antimicrobial effect. Lactoferrin iron chelation was identified as the primary means by which lactoferrin destabilises the bacterial membrane. By microarray analysis, 183 differentially expressed genes of ≥ 1.5-fold difference were detected. Interestingly, differentially expressed transcripts included the operon encoding components of the pyochelin biosynthesis pathway. Furthermore, siderophore detection verified that xylitol is the component of this novel synergistic treatment that inhibits the ability of the bacteria to produce siderophores under conditions of iron restriction. The findings presented here demonstrate that whilst lactoferrin treatment of P. aeruginosa biofilms results in destabilisation of the bacterial cell membrane though iron chelation, combined treatment with lactoferrin and xylitol inhibits the ability of P. aeruginosa biofilms to respond to environmental iron restriction. PMID:21377840

  10. Thermal inactivation of rabies and other rhabdoviruses: stabilization by the chelating agent ethylenediaminetetraacetic acid at physiological temperatures.

    PubMed

    Michalski, F; Parks, N F; Sokol, F; Clark, H F

    1976-07-01

    Thermal inactivation of rabies and several other rhabdoviruses was studied using virus suspended in several different diluents. Rabies serogroup viruses were more stable than Kern Canyon or vesicular stomatitis viruses. Limited studies of two fish rhabdoviruses requiring low temperatures (less than 33 C) for replication indicated that they were not markedly more thermolabile than rabies virus. Bovine serum protein components in complex cell culture media stabilized virus at 56 C, but at temperatures of less than or equal to 37 C, sodium tris (hydroxymethyl)-aminomethane (NT) buffer containing ethylenediaminetetraacetic acid (EDTA) (NTE) was a much more efficient stabilizer of virus infectivity. Chelating agents EDTA and ethyleneglycol-bis-(beta-aminoethyl ether)tetraacetic acid were equally efficient in protection of rabies virus infectivity; the effect of each was lost when excess Ca2+ was added. Bovine serum in NT or NTE buffers produced a thermostabilizing effect at 37 C not provided by the same serum concentration in complex cell culture media. Bovine serum was more efficient than EDTA in stabilizing virus infectivity during repeated cycles of freezing and thawing. PMID:181323

  11. Sequential application of chelating agents and innovative surfactants for the enhanced electroremediation of real sediments from toxic metals and PAHs.

    PubMed

    Hahladakis, John N; Lekkas, Nikolaos; Smponias, Andreas; Gidarakos, Evangelos

    2014-06-01

    This study focused on the sequential application of a chelating agent (citric acid) followed by a surfactant in the simultaneous electroremediation of real contaminated sediments from toxic metals and Polycyclic Aromatic Hydrocarbons (PAHs). Furthermore, the efficiency evaluation of two innovative non-ionic surfactants, commercially known as Poloxamer 407 and Nonidet P40, was investigated. The results indicated a removal efficacy of approximately 43% and 48% for the summation of PAHs (SUM PAHs), respectively for the aforementioned surfactants, much better than the one obtained by the use of Tween 80 (nearly 21%). Individual PAHs (e.g. fluorene) were removed in percentages that reached almost 84% and 92% in the respective electrokinetic experiments when these new surfactants were introduced. In addition, the combined-enhanced sequential electrokinetic treatment with citric acid improved dramatically the removal of Zn and As, compared to the unenhanced run, but did not favor the other toxic metals examined. Since no improvement in metal removal percentages occurred when Tween 80 was used, significant contribution to this matter should also be attributed to the solubilization capacity of these innovative, in electrokinetic remediation, non-ionic surfactants.

  12. Sequential application of chelating agents and innovative surfactants for the enhanced electroremediation of real sediments from toxic metals and PAHs.

    PubMed

    Hahladakis, John N; Lekkas, Nikolaos; Smponias, Andreas; Gidarakos, Evangelos

    2014-06-01

    This study focused on the sequential application of a chelating agent (citric acid) followed by a surfactant in the simultaneous electroremediation of real contaminated sediments from toxic metals and Polycyclic Aromatic Hydrocarbons (PAHs). Furthermore, the efficiency evaluation of two innovative non-ionic surfactants, commercially known as Poloxamer 407 and Nonidet P40, was investigated. The results indicated a removal efficacy of approximately 43% and 48% for the summation of PAHs (SUM PAHs), respectively for the aforementioned surfactants, much better than the one obtained by the use of Tween 80 (nearly 21%). Individual PAHs (e.g. fluorene) were removed in percentages that reached almost 84% and 92% in the respective electrokinetic experiments when these new surfactants were introduced. In addition, the combined-enhanced sequential electrokinetic treatment with citric acid improved dramatically the removal of Zn and As, compared to the unenhanced run, but did not favor the other toxic metals examined. Since no improvement in metal removal percentages occurred when Tween 80 was used, significant contribution to this matter should also be attributed to the solubilization capacity of these innovative, in electrokinetic remediation, non-ionic surfactants. PMID:24321329

  13. Therapeutic targets and potential of the novel brain- permeable multifunctional iron chelator-monoamine oxidase inhibitor drug, M-30, for the treatment of Alzheimer's disease.

    PubMed

    Avramovich-Tirosh, Yael; Amit, Tamar; Bar-Am, Orit; Zheng, Hailin; Fridkin, Mati; Youdim, Moussa B H

    2007-01-01

    Novel therapeutic approaches for the treatment of neurodegenerative disorders comprise drug candidates designed specifically to act on multiple CNS targets. We have synthesized a multifunctional non-toxic, brain permeable iron chelator drug, M-30, possessing propargyl monoamine oxidase (MAO) inhibitory neuroprotective and iron-chelating moieties, from our prototype iron chelator VK-28. In the present study M-30 was shown to possess a wide range of pharmacological activities, including pro-survival neurorescue effects, induction of neuronal differentiation and regulation of amyloid precursor protein (APP) and beta-amyloid (Abeta) levels. M-30 was found to decrease apoptosis of SH-SY5Y neuroblastoma cells in a neurorescue, serum deprivation model, via reduction of the pro-apoptotic proteins Bad and Bax, and inhibition of the apoptosis-associated phosphorylated H2A.X protein (Ser 139) and caspase 3 activation. In addition, M-30 induced the outgrowth of neurites, triggered cell cycle arrest in G(0)/G(1) phase and enhanced the expression of growth associated protein-43. Furthermore, M-30 markedly reduced the levels of cellular APP and beta-C-terminal fragment (beta-CTF) and the levels of the amyloidogenic Abeta peptide in the medium of SH-SY5Y cells and Chinese hamster ovary cells stably transfected with the APP 'Swedish' mutation. Levels of the non-amyloidogenic soluble APPalpha and alpha-CTF in the medium and cell lysate respectively were coordinately increased. These properties, together with its brain selective MAO inhibitory and propargylamine- dependent neuroprotective effects, suggest that M-30 might serve as an ideal drug for neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, in which oxidative stress and iron dysregulation have been implicated. PMID:17144902

  14. Utilization of microbial iron assimilation processes for the development of new antibiotics and inspiration for the design of new anticancer agents

    PubMed Central

    Zhu, Helen; Xu, Yanping; Wu, Chunrui; Walz, Andrew J.; Vergne, Anne; Roosenberg, John M.; Moraski, Garrett; Minnick, Albert A.; McKee-Dolence, Julia; Hu, Jingdan; Fennell, Kelley; Dolence, E. Kurt; Dong, Li; Franzblau, Scott; Malouin, Francois; Möllmann, Ute

    2014-01-01

    Pathogenic microbes rapidly develop resistance to antibiotics. To keep ahead in the “microbial war”, extensive interdisciplinary research is needed. A primary cause of drug resistance is the overuse of antibiotics that can result in alteration of microbial permeability, alteration of drug target binding sites, induction of enzymes that destroy antibiotics (ie., beta-lactamase) and even induction of efflux mechanisms. A combination of chemical syntheses, microbiological and biochemical studies demonstrate that the known critical dependence of iron assimilation by microbes for growth and virulence can be exploited for the development of new approaches to antibiotic therapy. Iron recognition and active transport relies on the biosyntheses and use of microbe-selective iron-chelating compounds called siderophores. Our studies, and those of others, demonstrate that siderophores and analogs can be used for iron transport-mediated drug delivery (“Trojan Horse” antibiotics) and induction of iron limitation/starvation (Development of new agents to block iron assimilation). Recent extensions of the use of siderophores for the development of novel potent and selective anticancer agents are also described. PMID:19130268

  15. Plant mechanisms of siderophore-iron utilization

    SciTech Connect

    Crowley, D.E.

    1986-01-01

    Mechanisms of siderophore iron-utilization by plants were examined to determine whether plants have direct mechanisms for acquiring iron from microbially-produced hydroxamate siderophores or simply take up inorganic iron in equilibrium with the chelate (shuttle mechanism). Experiments were designed to determine whether the monocot plant species, oat (Avena sativa L. cv. Victory) could acquire iron from ferrichrome under hydroponic conditions in which iron uptake was most likely to occur by direct use of the chelating agent. Ten-day-old iron-deficient seedlings, grown in aerated Hoagland's nutrient solution (minus iron) buffered at pH 7.4 with CaCO/sub 3/, were placed in fresh nutrient solution containing 10/sup -7.4/M radioactive /sup 55/FeCl/sub 3/ (23.7 mCi/mg) with the synthetic chelate, EDDHA (10..pi../sup 5/M), ferrichrome (10/sup -5/M), or with no chelate. After 6 days, shoot content of /sup 55/Fe in shoots of plants provided with ferrichrome was 100-fold greater than that in shoots of plants provided with EDDHA. Therefore iron uptake by oat under these conditions not only indicates direct use of ferrichrome, but also suggest that oat may be better able to acquire iron from siderophores than from synthetic chelates. One possible mechanism for direct use of chelating agents, may involve siderophore binding sites on the plasmalemma of root cortical cells where iron is split from the chelate by enzymatic reduction of ferric to ferrous iron. To demonstrate hypothesized siderophore binding sites on oat roots, experiments examined possible competition for presumed siderophore binding sites by an inert analog of ferrichrome constructed by irreversible chelation with chromium.

  16. Superparamagnetic iron oxide nanoparticles with variable size and an iron oxidation state as prospective imaging agents.

    PubMed

    Kucheryavy, Pavel; He, Jibao; John, Vijay T; Maharjan, Pawan; Spinu, Leonard; Goloverda, Galina Z; Kolesnichenko, Vladimir L

    2013-01-15

    Magnetite nanoparticles in the size range of 3.2-7.5 nm were synthesized in high yields under variable reaction conditions using high-temperature hydrolysis of the precursor iron(II) and iron(III) alkoxides in diethylene glycol solution. The average sizes of the particles were adjusted by changing the reaction temperature and time and by using a sequential growth technique. To obtain γ-iron(III) oxide particles in the same range of sizes, magnetite particles were oxidized with dry oxygen in diethylene glycol at room temperature. The products were characterized by DLS, TEM, X-ray powder diffractometry, TGA, chemical analysis, and magnetic measurements. NMR r(1) and r(2) relaxivity measurements in water and diethylene glycol (for OH and CH(2) protons) have shown a decrease in the r(2)/r(1) ratio with the particle size reduction, which correlates with the results of magnetic measurements on magnetite nanoparticles. Saturation magnetization of the oxidized particles was found to be 20% lower than that for Fe(3)O(4) with the same particle size, but their r(1) relaxivities are similar. Because the oxidation of magnetite is spontaneous under ambient conditions, it was important to learn that the oxidation product has no disadvantages as compared to its precursor and therefore may be a better prospective imaging agent because of its chemical stability.

  17. Effect of various concentrations of DTPA chelating agent in soil on uptake and distribution of /sup 241/Am in bush bean plants

    SciTech Connect

    Wallace, A.; Romney, E.M.; Mueller, R.T.

    1981-07-01

    We grew bush bean plants in pots containing Yolo loam soil in a glasshouse for 15 days with a uniformly applied level of /sup 241/Am in soil and with various concentrations of DTPA applied to the soil. The objective was to demonstrate that the effects assigned to this chelating agent on uptake of /sup 241/Am by plants will vary with concentration of the chelating agent. On a concentration basis, the DTPA resulted in transport of much more /sup 241/Am into primary leaves than into trifoliate leaves. The ratio of /sup 241/Am in primary leaves to that in trifoliate leaves increased with increasing concentration of DTPA. The concentration ratios in each plant part also increased with increasing DTPA.

  18. Crystal structure of rat heme oxygenase-1 in complex with biliverdin-iron chelate. Conformational change of the distal helix during the heme cleavage reaction.

    PubMed

    Sugishima, Masakazu; Sakamoto, Hiroshi; Higashimoto, Yuichiro; Noguchi, Masato; Fukuyama, Keiichi

    2003-08-22

    The crystal structure of rat heme oxygenase-1 in complex with biliverdin-iron chelate (biliverdin(Fe)-HO-1), the immediate precursor of the final product, biliverdin, has been determined at a 2.4-A resolution. The electron density in the heme pocket clearly showed that the tetrapyrrole ring of heme is cleaved at the alpha-meso edge. Like the heme bound to HO-1, biliverdin-iron chelate is located between the distal and proximal helices, but its accommodation state seems to be less stable in light of the disordering of the solvent-exposed propionate and vinyl groups. The middle of the distal helix is shifted away from the center of the active site in biliverdin(Fe)-HO-1, increasing the size of the heme pocket. The hydrogen-bonding interaction between Glu-29 and Gln-38, considered to restrain the orientation of the proximal helix in the heme-HO-1 complex, was lost in biliverdin(Fe)-HO-1, leading to relaxation of the helix. Biliverdin has a distorted helical conformation; the lactam oxygen atom of its pyrrole ring-A interacted with Asp-140 through a hydrogen-bonding solvent network. Because of the absence of a distal water ligand, the iron atom is five-coordinated with His-25 and four pyrrole nitrogen atoms. The coordination geometry deviates considerably from a square pyramid, suggesting that the iron may be readily dissociated. We speculate that the opened conformation of the heme pocket facilitates sequential product release, first iron then biliverdin, and that because of biliverdin's increased flexibility, iron release triggers its slow dissociation. PMID:12794075

  19. Chelation in metal intoxication--Principles and paradigms.

    PubMed

    Aaseth, Jan; Skaug, Marit Aralt; Cao, Yang; Andersen, Ole

    2015-01-01

    The present review provides an update of the general principles for the investigation and use of chelating agents in the treatment of intoxications by metals. The clinical use of the old chelators EDTA (ethylenediamine tetraacetate) and BAL (2,3-dimercaptopropanol) is now limited due to the inconvenience of parenteral administration, their own toxicity and tendency to increase the neurotoxicity of several metals. The hydrophilic dithiol chelators DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercapto-propanesulphonate) are less toxic and more efficient than BAL in the clinical treatment of heavy metal poisoning, and available as capsules for oral use. In copper overload, DMSA appears to be a potent antidote, although d-penicillamine is still widely used. In the chelation of iron, the thiols are inefficient, since iron has higher affinity for ligands with nitrogen and oxygen, but the new oral iron antidotes deferiprone and desferasirox have entered into the clinical arena. Comparisons of these agents and deferoxamine infusions are in progress. General principles for research and development of new chelators are briefly outlined in this review.

  20. Chelation in metal intoxication--Principles and paradigms.

    PubMed

    Aaseth, Jan; Skaug, Marit Aralt; Cao, Yang; Andersen, Ole

    2015-01-01

    The present review provides an update of the general principles for the investigation and use of chelating agents in the treatment of intoxications by metals. The clinical use of the old chelators EDTA (ethylenediamine tetraacetate) and BAL (2,3-dimercaptopropanol) is now limited due to the inconvenience of parenteral administration, their own toxicity and tendency to increase the neurotoxicity of several metals. The hydrophilic dithiol chelators DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercapto-propanesulphonate) are less toxic and more efficient than BAL in the clinical treatment of heavy metal poisoning, and available as capsules for oral use. In copper overload, DMSA appears to be a potent antidote, although d-penicillamine is still widely used. In the chelation of iron, the thiols are inefficient, since iron has higher affinity for ligands with nitrogen and oxygen, but the new oral iron antidotes deferiprone and desferasirox have entered into the clinical arena. Comparisons of these agents and deferoxamine infusions are in progress. General principles for research and development of new chelators are briefly outlined in this review. PMID:25457281

  1. Effect of the ultrasound-Fenton oxidation process with the addition of a chelating agent on the removal of petroleum-based contaminants from soil.

    PubMed

    Li, Ying; Li, Fangmin; Li, Fanxiu; Yuan, Fuqian; Wei, Pingfang

    2015-12-01

    The effects of ultrasonic irradiation, the chelating agent modified Fenton reaction, and a combination of ultrasound and the Fenton method in removing petroleum contaminants from a soil were studied. The results showed that the contaminant removal rate of the Fenton treatment combined with an oxalic acid chelating agent was 55.6% higher than that without a chelating agent. The average removal rate of the contaminants using the ultrasound-Fenton treatment was 59.0% higher than that without ultrasonic treatment. A combination of ultrasound and an Fe(2+)/Fe(3+)-oxalate complex-modified Fenton reagent resulted in significantly higher removal rates of n-alkanes (C(n)H(2n+2), n < 28), isoprenoid hydrocarbons, aromatic hydrocarbons, and saturated polycyclic terpenes compared with the ultrasound treatment alone or the Fenton method. The Fenton reaction and the ultrasound-Fenton treatment can unselectively remove multiple components of residual hydrocarbons and a number of benzene rings in polycyclic aromatic hydrocarbons. The chemistry of the heterocyclic compounds and the position and number of substituents can affect the degradation process.

  2. Inhibition of hereditary hepatitis and liver tumor development in Long-Evans cinnamon rats by the copper-chelating agent trientine dihydrochloride.

    PubMed

    Sone, K; Maeda, M; Wakabayashi, K; Takeichi, N; Mori, M; Sugimura, T; Nagao, M

    1996-04-01

    Trientine dihydrochloride (trientine) is an alternative medicinal copper chelating agent for patients with Wilson's disease of penicillamine intolerance. We examined the effects of trientine on the spontaneous development of hepatitis and hepatic tumors, by its short-term and long-term administration to Long-Evans cinnamon (LEC) rats with an accumulation of copper in the liver, as animal models of Wilson's disease. Male rats were given trientine in their drinking water at 1500 ppm for 18 weeks, from 6 weeks to 24 weeks of age in short-term experiment, and 1500 ppm for 27 weeks then 750 ppm for 52 weeks, from 8 to 87 weeks of age in the long-term experiment. Development of hepatitis was observed in the control LEC rats at 18 weeks of age. They had high levels of plasma transaminases (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT]), and on pathological examination, hepatocyte destruction was observed. Histological findings revealed that short-term administration of trientine inhibited the development of hepatitis remarkably. The plasma GOT and GPT levels of treated animals were only slightly higher than those of normal LEA (Long-Evans with agouti coat color) rats, a sibling line of LEC rats. Copper levels in the liver were decreased by a maximum of 50 percent. In the long-term administration of trientine, the incidence of hepatic cell carcinoma (HCC) in the treated rats was 67 percent that of the untreated LEC rats, and the number of HCCs per rat in the treated group was 0.7 +/- 0.5, being significantly lower as compared with 4.7 +/- 3.5 in the untreated rats. Additionally, the development of cholangiofibrosis in LEC rats was completely prevented by long-term administration of the agent. The copper level in the liver of treated rats was reduced by 33 percent at 87 weeks of age. Development of HCC in LEC rats might be partly, but not totally, because of copper accumulation. No effects on the levels of copper, iron, or zinc in the liver of

  3. Desferrioxamine, an iron chelator, inhibits CXCL10 expression induced by polyinosinic-polycytidylic acid in U373MG human astrocytoma cells.

    PubMed

    Imaizumi, Tadaatsu; Sakashita, Nina; Mushiga, Yasuaki; Yoshida, Hidemi; Hayakari, Ryo; Xing, Fei; Wang, Liang; Matsumiya, Tomoh; Tanji, Kunikazu; Chiba, Yuki; Furudate, Ken; Kawaguchi, Shogo; Murakami, Manabu; Tanaka, Hiroshi

    2015-05-01

    Although iron is essential in physiological processes, accumulation of iron in central nervous system is associated with various neurological diseases including Alzheimer's disease and Parkinson's disease. Innate immune reactions are involved in the pathogenesis of those diseases, but roles of iron in innate immunity are not known well. In the present study, pretreatment of U373MG human astrocytoma cells with an iron chelator desferrioxamine (DFX) inhibited the expression of CXCL10 induced by a Toll-like receptor 3 (TLR3) agonist polyinosinic-polycytidylic acid (poly IC). Induction of interferon-β (IFN-β) was not affected, but phosphorylation of signal transducer and transcription 1 (STAT1) was decreased by DFX. We have previously reported that various IFN-stimulated genes (ISGs) are involved in CXCL10 induction by poly IC. Pretreatment with DFX also decreased the expression of these ISGs. Pretreatment of cells with FeSO4 counteracted inhibitory effects of DFX on ISG56, retinoic acid-inducible gene-I (RIG-I), CXCL10 and phosphorylation of STAT1. These results suggest that iron may positively regulate STAT1 phosphorylation and following signaling to express ISG56, RIG-I and CXCL10 in U373MG cells treated with poly IC. Iron may contribute to innate immune and inflammatory reactions elicited by the TLR3 signaling in astrocytes, and may play an important role in neuroinflammatory diseases.

  4. Co-ordination of iron acquisition, iron porphyrin chelation and iron-protoporphyrin export via the cytochrome c biogenesis protein CcmC in Pseudomonas fluorescens.

    PubMed

    Baysse, Christine; Matthijs, Sandra; Schobert, Max; Layer, Gunhild; Jahn, Dieter; Cornelis, Pierre

    2003-12-01

    The cytoplasmic membrane protein CcmC is, together with other Ccm proteins, a component for the maturation of c-type cytochromes in Gram-negative bacteria. A Pseudomonas fluorescens ATCC 17400 ccmC mutant is cytochrome c-deficient and shows considerably reduced production of the two siderophores pyoverdine and quinolobactin, paralleled by a general inability to utilize various iron sources, with the exception of haem. The ccmC mutant accumulates in a 5-aminolevulinic acid-dependent synthesis a reddish, fluorescent pigment identified as protoporphyrin IX. As a consequence a visA phenotype similar to that of a ferrochelatase-deficient hemH mutant characterized by drastically reduced growth upon light exposure was observed for the ccmC mutant. The defect of iron-protoporphyrin formation was further demonstrated by the failure of ccmC cell-free proteinase K-treated extracts to stimulate the growth of a haem auxotrophic hemH indicator strain, compared to similarly prepared wild-type extracts. In addition, the ccmC mutant did not sustain hemH growth in cross-feeding experiments while the wild-type did. Significantly reduced resistance to oxidative stress mediated by haem-containing catalases was observed for the ccmC mutant. A double hemH ccmC mutant could not be obtained in the presence of external haem without the hemH gene in trans, indicating that the combination of the two mutations is lethal. It was concluded that CcmC, apart from its known function in cytochrome c biogenesis, plays a role in haem biosynthesis. A function in the regulatory co-ordination of iron acquisition via siderophores, iron insertion into porphyrin via ferrochelatase and iron-protoporphyrin export for cytochrome c formation is predicted. PMID:14663086

  5. An increase in hemoglobin, platelets and white blood cells levels by iron chelation as single treatment in multitransfused patients with myelodysplastic syndromes: clinical evidences and possible biological mechanisms.

    PubMed

    Breccia, Massimo; Voso, Maria Teresa; Aloe Spiriti, Maria Antonietta; Fenu, Susanna; Maurillo, Luca; Buccisano, Francesco; Tafuri, Agostino; Alimena, Giuliana

    2015-05-01

    Iron chelation therapy can improve hematopoiesis in myelodysplastic syndromes. Only few studies showed hematologic improvement with deferoxamine, and the erythroid responses were correlated with good compliance to long-term treatment. Indeed, single-case reports and data from clinical trials testing the efficacy of deferasirox reported hematologic improvements with varying rates of response in different lineages. Overall, about 760 myelodysplastic syndrome (MDS) patients with iron overload receiving deferasirox were included in six different studies, and an increase in hemoglobin level was reported to range from 6 to 44.5%, an increase in platelet count from 13 to 61%, and in neutrophil count from 3 to 76%. In all the published studies, hematologic improvements were not related to serum ferritin or to non-total binding iron changes; indeed, other pathways were indicated as possible pathogenetic mechanisms, such as decreased NF-kB activity, modulation of mTOR signalling, and reduced reactive oxygen species. The aims of this review are to provide all available information relating clinical and hematologic changes after chelation therapy and to discuss potential mechanisms involved in such responses.

  6. An increase in hemoglobin, platelets and white blood cells levels by iron chelation as single treatment in multitransfused patients with myelodysplastic syndromes: clinical evidences and possible biological mechanisms.

    PubMed

    Breccia, Massimo; Voso, Maria Teresa; Aloe Spiriti, Maria Antonietta; Fenu, Susanna; Maurillo, Luca; Buccisano, Francesco; Tafuri, Agostino; Alimena, Giuliana

    2015-05-01

    Iron chelation therapy can improve hematopoiesis in myelodysplastic syndromes. Only few studies showed hematologic improvement with deferoxamine, and the erythroid responses were correlated with good compliance to long-term treatment. Indeed, single-case reports and data from clinical trials testing the efficacy of deferasirox reported hematologic improvements with varying rates of response in different lineages. Overall, about 760 myelodysplastic syndrome (MDS) patients with iron overload receiving deferasirox were included in six different studies, and an increase in hemoglobin level was reported to range from 6 to 44.5%, an increase in platelet count from 13 to 61%, and in neutrophil count from 3 to 76%. In all the published studies, hematologic improvements were not related to serum ferritin or to non-total binding iron changes; indeed, other pathways were indicated as possible pathogenetic mechanisms, such as decreased NF-kB activity, modulation of mTOR signalling, and reduced reactive oxygen species. The aims of this review are to provide all available information relating clinical and hematologic changes after chelation therapy and to discuss potential mechanisms involved in such responses. PMID:25743685

  7. Combined chelation therapy with deferoxamine and deferiprone in β-thalassemia major: compliance and opinions of young thalassemic patients.

    PubMed

    Hatzipantelis, Emmanuel S; Karasmanis, Konstantinos; Perifanis, Vassilios; Vlachaki, Efthimia; Tziomalos, Konstantinos; Economou, Marina

    2014-01-01

    Treatment of β-thalassemia major (β-TM) includes regular blood transfusions and iron chelation with subcutaneous injection of deferoxamine (DFO). During the last decade, a new chelation agent, deferiprone (L1), was introduced. The purpose of our study was to determine the level of awareness/education regarding chelation therapy, the degree of compliance to this therapy and their views of L1 in patients with β-TM. A relevant questionnaire was administered to 36 patients (12-26 years old) who were on combination chelation therapy with both DFO and L1. The majority of patients was well aware/educated about chelation therapy (76.6%), was compliant with this therapy (74.4%) and had a positive view towards oral chelation (86.0%). In conclusion, most patients with β-TM who were on combination chelation therapy with DFO and L1 were satisfied with this treatment and this results in high compliance rates.

  8. Trientine, a copper-chelating agent, induced apoptosis in murine fibrosarcoma cells in vivo and in vitro.

    PubMed

    Hayashi, Masanobu; Nishiya, Hide; Chiba, Toshiaki; Endoh, Daiji; Kon, Yasuhiro; Okui, Toyo

    2007-02-01

    Anti-copper treatments have been investigated to determine whether they suppress angiogenesis and tumor development since Cu is widely accepted as being required for angiogenesis. We examined the effects of treatment with trientine, a copper-chelating agent, on tumor development in a murine xenograft model using fibrosarcoma-derived transplantable QRsp-11 cells and C57BL/6 mice and induction of apoptosis in tumor cells and endothelial cells in vivo and in vitro. The tumor volumes increased more slowly in trientine-treated mice than in untreated mice. Tumor volumes in the treated mice were significantly smaller than those in the untreated mice at 24 days postinoculation (d.p.i.) of tumor cells. A cluster of pyknotic tumor cells and morphological abnormalities in capillary endothelial cells were observed in the tumors of trientine-treated mice but not in the tumors of untreated mice. The proportions of apoptotic and necrotic cells in the tumors of treated mice were approximately 3.5-fold higher than those in the tumors of untreated mice at 14 d.p.i. When the cells were treated with trientine in vitro, mouse endothelial cells and bovine primary endothelial cells showed an approximately 10-fold higher sensitivity to trientine than QRsp-11 cells in terms of D37. However, the proportion of apoptotic cells in endothelial cells was significantly lower than that in QRsp-11 cells after treatment with trientine. These results show that apoptosis was induced in tumor cells by treatment with trientine in vivo and in vitro.

  9. Evaluation of the efficiency of DTPA and other new chelating agents for removing neptunium from target organs.

    PubMed

    Paquet, F; Metivier, H; Poncy, J L; Burgada, R; Bailly, T

    1997-05-01

    Diethylenetriamine pentaacetic acid (DTPA) has been tested with 8 other new chelators for neptunium decorporation after systemic contamination in the rat. The ligands were injected intravenously at a dosage of 30 mumol kg-1 and the animals killed 24 h later. The results show that none of the chelators tested was efficient in removing significant amounts of the radionuclide from the body. In order to understand why these chelators were ineffective, in vitro approaches have since been developed in which high concentrations of DTPA were added to Np-bearing ligands in the blood, liver and skeleton. The main conclusions were that under our experimental conditions neptunium was not chelatable after its organ deposition.

  10. The protective role of iron chelation and zinc supplements in atherosclerosis induced in New Zealand white rabbits: A nuclear microscopy study

    NASA Astrophysics Data System (ADS)

    Ren, M. Q.; Rajendran, R.; Pan, N.; Huat, B. T. K.; Halliwell, B.; Watt, F.

    2005-04-01

    The protective properties of iron chelator desferal and zinc supplements on atherosclerosis induced in New Zealand white rabbits were investigated using nuclear microscopy, incorporating particle induced X-ray emission (PIXE), Rutherford backscattering spectrometry (RBS) and scanning transmission ion microscopy (STIM). Firstly, we examined the effects of the desferal (desferrioxamine - a chelator which forms a stable complex with ferric iron) on atherosclerosis progression and lesion iron content in cholesterol-fed New Zealand white rabbits. Rabbits were fed with a 1% w/w cholesterol diet (HFD - high fat diet) for either 8 weeks (with the last 5 weeks injected daily with desferal), or for 12 weeks (with the last 9 weeks injected with desferal). Controls were injected with saline. A significant reduction in average lesion area (p = 0.038) was observed in the 12-week treated animals as compared with the 12-week controls. The average lesion iron level of the 12 week treated animals (58 ppm dry weight) was significantly lower (p = 0.03) than for the 12-week control animals (95 ppm dry weight). No reduction in lesion area or iron content was observed in the 8 week treated animals compared with controls, and no change in lesion zinc concentration was observed for either group. This data is consistent with the concept that iron contributes to the early stages in the development of atherosclerosis and that removal of iron from the lesion retards the progression of the disease. Secondly, the effect of zinc supplements on atherosclerotic lesion growth was examined. The rabbits in the test group received a 1% w/w cholesterol diet with Zn supplements for 8 weeks and the rabbits in the control group were fed only with a 1% w/w cholesterol diet for the same period of time. Lesion area analyses using light microscopy showed that the average lesion area was 1.0 mm2 for the test models compared with 3.0 mm2 for the control group models (p = 0.0045). Elemental analysis of the lesion

  11. Treatment of mild non-chemotherapy-induced iron deficiency anemia in cancer patients: comparison between oral ferrous bisglycinate chelate and ferrous sulfate.

    PubMed

    Ferrari, Paola; Nicolini, Andrea; Manca, Maria Laura; Rossi, Giuseppe; Anselmi, Loretta; Conte, Massimo; Carpi, Angelo; Bonino, Ferruccio

    2012-09-01

    In cancer patients mild-moderate non-chemotherapy-induced iron deficiency anemia (IDA) is usually treated with oral iron salts, mostly ferrous sulfate. In this study, we compare efficacy and toxicity of oral ferrous bisglycinate chelate and ferrous sulfate in cancer patients with mild IDA. Twenty-four patients operated on for solid tumors (10 breast, 12 colorectal, 2 gastric), aged 61±10 years (range 45-75), with non-chemotherapy-induced hemoglobin (Hb) values between 10 and 12 g/dL and ferritin lower than 30 ng/mL were randomized to receive oral ferrous bisglycinate chelate, 28 mg per day for 20 days, and then 14 mg per day for 40 days (12 patients) (A group) or oral ferrous sulphate, 105 mg per day for 60 days (12 patients) (B group). Values of hemoglobin and ferritin obtained at diagnosis, 1 and 2 months from the beginning of treatment were compared. Adverse events (AEs) related to the two treatments were recorded. In the 12 patients treated with ferrous bisglycinate chelate, basal hemoglobin and ferritin values (mean±SD) were 11.6±0.8 g/dL and 16.1±8.0 ng/mL. After 2 months of treatment, they were 13.0±1.4 g/dL and 33.8±22.0 ng/mL, respectively (P=0.0003 and P=0.020). In the group treated with ferrous sulphate, hemoglobin and ferritin mean values were 11.3±0.6 g/dL and 19.0±6.4 ng/mL basally, and 12.7±0.70 g/dL and 40.8±28.1 ng/mL (P<0.0001 and P=0.017) after 2 months of treatment. AEs occurred in six cases. In all these six cases, two (17%) treated with ferrous bisglycinate chelate and four (33%) with ferrous sulphate, toxicity was grade 1. In conclusion, these data suggest that ferrous bisglycinate chelate has similar efficacy and likely lower GI toxicity than ferrous sulphate given at the conventional dose of 105 mg per day for the same time.

  12. Chelation of bismuth by combining desferrioxamine and deferiprone in rats.

    PubMed

    Tubafard, S; Fatemi, S J

    2008-05-01

    Consumption and production of bismuth compounds are increasing, however, a little information on the toxic effect and also the effective method in removal of bismuth compounds are available. The present research aimed to characterize the potential efficiency of two chelators after bismuth administration for 55A days following two dose levels of 20 and 40A mg/kg body weight daily to male rats. However, we found abnormalities after bismuth administration in clinical signs, such as body weight, kidneys and liver damages, a black line on gums and skin reactions. Furthermore, the hypothesis that the two chelators might be more efficient as combined therapy than as single therapy in removing bismuth from the body was considered. Along this line, two known chelators deferiprone (1, 2-dimethy1-3-hydroxypyride-4-one, L(1)) and desferrioxamine (DFO) were chosen and tested in the acute rat model. Chelators were given orally (L(1)) or intraperitoneally (DFO) as a single or combined therapy for the period of a week. Doses of L(1) and DFO were 110A mg/kg body weight in experiments. Bismuth and iron concentrations in various tissues were determined by graphite furnace and flame atomic absorption spectrometry, respectively. The combined chelation therapy results show that DFO and L(1) are able to remove bismuth ions from the body, whereas iron concentration returned to the normal level and symptoms are also decreased. DFO was more effective than L1 in reducing bismuth concentration in tissues. The efficiency of DFOA +A L(1) is more than DFO or L(1) in removing bismuth from organs. Our results are indicative that the design procedure might be useful for preliminary in-vivo testing of the efficiency of chelating agents. Results of combined chelators' treatment should be confirmed in a different experimental model before extrapolation to other systems. This testing procedure of course does not provide all the relevant answers for efficiency of chelating agents in bismuth toxicity.

  13. Numerical simulation study of silica and calcite dissolution around a geothermal well by injecting high pH solutions with chelating agent.

    SciTech Connect

    Xu, Tianfu; Rose, Peter; Fayer, Scott; Pruess, Karsten

    2009-02-01

    Dissolution of silica, silicate, and calcite minerals in the presence of a chelating agent (NTA) at a high pH has been successfully performed in the laboratory using a high-temperature flow reactor. The mineral dissolution and porosity enhancement in the laboratory experiment has been reproduced by reactive transport simulation using TOUGHREACT. The chemical stimulation method has been applied by numerical modeling to a field geothermal injection well system, to investigate its effectiveness. Parameters from the quartz monzodiorite unit at the Enhanced Geothermal System (EGS) site at Desert Peak (Nevada) were used. Results indicate that the injection of a high pH chelating solution results in dissolution of both calcite and plagioclase minerals, and avoids precipitation of calcite at high temperature conditions. Consequently reservoir porosity and permeability can be enhanced especially near the injection well.

  14. Recycled chitosan nanofibril as an effective Cu(II), Pb(II) and Cd(II) ionic chelating agent: adsorption and desorption performance.

    PubMed

    Liu, Dagang; Li, Zehui; Zhu, Yi; Li, Zhenxuan; Kumar, Rakesh

    2014-10-13

    Mechanically disassembled chitosan nanofibrils were prepared and used as metal ion chelating agents. Structure and morphology of nanofibrils were investigated and ionic adsorption or desorption performance were validated to establish related fitting models. In single metal ion solution, the saturated adsorption capacities of Cu(II), Pb(II), Cd(II), Zn(II), and Ni(II) were 168.66, 118.00 and 60.85, 143.67, and 63.32 mg/g, respectively. In ternary metal ion solution, Cu(II) was more competitive to be adsorbed than Pb(II) and Cd(II) and its removal could arrive at 60%. Ions adsorbed by nanofibrils could be released by EDTA and the recovery could keep above 70% after 3 sorption-desorption cycles. Hence, renewable and recyclable nanofibrillar chitosan exhibited a great promising application in metal treatments attributed to its high adsorption capacity and chelation efficiency.

  15. Deferasirox for iron chelation in multitransfused children with sickle cell disease; long-term experience in the East London clinical haemoglobinopathy network.

    PubMed

    Tsouana, Eva; Kaya, Banu; Gadong, Nimze; Hemmaway, Claire; Newell, Heather; Simmons, Andrea; Whitmarsh, Simon; Telfer, Paul

    2015-04-01

    Deferasirox (DFX) has been licensed for iron chelation in patients with sickle cell disease (SCD), but there is limited data on its long-term efficacy and safety in children. This retrospective study included 62 regularly transfused children managed in the East London and Essex Clinical Haemoglobinopathy Network (mean age 9.2 ± 3.2 yr). Efficacy measurements consisted of monthly serum ferritin (SF) and annual R2 MRI-estimated liver iron concentration (LIC), and safety markers included serum creatinine and alanine aminotransferase (ALT). The mean duration of DFX treatment was 2.5 ± 1.4 yr, and mean dose at 36 months was 25 mg/kg/d. Mean SF at initiation of treatment was 2542 ± 952 ng/mL and increased to 4691 ± 2255 ng/mL at 36 months (P = 0.05). Mean LIC on first scan was 10.3 mg/g dry weight and did not decrease significantly on follow-up scans. There was a significant correlation between relative change in LIC and in SF (R(2) = 0.66, P < 0.001). Reversible transaminitis episodes, probably due to drug-induced hepatitis, were noted in 53% of patients. Responses to an adherence and acceptability questionnaire indicated that more than 50% of children had difficulties in taking DFX, commonly because of unpleasant taste. Our results show that more than 50% of children with SCD have inadequate control of iron overload with DFX. It is not clear whether this is because of frequent dose interruptions, poor tolerability and adherence, or poor efficacy of the drug. We recommend further studies to confirm these findings and to optimise iron chelation in this population.

  16. Deferasirox for iron chelation in multitransfused children with sickle cell disease; long-term experience in the East London clinical haemoglobinopathy network.

    PubMed

    Tsouana, Eva; Kaya, Banu; Gadong, Nimze; Hemmaway, Claire; Newell, Heather; Simmons, Andrea; Whitmarsh, Simon; Telfer, Paul

    2015-04-01

    Deferasirox (DFX) has been licensed for iron chelation in patients with sickle cell disease (SCD), but there is limited data on its long-term efficacy and safety in children. This retrospective study included 62 regularly transfused children managed in the East London and Essex Clinical Haemoglobinopathy Network (mean age 9.2 ± 3.2 yr). Efficacy measurements consisted of monthly serum ferritin (SF) and annual R2 MRI-estimated liver iron concentration (LIC), and safety markers included serum creatinine and alanine aminotransferase (ALT). The mean duration of DFX treatment was 2.5 ± 1.4 yr, and mean dose at 36 months was 25 mg/kg/d. Mean SF at initiation of treatment was 2542 ± 952 ng/mL and increased to 4691 ± 2255 ng/mL at 36 months (P = 0.05). Mean LIC on first scan was 10.3 mg/g dry weight and did not decrease significantly on follow-up scans. There was a significant correlation between relative change in LIC and in SF (R(2) = 0.66, P < 0.001). Reversible transaminitis episodes, probably due to drug-induced hepatitis, were noted in 53% of patients. Responses to an adherence and acceptability questionnaire indicated that more than 50% of children had difficulties in taking DFX, commonly because of unpleasant taste. Our results show that more than 50% of children with SCD have inadequate control of iron overload with DFX. It is not clear whether this is because of frequent dose interruptions, poor tolerability and adherence, or poor efficacy of the drug. We recommend further studies to confirm these findings and to optimise iron chelation in this population. PMID:25138173

  17. Effect of vitamin C and iron chelation on diesel exhaust particle and carbon black induced oxidative damage and cell adhesion molecule expression in human endothelial cells.

    PubMed

    Frikke-Schmidt, Henriette; Roursgaard, Martin; Lykkesfeldt, Jens; Loft, Steffen; Nøjgaard, Jacob Klenø; Møller, Peter

    2011-06-24

    Exposure to particulate matter is associated with oxidative stress and risk of cardiovascular diseases. We investigated if vitamin C and desferrioxamine (iron chelator) altered the levels of oxidative stress and expression of cell adhesion molecules upon exposure to diesel exhaust particles (DEP) and carbon black in cultured human umbilical vein endothelial cells (HUVECs). We found that the particles were only slightly cytotoxic in the high concentration ranges. Particle-induced intracellular reactive oxygen species (ROS) production was attenuated by vitamin C administration or iron chelation and particularly when combined (p<0.001). Only desferrioxamine protected the DNA from oxidative damage in terms of strand breaks and formamidopyrimidine DNA glycosylase sensitive sites induced by carbon black (p<0.01). Carbon black and small sized DEP generated from an Euro4 engine increased the surface expression of VCAM-1 and ICAM-1, whereas DEP from an engine representing an old combustion type engine (SRM2975) with larger particles did not affect the expression of cell adhesion molecules. These effects were also attenuated by desferrioxamine but not vitamin C. The study shows that exposure to carbon black and DEP in HUVECs can generate both oxidative stress and expression of cell surface adhesion molecules and that these effects can in part be attenuated by vitamin C and desferrioxamine.

  18. Magnetic bead-based enzyme-chromogenic substrate system for ultrasensitive colorimetric immunoassay accompanying cascade reaction for enzymatic formation of squaric acid-iron(III) chelate.

    PubMed

    Lai, Wenqiang; Tang, Dianping; Zhuang, Junyang; Chen, Guonan; Yang, Huanghao

    2014-05-20

    This work reports on a simple and feasible colorimetric immunoassay with signal amplification for sensitive determination of prostate-specific antigen (PSA, used as a model) at an ultralow concentration by using a new enzyme-chromogenic substrate system. We discovered that glucose oxidase (GOx), the enzyme broadly used in enzyme-linked immunosorbent assay (ELISA), has the ability to stimulate in situ formation of squaric acid (SQA)-iron(III) chelate. GOx-catalyzed oxidization of glucose leads to the formation of gluconic acid and hydrogen peroxide (H2O2). The latter can catalytically oxidize iron(II) to iron(III), which can rapidly (<1 min) coordinate with the SQA. Formation of the iron-squarate complex causes the color of the solution to change from bluish purple to bluish red accompanying the increasing absorbance with the increment of iron(III) concentration. On the basis of the SQA-iron(III) system, a new immunoassay protocol with GOx-labeled anti-PSA detection antibody can be designed for the detection of target PSA on capture antibody-functionalized magnetic immunosensing probe, monitored by recording the color or absorbance (λ = 468 nm) of the generated SQA-iron(III) chelate. The absorbance intensity shows to be dependent on the concentration of target PSA. A linear dependence between the absorbance and target PSA concentration is obtained under optimal conditions in the range from 1.0 pg mL(-1) to 30 ng mL(-1) with a detection limit (LOD) of 0.5 pg mL(-1) (0.5 ppt) estimated at the 3Sblank level. The sensitivity displays to be 3-5 orders of magnitude better than those of most commercialized human PSA ELISA kits. In addition, the developed colorimetric immunoassay was validated by assaying 12 human serum samples, receiving in good accordance with those obtained by the commercialized PSA ELISA kit. Importantly, the SQA-based immunosensing system can be further extended for the detection of other low-abundance proteins or biomarkers by controlling the target

  19. comparison of effects of different long-term iron-chelation regimens on myocardial and hepatic iron concentrations assessed with T2* magnetic resonance imaging in patients with beta-thalassemia major.

    PubMed

    Perifanis, Vassilios; Christoforidis, Athanasios; Vlachaki, Efthimia; Tsatra, Ioanna; Spanos, George; Athanassiou-Metaxa, Miranda

    2007-12-01

    The aim of this study was to compare the effect of different long-term chelation regimens on heart and liver iron stores with the use of T2* magnetic resonance imaging (MRI) in patients with transfusion-dependent beta-thalassemia major. Sixty-four patients (28 men, 36 women; mean age, 26.49 +/- 5.8 years) were enrolled in the study. The 3 groups were based on the chelation therapy received. The first group (19 patients) received deferiprone (DFP) (75 mg/kg per day orally), the second group (23 patients) received deferoxamine (DFO) (30-50 mg/kg per day subcutaneously at least 5 times/week), and the third group (22 patients) received a combination of DFO (30-50 mg/kg per day, 2-3 days/week) and DFP (75 mg/kg per day, 7 days/week). MRI scans were acquired with an imager equipped with a 1.5 T magnet, and the data included myocardial and hepatic iron measurements obtained by means of T2*, and ventricular volumes and ejection fractions obtained with standard cardiovascular MRI techniques. The results revealed that the DFP and the combined groups had significantly less myocardial iron than the DFO group (mean myocardial T2*, 35.77 +/- 18.3 milliseconds and 38.05 +/- 15.3 milliseconds versus 23.77 +/- 13 milliseconds [P = .02, and P = .001], respectively). On the contrary, the DFP group had a significantly higher hepatic iron content than the DFO and combined groups (mean hepatic T2*, 3.29 +/- 2.5 milliseconds versus 8.16 +/- 8.4 milliseconds and 11.3 +/- 10.9 milliseconds [P = .014, and P = .003], respectively). No correlation was observed between myocardial T2* and hepatic T2* values (r = -0.043; P = .37). Myocardial T2* values were inversely correlated with age (r = -0.249; P = .024) and positively correlated with both left and right ventricular ejection fractions (r = 0.33 [P = .004], and r = 0.279 [P = .014], respectively). Finally, liver T2* was strongly and inversely correlated with serum ferritin concentration (r = -0.465; P = .001). In conclusion, combined

  20. N-Acetyl-Cysteine as Effective and Safe Chelating Agent in Metal-on-Metal Hip-Implanted Patients: Two Cases

    PubMed Central

    Lonati, Davide; Ragghianti, Benedetta; Ronchi, Anna; Vecchio, Sarah; Locatelli, Carlo Alessandro

    2016-01-01

    Systemic toxicity associated with cobalt (Co) and chromium (Cr) containing metal hip alloy may result in neuropathy, cardiomyopathy, and hypothyroidism. However clinical management concerning chelating therapy is still debated in literature. Here are described two metal-on-metal hip-implanted patients in which N-acetyl-cysteine decreased elevated blood metal levels. A 67-year-old male who underwent Co/Cr hip implant in September 2009 referred to our Poison Control Centre for persisting elevated Co/Cr blood levels (from March 2012 to November 2014). After receiving oral high-dose N-acetyl-cysteine, Co/Cr blood concentrations dropped by 86% and 87% of the prechelation levels, respectively, and persisted at these latter concentrations during the following 6 months of follow-up. An 81-year-old female who underwent Co/Cr hip implant in January 2007 referred to our Centre for detection of high Co and Cr blood levels in June 2012. No hip revision was indicated. After a therapy with oral high-dose N-acetyl-cysteine Co/Cr blood concentrations decreased of 45% and 24% of the prechelation levels. Chelating agents reported in hip-implanted patients (EDTA, DMPS, and BAL) are described in few cases. N-acetyl-cysteine may provide chelating sites for metals and in our cases reduced Co and Cr blood levels and resulted well tolerable. PMID:27148463

  1. Deferasirox is a powerful NF-κB inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging

    PubMed Central

    Messa, Emanuela; Carturan, Sonia; Maffè, Chiara; Pautasso, Marisa; Bracco, Enrico; Roetto, Antonella; Messa, Francesca; Arruga, Francesca; Defilippi, Ilaria; Rosso, Valentina; Zanone, Chiara; Rotolo, Antonia; Greco, Elisabetta; Pellegrino, Rosa M.; Alberti, Daniele; Saglio, Giuseppe; Cilloni, Daniela

    2010-01-01

    Background Usefulness of iron chelation therapy in myelodysplastic patients is still under debate but many authors suggest its possible role in improving survival of low-risk myelodysplastic patients. Several reports have described an unexpected effect of iron chelators, such as an improvement in hemoglobin levels, in patients affected by myelodysplastic syndromes. Furthermore, the novel chelator deferasirox induces a similar improvement more rapidly. Nuclear factor-κB is a key regulator of many cellular processes and its impaired activity has been described in different myeloid malignancies including myelodysplastic syndromes. Design and Methods We evaluated deferasirox activity on nuclear factor-κB in myelodysplastic syndromes as a possible mechanism involved in hemoglobin improvement during in vivo treatment. Forty peripheral blood samples collected from myelodysplastic syndrome patients were incubated with 50 μM deferasirox for 18h. Results Nuclear factor-κB activity dramatically decreased in samples showing high basal activity as well as in cell lines, whereas no similar behavior was observed with other iron chelators despite a similar reduction in reactive oxygen species levels. Additionally, ferric hydroxyquinoline incubation did not decrease deferasirox activity in K562 cells suggesting the mechanism of action of the drug is independent from cell iron deprivation by chelation. Finally, incubation with both etoposide and deferasirox induced an increase in K562 apoptotic rate. Conclusions Nuclear factor-κB inhibition by deferasirox is not seen from other chelators and is iron and reactive oxygen species scavenging independent. This could explain the hemoglobin improvement after in vivo treatment, such that our hypothesis needs to be validated in further prospective studies. PMID:20534700

  2. Tenellin acts as an iron chelator to prevent iron-generated reactive oxygen species toxicity in the entomopathogenic fungus Beauveria bassiana.

    PubMed

    Jirakkakul, Jiraporn; Cheevadhanarak, Supapon; Punya, Juntira; Chutrakul, Chanikul; Senachak, Jittisak; Buajarern, Taridaporn; Tanticharoen, Morakot; Amnuaykanjanasin, Alongkorn

    2015-01-01

    Iron is an essential element for life. However, the iron overload can be toxic. Here, we investigated the significant increase of tenellin and iron-tenellin complex production in ferricrocin-deficient mutants of Beauveria bassiana. Our chemical analysis indicated that the ferricrocin-deficient mutants T1, T3 and T5 nearly abolished ferricrocin production. In turn, these mutants had significant accumulation of iron-tenellin complex in their mycelia at 247-289 mg g(-1) cell dry weight under iron-replete condition. Both tenellin and iron-tenellin complex were not detected in the wild-type under such condition. Mass analysis of the mutants' crude extracts demonstrated that tenellin formed a 3:1 complex with iron in the absence of ferricrocin. The unexpected link between ferricrocin and tenellin biosynthesis in ferricrocin-deficient mutants could be a survival strategy during iron-mediated oxidative stress. PMID:25670702

  3. Comparing soluble ferric pyrophosphate to common iron salts and chelates as sources of bioavailable iron in a caco-2 cell culture model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Iron bioavailability from supplements and fortificants varies depending upon the form of the iron and the presence or absence of iron absorption enhancers and inhibitors. Our objectives were to compare the effects of pH and selected enhancers and inhibitors and food matrices on the bioavailability o...

  4. A simple fluorescent probe for the determination of dissolved oxygen based on the catalytic activation of oxygen by iron(II) chelates.

    PubMed

    Luo, Wei; Abbas, M E; Zhu, Lihua; Zhou, Wenyi; Li, Kejing; Tang, Heqing; Liu, Shushen; Li, Weiying

    2009-04-27

    This work aims at establishing a simple fluorescent probe for the determination of dissolved oxygen. It is found that iron(II) ions activate oxygen to produce reactive species being capable of oxidizing non-fluorescent coumarin to fluorescent 7-hydroxycoumarin. However, this process is not effective because the yield of the reactive species is very low in the presence of simple iron(II) salts alone. The addition of organic ligands such as oxalate results in the formation of complexes between iron(II) ions, which leads to considerable increase in the yield of reactive species (such as hydroxyl radicals) and then increase in the fluorescence intensity of 7-hydroxycoumarin to a significant level. It has been observed that in the mixture solution of iron(II) ions, ligand, coumarin, and dissolved oxygen, there is an excellent linear response between the fluorescence and dissolved oxygen. Therefore, a new spectrofluorimetric method has been proposed for the determination of dissolved oxygen by using catalytic activation of O(2) by iron(II) chelates. Under optimized conditions, a linear correlation (r=0.995) has been observed between the fluorescence intensity of 7-hydroxycoumarin at 456 nm and the concentration of dissolved oxygen over the range of 0.96-9.22 mg L(-1). The limit of detection for dissolved oxygen at a signal-to-noise ratio of 3 has been estimated to be 0.35 mg L(-1). The proposed method has been applied to determine the concentration of dissolved oxygen in practical water samples with results as satisfactory as that obtained by the standard iodometric method.

  5. Iron-control additives improve acidizing

    SciTech Connect

    Walker, M.; Dill, W. ); Besler, M. )

    1989-07-24

    Iron sulfide and sulfur precipitation in sour wells can be controlled with iron-sequestering agents and sulfide modifiers. Oil production has been routinely increased in sour wells where precipitation of iron sulfide and elemental sulfur has been brought under control. Production increases have been especially noteworthy on wells that had a history of rapid production decline after acid stimulation. Twenty-fold production increases have been recorded. Key to the production increase has been to increase permeability with: Iron chelating agents that control precipitation of iron sulfide. A sulfide modifier that reduces precipitation of solids in the presence of excessive amounts of hydrogen sulfide and prevents precipitation of elemental sulfur.

  6. In vivo studies of cadmium-induced apoptosis in testicular tissue of the rat and its modulation by a chelating agent.

    PubMed

    Xu, C; Johnson, J E; Singh, P K; Jones, M M; Yan, H; Carter, C E

    1996-01-22

    In vivo CdCl2-induced apoptotic DNA fragmentation in the testes of the male Wistar rat has been demonstrated on agarose gel. Characteristic DNA migration patterns (laddering) provide evidence of apoptosis (programmed cell death) in testicular tissue of rats administered CdCl2 at a level of 0.03 mmol/kg 48 h previously. Evidence that administration of an appropriate cadmium chelating agent within the first 24 h can suppress some or all of the apoptotic changes in testicular DNA has also been obtained for the first time. A greater reduction in apoptosis is observed as the interval between the administration of the cadmium and that of the chelating agent is shortened. Administration of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) to male Wistar rats given CdCl2 is effective in the modulation of the typically apoptotic DNA fragmentation and associated histopathologic injury when the antagonist is given within approximately 1 h after the CdCl2 exposure. When the antagonist is given at later times there is a progressively more pronounced degradation of the DNA into oligonucleotides as seen in the typical electrophoretic DNA ladder pattern found with apoptosis. There is also a progressive increase in histopathological tissue changes as the antagonist is administered at progressively greater intervals after the cadmium. PMID:8597027

  7. Use of HPLC for the detection of iron chelators in cultures of bacteria, fungi, and algae. [E. coli; Bacillus megaterium; Ustilago sphaerogena; Anabaena flos-aqua

    SciTech Connect

    Boyer, G.L.; Speirs, R.J.; Morse, P.D. )

    1990-06-01

    Iron is essential for the growth of living cells. To meet biochemical needs, microorganisms, including algae, produce high affinity chelators termed siderophores. These compounds solubilize Fe and increase its bioavailability. We have developed a new method to study siderophore formation in cultured and natural environments. Based on the fact siderophores tightly bind 55-Fe, the radioactive complexes can be separated by HPLC using an inert PRP-1 column and detected by scintillation counting. This method cleanly resolves several known siderophores, including ferrichrome A, ferrichrome, desferal, and rhodotorulic acid. The optimization of the method and its use for analysis of siderophore formation in bacteria (E. coli, and Bacillus megaterium), fungi (Ustilago sphaerogena), and cyanobacteria (Anabaena flos-aqua UTEX 1444 and Anabaena sp. ATCC 27898) will be presented.

  8. Discovery of an extended bundle sheath in Ricinus communis L. and its role as a temporal storage compartment for the iron chelator nicotianamine.

    PubMed

    Rutten, T; Krüger, C; Melzer, M; Stephan, U W; Hell, R

    2003-07-01

    The extended bundle sheath (EBS) is a specialized layer of cells that enhances the lateral transport of photoassimilates within the leaf. This little-known tissue is often considered to be legume-specific. We identified an EBS in cotyledons and leaves of the non-legume Ricinus communis L. By means of cytological and immunological studies and using the localization of the iron-chelator nicotianamine as an established indicator for mass transport, we confirmed its role as a transport tissue and a temporal sink. Observations on cotyledons of Ricinus seedlings further proved that the EBS carries out these tasks from a very early stage of development onwards. This is the first time that information has been obtained on the physiological role of an EBS in a non-legume. Our results support the idea of its widespread occurrence among higher plants. PMID:14520566

  9. Induction of the SOS DNA repair response in Escherichia coli by nitric oxide donating agents: dinitrosyl iron complexes with thiol-containing ligands and S-nitrosothiols.

    PubMed

    Lobysheva, I I; Stupakova, M V; Mikoyan, V D; Vasilieva, S V; Vanin, A F

    1999-07-01

    The ability of nitric oxide (NO) donor compounds to induce the SOS DNA repair response in Escherichia coli is reported. Dinitrosyl iron complexes with glutathione and cysteine (DNIC) are the most potent SOS-inducers. S-Nitrosothiols (RSNO) mediate a similar response at 10-100 microM, but the response decreases sharply at concentrations above 0.5 mM. Pretreatment of the cells with the chelating agent o-phenanthroline (OP) prevents induction of the SOS response by all agents used. On the other hand, the toxicity of S-nitrosothiols is higher than that of DNIC. The EPR study shows the appearance of an EPR DNIC-type signal after incubation of the cells with S-nitrosoglutathione because of mutual transformation between RSNO and DNIC in the presence of accessible iron inside the cells. Pretreatment of the cells with OP leads to a decrease in this signal. Analysis of NO donor effects reveals a dual role of the iron ions in reactivity and toxicity of the compounds studied, i.e. (i) stabilization of the cytotoxic RSNO and (ii) generation of the SOS signal. PMID:10431802

  10. Effects of iron-glycine chelate on growth, carcass characteristic, liver mineral concentrations and haematological and biochemical blood parameters in broilers.

    PubMed

    Kwiecień, M; Samolińska, W; Bujanowicz-Haraś, B

    2015-12-01

    Studies were carried out to determine the effect of additive iron-glycine chelate on the production performance, slaughter yield, mineral deposition in the liver and the metabolic blood panel in broiler chickens. A total of 250 one-day-old Ross 308 chicks were allotted into five groups with five replicates of 10 birds each. Diets were supplemented with the organic form iron (Fe-Gly at the rate of 25%, 50% or 100% of the total requirements of the elements) and inorganic Fe (FeSO4 at the rate of 50% or 100%). In the experiment, iron was added to the premix (containing no Fe) in an amount of 40 or 20 mg per kg of basal diet, in groups I and II, in the form of FeSO4 , and in an amount of 40, 20 or 10 mg per kg of basal diet, in groups III, IV and V, in the form of Fe-Gly. The study covering the period from the first to the 42nd day of breeding revealed that the production performance and slaughter yield were not dependent on the form and amount of added Fe. In the experimental groups with the addition of Fe-Gly of 20 or 10 mg/kg, there were no deaths of chickens during the whole fattening period. As a result, introducing an organic form of iron covering 50% and 25% of the birds' requirement increased the effectiveness of chicken fattening (European Efficiency Index) (p < 0.01). An organic Fe compound (40, 20 or 10 mg/kg) added to mixtures contributed to significant changes in the level of biochemical and haematological indicators in blood. The study demonstrated that an addition of Fe-Gly to mixtures for broilers can be fully effective in terms of production and health performance even if the suggested requirement for this element is 50% or 25% covered.

  11. Carot-4-en-9,10-diol, a conidiation-inducing sesquiterpene diol produced by Trichoderma virens PS1-7 upon exposure to chemical stress from highly active iron chelators.

    PubMed

    Wang, Mengcen; Hashimoto, Makoto; Hashidoko, Yasuyuki

    2013-03-01

    To screen biocontrol agents against Burkholderia plantarii, the causative agent of rice seedling blight, we employed catechol, an analog of the virulence factor tropolone, to obtain chemical stress-resistant microorganisms. The fungal isolate PS1-7, identified as a strain of Trichoderma virens, showed the highest resistance to catechol (20 mM) and exhibited efficacy as a biocontrol agent for rice seedling blight. During investigation of metabolic traits of T. virens PS1-7 exposed to catechol, we found a secondary metabolite that was released extracellularly and uniquely accumulated in the culture. The compound induced by chemical stress due to catechol was subsequently isolated and identified as a sesquiterpene diol, carot-4-en-9,10-diol, based on spectroscopic analyses. T. virens PS1-7 produced carot-4-en-9,10-diol as a metabolic response to tropolone at concentrations from 0.05 to 0.2 mM, and the response was enhanced in a dose-dependent manner, similar to its response to catechol at concentrations from 0.1 to 1 mM. Some iron chelators, such as pyrogallol, gallic acid, salicylic acid, and citric acid, at 0.5 mM also showed activation of T. virens PS1-7 production of carot-4-en-9,10-diol. This sesquiterpene diol, formed in response to chemical stress, promoted conidiation of T. virens PS1-7, suggesting that it is involved in an autoregulatory signaling system. In a bioassay of the metabolic and morphological responses of T. virens PS1-7, conidiation in hyphae grown on potato dextrose agar (PDA) plates was either promoted or induced by carot-4-en-9,10-diol. Carot-4-en-9,10-diol can thus be regarded as an autoregulatory signal in T. virens, and our findings demonstrate that intrinsic intracellular signaling regulates conidiation of T. virens. PMID:23315728

  12. Carot-4-en-9,10-Diol, a Conidiation-Inducing Sesquiterpene Diol Produced by Trichoderma virens PS1-7 upon Exposure to Chemical Stress from Highly Active Iron Chelators

    PubMed Central

    Wang, Mengcen; Hashimoto, Makoto

    2013-01-01

    To screen biocontrol agents against Burkholderia plantarii, the causative agent of rice seedling blight, we employed catechol, an analog of the virulence factor tropolone, to obtain chemical stress-resistant microorganisms. The fungal isolate PS1-7, identified as a strain of Trichoderma virens, showed the highest resistance to catechol (20 mM) and exhibited efficacy as a biocontrol agent for rice seedling blight. During investigation of metabolic traits of T. virens PS1-7 exposed to catechol, we found a secondary metabolite that was released extracellularly and uniquely accumulated in the culture. The compound induced by chemical stress due to catechol was subsequently isolated and identified as a sesquiterpene diol, carot-4-en-9,10-diol, based on spectroscopic analyses. T. virens PS1-7 produced carot-4-en-9,10-diol as a metabolic response to tropolone at concentrations from 0.05 to 0.2 mM, and the response was enhanced in a dose-dependent manner, similar to its response to catechol at concentrations from 0.1 to 1 mM. Some iron chelators, such as pyrogallol, gallic acid, salicylic acid, and citric acid, at 0.5 mM also showed activation of T. virens PS1-7 production of carot-4-en-9,10-diol. This sesquiterpene diol, formed in response to chemical stress, promoted conidiation of T. virens PS1-7, suggesting that it is involved in an autoregulatory signaling system. In a bioassay of the metabolic and morphological responses of T. virens PS1-7, conidiation in hyphae grown on potato dextrose agar (PDA) plates was either promoted or induced by carot-4-en-9,10-diol. Carot-4-en-9,10-diol can thus be regarded as an autoregulatory signal in T. virens, and our findings demonstrate that intrinsic intracellular signaling regulates conidiation of T. virens. PMID:23315728

  13. Current recommendations for chelation for transfusion-dependent thalassemia.

    PubMed

    Kwiatkowski, Janet L

    2016-03-01

    Regular red cell transfusions used to treat thalassemia cause iron loading that must be treated with chelation therapy. Morbidity and mortality in thalassemia major are closely linked to the adequacy of chelation. Chelation therapy removes accumulated iron and detoxifies iron, which can prevent and reverse much of the iron-mediated organ injury. Currently, three chelators are commercially available--deferoxamine, deferasirox, and deferiprone--and each can be used as monotherapy or in combination. Close monitoring of hepatic and cardiac iron burden is central to tailoring chelation. Other factors, including properties of the individual chelators, ongoing transfusional iron burden, and patient preference, must be considered. Monotherapy generally is utilized if the iron burden is in an acceptable or near-acceptable range and the dose is adjusted accordingly. Combination chelation often is employed for patients with high iron burden, iron-related organ injury, or where adverse effects of chelators preclude administration of an appropriate chelator dose. The combination of deferoxamine and deferiprone is the best studied, but increasing data are available on the safety and efficacy of newer chelator combinations, including deferasirox with deferoxamine and the oral-only combination of deferasirox with deferiprone. The expanding chelation repertoire should enable better control of iron burden and improved outcomes.

  14. Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability.

    PubMed

    Lux, Jacques; Chan, Minnie; Elst, Luce Vander; Schopf, Eric; Mahmoud, Enas; Laurent, Sophie; Almutairi, Adah

    2013-12-14

    We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd(3+) within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd(3+). This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy.

  15. Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability

    PubMed Central

    Elst, Luce Vander; Schopf, Eric; Mahmoud, Enas; Laurent, Sophie; Almutairi, Adah

    2013-01-01

    We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd3+ within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd3+. This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy. PMID:24505553

  16. Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability.

    PubMed

    Lux, Jacques; Chan, Minnie; Elst, Luce Vander; Schopf, Eric; Mahmoud, Enas; Laurent, Sophie; Almutairi, Adah

    2013-12-14

    We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd(3+) within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd(3+). This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy. PMID:24505553

  17. Updated recommendations on the management of gastrointestinal disturbances during iron chelation therapy with Deferasirox in transfusion dependent patients with myelodysplastic syndrome - Emphasis on optimized dosing schedules and new formulations.

    PubMed

    Nolte, Florian; Angelucci, Emanuele; Breccia, Massimo; Gattermann, Norbert; Santini, Valeria; Vey, Norbert; Hofmann, Wolf-Karsten

    2015-10-01

    Myelodysplastic syndromes (MDS) are oligoclonal hematopoietic disorders characterized by peripheral cytopenias with anemias being the most prevalent feature. The majority of patients will depend on regular transfusions of packed red blood cells (PRBC) during the course of the disease. Particularly patients with MDS and low risk for transformation into acute myeloid leukemia and low risk of early death will receive PRBC transfusions on a regular basis, which puts them at high risk for transfusional iron overload. Transfusion dependence has been associated with negative impact on organ function and reduced life expectancy. Recently, several retrospective but also some prospective studies have indicated, that transfusion dependent patients with MDS might benefit from consequent iron chelation with regard to morbidity and mortality. However, low treatment adherence due to adverse events mainly gastrointestinal in nature is an important obstacle in achieving sufficient iron chelation in MDS patients. Here, we will summarize and discuss the existing data on Deferasirox in low risk MDS published so far and provide recommendations for optimal management of gastrointestinal adverse events during iron chelation aiming at improving treatment compliance and, hence, sufficiently removing excess iron from the patients.

  18. Updated recommendations on the management of gastrointestinal disturbances during iron chelation therapy with Deferasirox in transfusion dependent patients with myelodysplastic syndrome - Emphasis on optimized dosing schedules and new formulations.

    PubMed

    Nolte, Florian; Angelucci, Emanuele; Breccia, Massimo; Gattermann, Norbert; Santini, Valeria; Vey, Norbert; Hofmann, Wolf-Karsten

    2015-10-01

    Myelodysplastic syndromes (MDS) are oligoclonal hematopoietic disorders characterized by peripheral cytopenias with anemias being the most prevalent feature. The majority of patients will depend on regular transfusions of packed red blood cells (PRBC) during the course of the disease. Particularly patients with MDS and low risk for transformation into acute myeloid leukemia and low risk of early death will receive PRBC transfusions on a regular basis, which puts them at high risk for transfusional iron overload. Transfusion dependence has been associated with negative impact on organ function and reduced life expectancy. Recently, several retrospective but also some prospective studies have indicated, that transfusion dependent patients with MDS might benefit from consequent iron chelation with regard to morbidity and mortality. However, low treatment adherence due to adverse events mainly gastrointestinal in nature is an important obstacle in achieving sufficient iron chelation in MDS patients. Here, we will summarize and discuss the existing data on Deferasirox in low risk MDS published so far and provide recommendations for optimal management of gastrointestinal adverse events during iron chelation aiming at improving treatment compliance and, hence, sufficiently removing excess iron from the patients. PMID:26293555

  19. 1: Mass asymmetric fission barriers for {sup 98}Mo; 2: Synthesis and characterization of actinide-specific chelating agents

    SciTech Connect

    Veeck, A.C. ||

    1996-08-01

    Excitation functions have been measured for complex fragment emission from the compound nucleus {sup 98}Mo, produced by the reaction of {sup 86}Kr with {sup 12}C. Mass asymmetric fission barriers have been obtained by fitting the excitation functions with a transition state formalism. The extracted barriers are {approximately} 5.7 MeV higher, on average, than the calculations of the Rotating Finite Range Model (RFRM). These data clearly show an isospin dependence of the conditional barriers when compared with the extracted barriers from {sup 90}Mo and {sup 94}Mo. Eleven different liquid/liquid extractants were synthesized based upon the chelating moieties 3,2-HOPO and 3,4-HOPO; additionally, two liquid/liquid extractants based upon the 1,2-HOPO chelating moiety were obtained for extraction studies. The Pu(IV) extractions, quite surprisingly, yielded results that were very different from the Fe(III) extractions. The first trend remained the same: the 1,2-HOPOs were the best extractants, followed closely by the 3,2-HOPOs, followed by the 3,4-HOPOs; but in these Pu(IV) extractions the 3,4-HOPOs performed much better than in the Fe(III) extractions. 129 refs.

  20. New biodegradable organic-soluble chelating agents for simultaneous removal of heavy metals and organic pollutants from contaminated media.

    PubMed

    Ullmann, Amos; Brauner, Neima; Vazana, Shlomi; Katz, Zhanna; Goikhman, Roman; Seemann, Boaz; Marom, Hanit; Gozin, Michael

    2013-09-15

    Advanced biodegradable and non-toxic organic chelators, which are soluble in organic media, were synthesized on the basis of the S,S-ethylenediamine-disuccinate (S,S-EDDS) ligand. The modifications suggested in this work include attachment of a lipophilic hydrocarbon chain ("tail") to one or both nitrogen atoms of the S,S-EDDS. The new ligands were designed and evaluated for application in the Sediments Remediation Phase Transition Extraction (SR-PTE) process. This novel process is being developed for the simultaneous removal of both heavy metals and organic pollutants from contaminated soils, sediments or sludge. The new chelators were designed to bind various target metal ions, to promote extraction of these ions into organic solvents. Several variations of attached tails were synthesized and tested. The results for one of them, N,N'-bis-dodecyl-S,S-EDDS (C24-EDDS), showed that the metal-ligand complexes are concentrated in the organic-rich phase in the Phase Transition Extraction process (more than 80%). Preliminary applications of the SR-PTE process with the C24-EDDS ligand were conducted also on actually contaminated sludge (field samples). The extraction of five toxic metals, namely, Cd, Cu, Ni, Pb and Zn was examined. In general, the extraction performance of the new ligand was not less than that of S,S-EDDS when a sufficient ligand-to-extracted ion ratio (about 4:1 was applied.

  1. Iron chelation therapy in thalassemia major: a systematic review with meta-analyses of 1520 patients included on randomized clinical trials.

    PubMed

    Maggio, Aurelio; Filosa, Aldo; Vitrano, Angela; Aloj, Giuseppina; Kattamis, Antonis; Ceci, Adriana; Fucharoen, Suthat; Cianciulli, Paolo; Grady, Robert W; Prossomariti, Luciano; Porter, John B; Iacono, Angela; Cappellini, Maria Domenica; Bonifazi, Fedele; Cassarà, Filippo; Harmatz, Paul; Wood, John; Gluud, Christian

    2011-10-15

    The effectiveness of deferoxamine (DFO), deferiprone (DFP), or deferasirox (DFX) in thalassemia major was assessed. Outcomes were reported as means±SD, mean differences with 95% CI, or standardized mean differences. Statistical heterogeneity was tested using χ2 (Q) and I2. Sources of bias and Grading of Recommendations Assessment, Development and Evaluation system (GRADE) were considered. Overall, 1520 patients were included. Only 7.4% of trials were free of bias. Overall measurements suggest low trial quality (GRADE). The meta-analysis suggests lower final liver iron concentrations during associated versus monotherapy treatment (p<0.0001), increases in serum ferritin levels during DFX 5, 10, and 20 mg/kg versus DFO-treated groups (p<0.00001, p<0.00001, and p=0.002, respectively), but no statistically significant difference during DFX 30 mg/kg versus DFO (p=0.70), no statistically significant variations in heart T2* signal during associated or sequential versus mono-therapy treatment (p=0.46 and p=0.14, respectively), increases in urinary iron excretion during associated or sequential versus monotherapy treatment (p=0.008 and p=0.02, respectively), and improved ejection fraction during associated or sequential versus monotherapy treatment (p=0.01 and p<0.00001, respectively). These findings do not support any specific chelation treatment. The literature shows risks of bias, and additional larger and longer trials are needed.

  2. In vivo efficacy, toxicity and biodistribution of ultra-long circulating desferrioxamine based polymeric iron chelator.

    PubMed

    Hamilton, Jasmine L; Imran Ul-Haq, Muhammad; Abbina, Srinivas; Kalathottukaren, Manu Thomas; Lai, Benjamin F L; Hatef, Azadeh; Unniappan, Suraj; Kizhakkedathu, Jayachandran N

    2016-09-01

    Desferrioxamine (DFO) is currently in clinical use to remove iron from transfusion-dependent patients with β-thalassemia major, sickle-cell anemia and the myelodysplastic syndromes. However, its short half-life, burdensome, subcutaneous mode of administration and propensity to cause neurotoxicity at high doses greatly hinder its use. Thus, developing an optimized version of DFO with extended half-life, and reduced toxicity is a major goal. Using high molecular weight (MW), non-toxic, hyperbranched polyglycerol with high functionality, we demonstrate that the efficacy of DFO can be tuned with considerable reduction in toxicity. Using zebrafish embryos and mice, we tested toxicity, iron removal efficacy with low dosing and the biodistribution of ultra-long circulating DFO (ULC-DFO) conjugates. There was no significant difference in the mortality and development of zebrafish embryos upon exposure to ULC-DFO. Similarly, body weights and serum lactate dehydrogenase levels in mice treated with ULC-DFO remained within the normal range throughout the tolerance study. Moreover, ULC-DFO is significantly more effective than low MW DFO in promoting iron removal both from organs and via urine in iron overloaded mice despite using a moderate, once-weekly dosing schedule. This is probably due to the extended circulation half-life of ULC-DFO. The MW of ULC-DFO influences the accumulation and biodistribution, with highest MW (637 KDa) associated with up to 12% accumulation in the liver. In contrast, ULC-DFO with MWs of 75 KDa and lower were associated with relatively low organ accumulation, indicating that biodistribution of ULC-DFO can be tuned. Since ULC-DFO has improved iron removal properties, longer plasma retention time and possesses excellent biocompatibility, it represents a polymer conjugate with high clinical utility in comparison to DFO for the treatment of transfusion dependent iron overload. More importantly, ULC-DFO is anticipated to reduce the requirement for

  3. Accumulation and distribution of iron, cadmium, lead and nickel in cucumber plants grown in hydroponics containing two different chelated iron supplies.

    PubMed

    Csog, Árpád; Mihucz, Victor G; Tatár, Eniko; Fodor, Ferenc; Virág, István; Majdik, Cornelia; Záray, Gyula

    2011-07-01

    Cucumber plants grown in hydroponics containing 10 μM Cd(II), Ni(II) and Pb(II), and iron supplied as Fe(III) EDTA or Fe(III) citrate in identical concentrations, were investigated by total-reflection X-ray fluorescence spectrometry with special emphasis on the determination of iron accumulation and distribution within the different plant compartments (root, stem, cotyledon and leaves). The extent of Cd, Ni and Pb accumulation and distribution were also determined. Generally, iron and heavy-metal contaminant accumulation was higher when Fe(III) citrate was used. The accumulation of nickel and lead was higher by about 20% and 100%, respectively, if the iron supply was Fe(III) citrate. The accumulation of Cd was similar. In the case of Fe(III) citrate, the total amounts of Fe taken up were similar in the control and heavy-metal-treated plants (27-31 μmol/plant). Further, the amounts of iron transported from the root towards the shoot of the control, lead- and nickel-contaminated plants were independent of the iron(III) form. Although Fe mobility could be characterized as being low, its distribution within the shoot was not significantly affected by the heavy metals investigated.

  4. Effect of Surface Modification by Chelating Agents on Fischer–Tropsch Performance of Co/SiO2 Catalysts

    SciTech Connect

    Bambal, Ashish S.; Kugler, Edwin L.; Gardner, Todd H.; Dadyburjor, Dady B.

    2013-11-27

    The silica support of a Co-based catalyst for Fischer–Tropsch (FT) synthesis was modified by the chelating agents (CAs) nitrilotriacetic acid (NTA) and ethylenediaminetetraacetic acid (EDTA). After the modification, characterization of the fresh and spent catalysts shows reduced crystallite sizes, a better-dispersed Co3O4 phase on the calcined samples, and increased metal dispersions for the reduced samples. The CA-modified catalysts display higher CO conversions, product yields, reaction rates, and rate constants. The improved FT performance of CA-modified catalysts is attributed to the formation of stable complexes with Co. Finally, the superior performance of the EDTA-modified catalyst in comparison to the NTA-modified catalyst is due to the higher affinity of the former for complex formation with Co ions.

  5. Microstructure, Optical and Photocatalytic Properties of TiO₂ Thin Films Prepared by Chelating-Agent Assisted Sol-Gel Method.

    PubMed

    Matĕjová, Lenka; Cieslarová, Monika; Matĕj, Zdenĕk; Danis, Stanislav; Peikertová, Pavlína; Sihor, Marcel; Lang, Jaroslav; Matĕjka, Vlastimil

    2016-01-01

    Single and multilayer TiO₂ thin films coated on two types of soda-lime glass substrates (microscope slides and cylinders) were prepared by a chelating agent-assisted sol-gel method, using ethyl acetoacetate as a chelating agent, dip-coating and calcination at 500 °C for 2 h in air. Phase composition, microstructural, morphological and optical properties of thin films were comprehensively investigated by using XRF, advanced XRD analysis, Raman and UV-vis spectroscopy and AFM. It was found out that the thickness of thin films increases linearly with increasing number of deposited layers, indicating a good adhesion of the titania solution to a glass substrate as well as to a previously calcined layer. 1 layer film crystallized to anatase-TiO₂(B) mixture with minor/negligible amount of nanosized brookite, 2-4 layers films crystallized to anatase-brookite-TiO₂(B) mixture. In contrast to other multilayers films, 4 layers film was highly inhomogeneous. The different phase composition of thin films was clarified based on the crystallization via titanate/s and metastable monoclinic TiO₂(B) as a consequence of several phenomena; the diffusion of Na⁺ ions from a soda-lime glass substrate, acidic conditions and repeated thermal treatment. The multilayer films were in average highly transparent (80-95%) in the visible light region with the sharp absorption edge in the UV light region. Additionally, the photocatalytic properties of selected multilayer films were compared in AO7 photodegradation. Photocatalytic experiments showed that thicker 4 layers film of tricrystalline anatase-brookite-TiO₂(B) phase mixture was similarly active as thinner 3 layers film of similar phase composition, which may be a consequence of the inhomogeneity of the thicker film. PMID:27398480

  6. Microstructure, Optical and Photocatalytic Properties of TiO₂ Thin Films Prepared by Chelating-Agent Assisted Sol-Gel Method.

    PubMed

    Matĕjová, Lenka; Cieslarová, Monika; Matĕj, Zdenĕk; Danis, Stanislav; Peikertová, Pavlína; Sihor, Marcel; Lang, Jaroslav; Matĕjka, Vlastimil

    2016-01-01

    Single and multilayer TiO₂ thin films coated on two types of soda-lime glass substrates (microscope slides and cylinders) were prepared by a chelating agent-assisted sol-gel method, using ethyl acetoacetate as a chelating agent, dip-coating and calcination at 500 °C for 2 h in air. Phase composition, microstructural, morphological and optical properties of thin films were comprehensively investigated by using XRF, advanced XRD analysis, Raman and UV-vis spectroscopy and AFM. It was found out that the thickness of thin films increases linearly with increasing number of deposited layers, indicating a good adhesion of the titania solution to a glass substrate as well as to a previously calcined layer. 1 layer film crystallized to anatase-TiO₂(B) mixture with minor/negligible amount of nanosized brookite, 2-4 layers films crystallized to anatase-brookite-TiO₂(B) mixture. In contrast to other multilayers films, 4 layers film was highly inhomogeneous. The different phase composition of thin films was clarified based on the crystallization via titanate/s and metastable monoclinic TiO₂(B) as a consequence of several phenomena; the diffusion of Na⁺ ions from a soda-lime glass substrate, acidic conditions and repeated thermal treatment. The multilayer films were in average highly transparent (80-95%) in the visible light region with the sharp absorption edge in the UV light region. Additionally, the photocatalytic properties of selected multilayer films were compared in AO7 photodegradation. Photocatalytic experiments showed that thicker 4 layers film of tricrystalline anatase-brookite-TiO₂(B) phase mixture was similarly active as thinner 3 layers film of similar phase composition, which may be a consequence of the inhomogeneity of the thicker film.

  7. p-carboxyethyl-phenylglyoxal bis(n-methylthiosemicarbazone) (CE-DTS), a bifunctional chelating agent for Tc-99m labeled monoclonal antibody

    SciTech Connect

    Arano, Y.; Yokoyama, A.; Furukawa, T.; Saji, H.; Endo, K.; Torizaka, K.

    1985-05-01

    In the search for bifunctional chelating agents (BCA) with better affinity, selectivity and stability as for Tc-99m, synthesis of a novel BCA containing di-thio-semicarbazone as for Tc-99m chelating site has offered interesting characteristics for the labeling of macromolecules. In the present paper, monoclonal IgG (MoAb) against human thyroglobulin was selected as a model and conditions for coupling, labeling reactions were tested along with immunological reactivity. CE-DTS was coupled to MoAb by the azido method and effect of conjugation on the MoAb immunoreactivity was followed by RIA. When CE-DTS was coupled to MoAb at the molar ratio of 1:1, no loss of its original immunoreactivity was observed. Tc-99m labeling, using the stannous ion reducing method, indicated the reaction pH as being a determinant parameter. The reducing agent prepared in tartrate buffer (pH 3) offered high yield and stable Tc-99m-CE-DTS-MoAb, as evidence by HPLC. In vivo studies in mice indicated percent of injected dose and blood clearance alike the I-131-MoAb. This good labeled state of Tc-99m-CE-DTS-MoAb was also demonstrated by using second antibody reaction in serum of mice. The newly synthesized CE-DTS offered good basis for the Tc-99m labeling of monclonal antibodies with preserved immunological properties, as desirable for the radioimmunodetection. Work with tumor related monoclonal antibodies is under progress.

  8. Evaluation of a new tablet formulation of deferasirox to reduce chronic iron overload after long-term blood transfusions

    PubMed Central

    Chalmers, Anna W; Shammo, Jamile M

    2016-01-01

    Transfusion-dependent anemia is a common feature in a wide array of hematological disorders, including thalassemia, sickle cell disease, aplastic anemia, myelofibrosis, and myelo-dysplastic syndromes. In the absence of a physiological mechanism to excrete excess iron, chronic transfusions ultimately cause iron overload. Without correction, iron overload can lead to end-organ damage, resulting in cardiac, hepatic, and endocrine dysfunction/failure. Iron chelating agents are utilized to reduce iron overload, as they form a complex with iron, leading to its clearance. Iron chelation has been proven to decrease organ dysfunction and improve survival in certain transfusion-dependent anemias, such as β-thalassemia. Several chelating agents have been approved by the United States Food and Drug Administration for the treatment of iron overload, including deferoxamine, deferiprone, and deferasirox. A variety of factors have to be considered when choosing an iron chelator, including dosing schedule, route of administration, tolerability, and side effect profile. Deferasirox is an orally administered iron chelator with proven efficacy and safety in multiple hematological disorders. There are two formulations of deferasirox, a tablet for suspension, and a new tablet form. This paper is intended to provide an overview of iron overload, with a focus on deferasirox, and its recently approved formulation Jadenu® for the reduction of transfusional iron overload in hematological disorders. PMID:26929633

  9. Iron-binding compounds impair Pseudomonas aeruginosa biofilm formation, especially under anaerobic conditions.

    PubMed

    O'May, Che Y; Sanderson, Kevin; Roddam, Louise F; Kirov, Sylvia M; Reid, David W

    2009-06-01

    The success of Pseudomonas aeruginosa in cystic fibrosis (CF) and other chronic infections is largely attributed to its ability to grow in antibiotic-resistant biofilm communities. This study investigated the effects of limiting iron levels as a strategy for preventing/disrupting P. aeruginosa biofilms. A range of synthetic and naturally occurring iron-chelating agents were examined. Biofilm development by P. aeruginosa strain PAO1 and CF sputum isolates from chronically infected individuals was significantly decreased by iron removal under aerobic atmospheres. CF strains formed poor biofilms under anaerobic conditions. Strain PAO1 was also tested under anaerobic conditions. Biofilm formation by this model strain was almost totally prevented by several of the chelators tested. The ability of synthetic chelators to impair biofilm formation could be reversed by iron addition to cultures, providing evidence that these effective chelating compounds functioned by directly reducing availability of iron to P. aeruginosa. In contrast, the biological chelator lactoferrin demonstrated enhanced anti-biofilm effects as iron supplementation increased. Hence biofilm inhibition by lactoferrin appeared to occur through more complex mechanisms to those of the synthetic chelators. Overall, our results demonstrate the importance of iron availability to biofilms and that iron chelators have potential as adjunct therapies for preventing biofilm development, especially under low oxygen conditions such as encountered in the chronically infected CF lung. PMID:19429753

  10. Biomimetic Actinide Chelators: An Update on the Preclinical Development of the Orally Active Hydroxypyridonate Decorporation Agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO)

    SciTech Connect

    Durbin, Patricia W.; Kullgren, Birgitta; Ebbe, Shirley N.; Xu, Jide; Chang, Polly Y.; Bunin, Deborah I.; Blakely, Eleanor A.; Bjornstad, Kathleen A.; Rosen, Chris J.; Shuh, David K.; Raymond, Kenneth N.

    2011-07-13

    The threat of a dirty bomb or other major radiological contamination presents a danger of large-scale radiation exposure of the population. Because major components of such contamination are likely to be actinides, actinide decorporation treatments that will reduce radiation exposure must be a priority. Current therapies for the treatment of radionuclide contamination are limited and extensive efforts must be dedicated to the development of therapeutic, orally bioavailable, actinide chelators for emergency medical use. Using a biomimetic approach based on the similar biochemical properties of plutonium(IV) and iron(III), siderophore-inspired multidentate hydroxypyridonate ligands have been designed and are unrivaled in terms of actinide-affinity, selectivity, and efficiency. A perspective on the preclinical development of two hydroxypyridonate actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), is presented. The chemical syntheses of both candidate compounds have been optimized for scale-up. Baseline preparation and analytical methods suitable for manufacturing large amounts have been established. Both ligands show much higher actinide-removal efficacy than the currently approved agent, diethylenetriaminepentaacetic acid (DTPA), with different selectivity for the tested isotopes of plutonium, americium, uranium and neptunium. No toxicity is observed in cells derived from three different human tissue sources treated in vitro up to ligand concentrations of 1 mM, and both ligands were well tolerated in rats when orally administered daily at high doses (>100 micromol kg d) over 28 d under good laboratory practice guidelines. Both compounds are on an accelerated development pathway towards clinical use.

  11. Biomimetic actinide chelators: an update on the preclinical development of the orally active hydroxypyridonate decorporation agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO).

    PubMed

    Abergel, Rebecca J; Durbin, Patricia W; Kullgren, Birgitta; Ebbe, Shirley N; Xu, Jide; Chang, Polly Y; Bunin, Deborah I; Blakely, Eleanor A; Bjornstad, Kathleen A; Rosen, Chris J; Shuh, David K; Raymond, Kenneth N

    2010-09-01

    The threat of a dirty bomb or other major radiological contamination presents a danger of large-scale radiation exposure of the population. Because major components of such contamination are likely to be actinides, actinide decorporation treatments that will reduce radiation exposure must be a priority. Current therapies for the treatment of radionuclide contamination are limited and extensive efforts must be dedicated to the development of therapeutic, orally bioavailable, actinide chelators for emergency medical use. Using a biomimetic approach based on the similar biochemical properties of plutonium(IV) and iron(III), siderophore-inspired multidentate hydroxypyridonate ligands have been designed and are unrivaled in terms of actinide-affinity, selectivity, and efficiency. A perspective on the preclinical development of two hydroxypyridonate actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), is presented. The chemical syntheses of both candidate compounds have been optimized for scale-up. Baseline preparation and analytical methods suitable for manufacturing large amounts have been established. Both ligands show much higher actinide-removal efficacy than the currently approved agent, diethylenetriaminepentaacetic acid (DTPA), with different selectivity for the tested isotopes of plutonium, americium, uranium and neptunium. No toxicity is observed in cells derived from three different human tissue sources treated in vitro up to ligand concentrations of 1 mM, and both ligands were well tolerated in rats when orally administered daily at high doses (>100 micromol kg d) over 28 d under good laboratory practice guidelines. Both compounds are on an accelerated development pathway towards clinical use.

  12. Biomimetic actinide chelators: an update on the preclinical development of the orally active hydroxypyridonate decorporation agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO).

    PubMed

    Abergel, Rebecca J; Durbin, Patricia W; Kullgren, Birgitta; Ebbe, Shirley N; Xu, Jide; Chang, Polly Y; Bunin, Deborah I; Blakely, Eleanor A; Bjornstad, Kathleen A; Rosen, Chris J; Shuh, David K; Raymond, Kenneth N

    2010-09-01

    The threat of a dirty bomb or other major radiological contamination presents a danger of large-scale radiation exposure of the population. Because major components of such contamination are likely to be actinides, actinide decorporation treatments that will reduce radiation exposure must be a priority. Current therapies for the treatment of radionuclide contamination are limited and extensive efforts must be dedicated to the development of therapeutic, orally bioavailable, actinide chelators for emergency medical use. Using a biomimetic approach based on the similar biochemical properties of plutonium(IV) and iron(III), siderophore-inspired multidentate hydroxypyridonate ligands have been designed and are unrivaled in terms of actinide-affinity, selectivity, and efficiency. A perspective on the preclinical development of two hydroxypyridonate actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), is presented. The chemical syntheses of both candidate compounds have been optimized for scale-up. Baseline preparation and analytical methods suitable for manufacturing large amounts have been established. Both ligands show much higher actinide-removal efficacy than the currently approved agent, diethylenetriaminepentaacetic acid (DTPA), with different selectivity for the tested isotopes of plutonium, americium, uranium and neptunium. No toxicity is observed in cells derived from three different human tissue sources treated in vitro up to ligand concentrations of 1 mM, and both ligands were well tolerated in rats when orally administered daily at high doses (>100 micromol kg d) over 28 d under good laboratory practice guidelines. Both compounds are on an accelerated development pathway towards clinical use. PMID:20699704

  13. Biomimetic Actinide Chelators: An Update on the Preclinical Development of the Orally Active Hydroxypyridonate Decorporation Agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO)

    PubMed Central

    Abergel, Rebecca J.; Durbin, Patricia W.; Kullgren, Birgitta; Ebbe, Shirley N.; Xu, Jide; Chang, Polly Y.; Bunin, Deborah I.; Blakely, Eleanor A.; Bjornstad, Kathleen A.; Rosen, Chris J.; Shuh, David K.; Raymond, Kenneth N.

    2010-01-01

    The threat of a dirty bomb or other major radiological contamination presents a danger of large-scale radiation exposure of the population. Because major components of such contamination are likely to be actinides, actinide decorporation treatments that will reduce radiation exposure must be a priority. Current therapies for the treatment of radionuclide contamination are limited and extensive efforts must be dedicated to the development of therapeutic, orally bioavailable, actinide chelators for emergency medical use. Using a biomimetic approach based on the similar biochemical properties of plutonium(IV) and iron(III), siderophore-inspired multidentate hydroxypyridonate ligands have been designed and are unrivaled in terms of actinide-affinity, selectivity and efficiency. A perspective on the preclinical development of two hydroxypyridonate actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), is presented. The chemical syntheses of both candidate compounds have been optimized for scale-up. Baseline preparation and analytical methods suitable for manufacturing large amounts have been established. Both ligands show much higher actinide-removal efficacy than the currently approved agent, diethylenetriaminepentaacetic acid (DTPA), with different selectivity for the tested isotopes of plutonium, americium, uranium and neptunium. No toxicity is observed in cells derived from three different human tissue sources treated in vitro up to ligand concentrations of 1 mM, and both ligands were well tolerated in rats when orally administered daily at high doses (> 100 μmol kg−1 day−1) over 28 days under good laboratory practice (GLP) guidelines. Both compounds are on an accelerated development pathway towards clinical use. PMID:20699704

  14. Effective combination therapy of deferiprone and deferoxamine for the rapid clearance of excess cardiac IRON and the prevention of heart disease in thalassemia. The Protocol of the International Committee on Oral Chelators.

    PubMed

    Kolnagou, Annita; Kontoghiorghes, George J

    2006-01-01

    The International Committee on Oral Chelators (ICOC) combination therapy protocol involving the administration of deferiprone (L1) during the day (80-110 mg/kg/day) and deferoxamine (DFO) (40-60 mg/kg at least 3 days/week) during the night for 8-12 hours using a pump, or the whole 24 hours using an elastomeric pump infuser, has been tested in 11 thalassemia patients (seven males, four females) over a period of 9-28 months. The patients had variable serum ferritin levels (0.54-4.6 mg/L) and cardiac iron load ranging from normal to severe siderosis levels (MRI T2*: 4.7-45 ms). There was a substantial overall reduction in serum ferritin levels (0.17-2.16 mg/L) and normalization of cardiac iron (MRI T2* >20 ms) in all patients. In two patients with severe and moderate cardiac iron load range levels, cardiac iron normalization was achieved within 9-10 months. Two patients on L1 monotherapy (80-120 mg/kg/day) maintained normal range MRI T2* cardiac iron levels over the same period. The ICOC combination therapy protocol appears to be the most effective and least cumbersome form of chelation treatment for the rapid clearance of excess iron from the heart. PMID:16798649

  15. Shape control of the magnetic iron oxide nanoparticles under different chain length of reducing agents

    SciTech Connect

    Ngoi, Kuan Hoon; Chia, Chin-Hua Zakaria, Sarani; Chiu, Wee Siong

    2015-09-25

    We report on the effect of using reducing agents with different chain-length on the synthesis of iron oxide nanoparticles by thermal decomposition of iron (III) acetylacetonate in 1-octadecene. This modification allows us to control the shape of nanoparticles into spherical and cubic iron oxide nanoparticles. The highly monodisperse 14 nm spherical nanoparticles are obtained under 1,2-dodecanediol and average 14 nm edge-length cubic iron oxide nanoparticles are obtained under 1,2-tetradecanediol. The structural characterization such as transmission electron microscope (TEM) and X-ray diffraction (XRD) shows similar properties between two particles with different shapes. The vibrating sample magnetometer (VSM) shows no significant difference between spherical and cubic nanoparticles, which are 36 emu/g and 37 emu/g respectively and superparamagnetic in nature.

  16. Synthesis of 4-substituted-trans-1,2-diaminocyclohexyl polyaminocarboxylate metal chelating agents for the preparation of stable radiometal antibody immunoconjugates for therapy and SPECT and PET imaging

    DOEpatents

    Mease, R.C.; Kolsky, K.L.; Mausner, L.F.; Srivastava, S.C.

    1997-06-03

    Cyclohexyl chelating agents useful in forming antibody-metal conjugates which are used for diagnostic and therapeutic purposes are synthesized. New compounds and processes of forming these compounds are disclosed including 4-haloacetamido-trans-1,2-diaminocyclohexyl polyaminocarboxylate and 4-isothiocyanato-trans-1,2-diamino cyclohexane-N,N,N{prime},N{prime}-tetra acetic acid.

  17. Synthesis of 4-substituted-trans-1,2-diaminocyclohexyl polyaminocarboxylate metal chelating agents for the preparation of stable radiometal antibody immunoconjugates for therapy and spect and pet imaging

    DOEpatents

    Mease, Ronnie C.; Kolsky, Kathryn L.; Mausner, Leonard F.; Srivastava, Suresh C.

    1997-06-03

    Cyclohexyl chelating agents useful in forming antibody-metal conjugates useful for diagnostic and therapeutic purposes. New compounds and processes of forming these compounds are disclosed including 4-haloacetamido-trans-1,2-diaminocyclohexyl polyaminocarboxylate and 4-isothiocyanato-trans-1,2-diamino cyclohexane-N, N, N', N'-tetra acetic acid.

  18. Chemistry of bifunctional photoprobes. 3 -- Correlation between the efficiency of CH insertion by photolabile chelating agents and lifetimes of singlet nitrenes by flash photolysis: First example of photochemical attachment of {sup 99m}Tc-complex with human serum albumin

    SciTech Connect

    Pandurangi, R.S.; Lusiak, P.; Kuntz, R.R.; Volkert, W.A.; Rogowski, J.; Platz, M.S.

    1998-11-27

    Systematic functionalization of perfluoroaryl azides with chelating agents capable of complexing transition metals produces a new class of bifunctional photolabile chelating agents (BFPCAs). The strategy is shield the azide functionality from the electronic and steric influence of the electron-rich metal Pd through ester and amide bridges raised CH insertion efficiency to unprecedented levels (>92%) in a model solvent (cyclohexane). In contrast, perfluoroaryl azides attached to chelating agents via hydrazones show no significant CH insertion in cyclohexane upon photolysis. Measurements of the lifetimes of the singlet nitrenes derived from these agents by flash photolysis techniques correlate well with the efficiency of CH insertion by demonstrating longer lifetimes (10--50 times) for singlet nitrenes derived from azidotetrafluorinated esters and amides compared with the related hydrazones, which failed to yield significant CH insertion. A representative BFPCA 12 is chelated to diagnostic radionuclide {sup 99m}Tc and covalently attached to human serum albumin via photochemical activation extending the favorable bimolecular insertion characteristics of BFPCA to tracer level concentrations in buffer conditions. Flash photolysis experiments correlate singlet nitrene lifetimes with the efficiency of intermolecular insertion reactions. This work provides new photo-cross-linking technology, useful in radiodiagnostics and radiotherapy in nuclear medicine.

  19. In Vitro Metabolism and Stability of the Actinide Chelating Agent 3,4,3-LI(1,2-HOPO)

    DOE PAGESBeta

    Choi, Taylor A.; Furimsky, Anna M.; Swezey, Robert; Bunin, Deborah I.; Byrge, Patricia; Iyer, Lalitha V.; Chang, Polly Y.; Abergel, Rebecca J.

    2015-02-27

    We report that the hydroxypyridinonate ligand 3,4,3-LI(1,2-HOPO) is currently under development for radionuclide chelation therapy. The preclinical characterization of this highly promising ligand comprised the evaluation of its in vitro properties, including microsomal, plasma, and gastrointestinal fluid stability, cytochrome P450 inhibition, plasma protein binding, and intestinal absorption using the Caco-2 cell line. When mixed with active human liver microsomes, no loss of parent compound was observed after 60 minutes, indicating compound stability in the presence of liver microsomal P450. At the tested concentrations, 3,4,3-LI(1,2-HOPO) did not significantly influence the activities of any of the cytochromal isoforms screened. Thus, 3,4,3-LI(1,2-HOPO) ismore » unlikely to cause drug-drug interactions by inhibiting the metabolic clearance of co-administered drugs metabolized by these enzymes. Plasma protein binding assays revealed that the compound is protein-bound in dogs and less extensively in rats and humans. In the plasma stability study, the compound was stable after 1 h at 37°C in mouse, rat, dog, and human plasma samples. Finally, a bi-directional permeability assay demonstrated that 3,4,3-LI(1,2-HOPO) is not permeable across the Caco-2 monolayer, highlighting the need to further evaluate the effects of various compounds with known permeability enhancement properties on the permeability of the ligand in future studies.« less

  20. Chelating agent-free, vapor-assisted crystallization method to synthesize hierarchical microporous/mesoporous MIL-125 (Ti).

    PubMed

    McNamara, Nicholas D; Hicks, Jason C

    2015-03-11

    Titanium-based microporous heterogeneous catalysts are widely studied but are often limited by the accessibility of reactants to active sites. Metal-organic frameworks (MOFs), such as MIL-125 (Ti), exhibit enhanced surface areas due to their high intrinsic microporosity, but the pore diameters of most microporous MOFs are often too small to allow for the diffusion of larger reactants (>7 Å) relevant to petroleum and biomass upgrading. In this work, hierarchical microporous MIL-125 exhibiting significantly enhanced interparticle mesoporosity was synthesized using a chelating-free, vapor-assisted crystallization method. The resulting hierarchical MOF was examined as an active catalyst for the oxidation of dibenzothiophene (DBT) with tert-butyl hydroperoxide and outperformed the solely microporous analogue. This was attributed to greater access of the substrate to surface active sites, as the pores in the microporous analogues were of inadequate size to accommodate DBT. Moreover, thiophene adsorption studies suggested the mesoporous MOF contained larger amounts of unsaturated metal sites that could enhance the observed catalytic activity. PMID:25695286

  1. In vitro metabolism and stability of the actinide chelating agent 3,4,3-LI(1,2-HOPO).

    PubMed

    Choi, Taylor A; Furimsky, Anna M; Swezey, Robert; Bunin, Deborah I; Byrge, Patricia; Iyer, Lalitha V; Chang, Polly Y; Abergel, Rebecca J

    2015-05-01

    The hydroxypyridinonate ligand 3,4,3-LI(1,2-HOPO) is currently under development for radionuclide chelation therapy. The preclinical characterization of this highly promising ligand comprised the evaluation of its in vitro properties, including microsomal, plasma, and gastrointestinal fluid stability, cytochrome P450 inhibition, plasma protein binding, and intestinal absorption using the Caco-2 cell line. When mixed with active human liver microsomes, no loss of parent compound was observed after 60 min, indicating compound stability in the presence of liver microsomal P450. At the tested concentrations, 3,4,3-LI(1,2-HOPO) did not significantly influence the activities of any of the cytochromal isoforms screened. Thus, 3,4,3-LI(1,2-HOPO) is unlikely to cause drug-drug interactions by inhibiting the metabolic clearance of coadministered drugs metabolized by these enzymes. Plasma protein-binding assays revealed that the compound is protein-bound in dogs and less extensively in rats and humans. In the plasma stability study, the compound was stable after 1 h at 37°C in mouse, rat, dog, and human plasma samples. Finally, a bidirectional permeability assay demonstrated that 3,4,3-LI(1,2-HOPO) is not permeable across the Caco-2 monolayer, highlighting the need to further evaluate the effects of various compounds with known permeability enhancement properties on the permeability of the ligand in future studies.

  2. In Vitro Metabolism and Stability of the Actinide Chelating Agent 3,4,3-LI(1,2-HOPO)

    PubMed Central

    Choi, Taylor A.; Furimsky, Anna M.; Swezey, Robert; Bunin, Deborah I.; Byrge, Patricia; Iyer, Lalitha V.; Chang, Polly Y.; Abergel, Rebecca J.

    2015-01-01

    The hydroxypyridinonate ligand 3,4,3-LI(1,2-HOPO) is currently under development for radionuclide chelation therapy. The preclinical characterization of this highly promising ligand comprised the evaluation of its in vitro properties, including microsomal, plasma, and gastrointestinal fluid stability, cytochrome P450 inhibition, plasma protein binding, and intestinal absorption using the Caco-2 cell line. When mixed with active human liver microsomes, no loss of parent compound was observed after 60 minutes, indicating compound stability in the presence of liver microsomal P450. At the tested concentrations, 3,4,3-LI(1,2-HOPO) did not significantly influence the activities of any of the cytochromal isoforms screened. Thus, 3,4,3-LI(1,2-HOPO) is unlikely to cause drug-drug interactions by inhibiting the metabolic clearance of co-administered drugs metabolized by these enzymes. Plasma protein binding assays revealed that the compound is protein-bound in dogs and less extensively in rats and humans. In the plasma stability study, the compound was stable after 1 h at 37°C in mouse, rat, dog, and human plasma samples. Finally, a bi-directional permeability assay demonstrated that 3,4,3-LI(1,2-HOPO) is not permeable across the Caco-2 monolayer, highlighting the need to further evaluate the effects of various compounds with known permeability enhancement properties on the permeability of the ligand in future studies. PMID:25727482

  3. In Vitro Metabolism and Stability of the Actinide Chelating Agent 3,4,3-LI(1,2-HOPO)

    SciTech Connect

    Choi, Taylor A.; Furimsky, Anna M.; Swezey, Robert; Bunin, Deborah I.; Byrge, Patricia; Iyer, Lalitha V.; Chang, Polly Y.; Abergel, Rebecca J.

    2015-02-27

    We report that the hydroxypyridinonate ligand 3,4,3-LI(1,2-HOPO) is currently under development for radionuclide chelation therapy. The preclinical characterization of this highly promising ligand comprised the evaluation of its in vitro properties, including microsomal, plasma, and gastrointestinal fluid stability, cytochrome P450 inhibition, plasma protein binding, and intestinal absorption using the Caco-2 cell line. When mixed with active human liver microsomes, no loss of parent compound was observed after 60 minutes, indicating compound stability in the presence of liver microsomal P450. At the tested concentrations, 3,4,3-LI(1,2-HOPO) did not significantly influence the activities of any of the cytochromal isoforms screened. Thus, 3,4,3-LI(1,2-HOPO) is unlikely to cause drug-drug interactions by inhibiting the metabolic clearance of co-administered drugs metabolized by these enzymes. Plasma protein binding assays revealed that the compound is protein-bound in dogs and less extensively in rats and humans. In the plasma stability study, the compound was stable after 1 h at 37°C in mouse, rat, dog, and human plasma samples. Finally, a bi-directional permeability assay demonstrated that 3,4,3-LI(1,2-HOPO) is not permeable across the Caco-2 monolayer, highlighting the need to further evaluate the effects of various compounds with known permeability enhancement properties on the permeability of the ligand in future studies.

  4. Electrochemical regeneration of iron-chelates for combined NO{sub x} and SO{sub 2} removal from combustion flue gas

    SciTech Connect

    Tseng, S.; Babu, M.; Niksa, M.; Coin, R.

    1996-12-31

    To control SO{sub 2} emissions utility stations can choose to switch to fuels containing lesser sulfur or they can build wet or dry scrubbers. The control of the NO{sub x} emissions is more complicated. Available technologies to reduce the NO{sub x} emissions include selective catalytic reduction (SCR), selective non-catalytic reduction (SNCR) and combustion modifications such as the installation of low NO{sub x} burners and utilization of gas reburn techniques. The ThioNO{sub x}{reg_sign} process under development by Dravo Lime Company (DLC) is an emerging post-combustion flue gas clean-up technology. It can simultaneously remove NO{sub x} and SO{sub 2} from boilers burning high-sulfur coals. In this process, SO{sub 2} is removed by scrubbing the flue gas with slaked Thiosorbic{reg_sign} lime (a magnesium-enhanced lime) slurry. The removal of NO{sub x} is achieved by adding to the scrubbing liquor iron-EDTA, a metal chelate, which binds and removes NO from the flue gas. The ThioNO{sub x} process is an attractive option for utility stations already equipped with wet scrubbers to reduce the emissions of SO{sub 2}.

  5. Chelating bis-N-heterocyclic carbene complexes of iron(ii) containing bipyridyl ligands as catalyst precursors for oxidation of alcohols.

    PubMed

    Pinto, Mara F; Cardoso, Bernardo de P; Barroso, Sónia; Martins, Ana M; Royo, Beatriz

    2016-09-14

    Chelating bis-N-heterocyclic carbene (bis-NHC) complexes of iron(ii) containing pyridyl ligands have been prepared by the reaction of [FeCl2L] [L = bipy (1), phen (2)] with [LiN(SiMe3)2] and a bis(imidazolium) salt. The [Fe(bis-NHC)L(I)2] complexes were active pre-catalysts in the oxidation of 1-phenylethanol with tert-butyl hydroperoxide in neat conditions, affording a quantitative yield of acetophenone in 4.5 h. The catalyst could be reused up to six cycles giving a turnover number (TON) of 1500. Various secondary alcohols, both aromatic and aliphatic were selectivity oxidised to the corresponding ketones in excellent yields. Compound 1 is stable in acetonitrile solution for ca. 4 h, although after 16 h, it evolves to a mixture of [Fe(bis-NHC)(bipy)2]I2 (3), [Fe(bipy)3](2+) and bis-imidazolium salt. The molecular structure of 3 has been determined by X-ray diffraction studies. PMID:27506414

  6. Iron oxide decorated MoS2 nanosheets with double PEGylation for chelator-free radiolabeling and multimodal imaging guided photothermal therapy.

    PubMed

    Liu, Teng; Shi, Sixiang; Liang, Chao; Shen, Sida; Cheng, Liang; Wang, Chao; Song, Xuejiao; Goel, Shreya; Barnhart, Todd E; Cai, Weibo; Liu, Zhuang

    2015-01-27

    Theranostics for in vivo cancer diagnosis and treatment generally requires well-designed nanoscale platforms with multiple integrated functionalities. In this study, we uncover that functionalized iron oxide nanoparticles (IONPs) could be self-assembled on the surface of two-dimensional MoS2 nanosheets via sulfur chemistry, forming MoS2-IO nanocomposites, which are then modified with two types of polyethylene glycol (PEG) to acquire enhanced stability in physiological environments. Interestingly, (64)Cu, a commonly used positron-emitting radioisotope, could be firmly adsorbed on the surface of MoS2 without the need of chelating molecules, to enable in vivo positron emission tomography (PET) imaging. On the other hand, the strong near-infrared (NIR) and superparamagnetism of MoS2-IO-PEG could also be utilized for photoacoustic tomography (PAT) and magnetic resonance (MR) imaging, respectively. Under the guidance by such triple-modal imaging, which uncovers efficient tumor retention of MoS2-IO-(d)PEG upon intravenous injection, in vivo photothermal therapy is finally conducted, achieving effective tumor ablation in an animal tumor model. Our study highlights the promise of constructing multifunctional theranostic nanocomposites based on 2D transitional metal dichalcogenides for multimodal imaging-guided cancer therapy.

  7. Iron Oxide Decorated MoS2 Nanosheets with Double PEGylation for Chelator-Free Radiolabeling and Multimodal Imaging Guided Photothermal Therapy

    PubMed Central

    Liu, Teng; Shi, Sixiang; Liang, Chao; Shen, Sida; Cheng, Liang; Wang, Chao; Song, Xuejiao; Goel, Shreya; Barnhart, Todd E.; Cai, Weibo; Liu, Zhuang

    2015-01-01

    Theranostics for in vivo cancer diagnosis and treatment generally requires well-designed nanoscale platforms with multiple integrated functionalities. In this study, we uncover that functionalized iron oxide nanoparticles (IONPs) could be self-assembled on the surface of two-dimensional MoS2 nanosheets via sulfur chemistry, forming MoS2-IO nanocomposites, which are then modified with two types of polyethylene glycol (PEG) to acquire enhanced stability in physiological environments. Interestingly, 64Cu, a commonly used positron-emitting radioisotope, could be firmly adsorbed on the surface of MoS2 without the need of chelating molecules, to enable in vivo positron emission tomography (PET) imaging. On the other hand, the strong near-infrared (NIR) and superparamagnetism of MoS2-IO-PEG could also be utilized for photoacoustic tomography (PAT) and magnetic resonance (MR) imaging, respectively. Under the guidance by such triple-modal imaging, which uncovers efficient tumor retention of MoS2-IO-(d)PEG upon intravenous injection, in vivo photothermal therapy is finally conducted, achieving effective tumor ablation in an animal tumor model. Our study highlights the promise of constructing multifunctional theranostic nanocomposites based on 2D transitional metal dichalcogenides for multimodal imaging-guided cancer therapy. PMID:25562533

  8. Lauriston S. Taylor Lecture: the quest for therapeutic actinide chelators.

    PubMed

    Durbin, Patricia W

    2008-11-01

    All of the actinides are radioactive. Taken into the body, they damage and induce cancer in bone and liver, and in the lungs if inhaled, and U(VI) is a chemical kidney poison. Containment of radionuclides is fundamental to radiation protection, but if it is breached accidentally or deliberately, decontamination of exposed persons is needed to reduce the consequences of radionuclide intake. The only known way to reduce the health risks of internally deposited actinides is to accelerate their excretion with chelating agents. Ethylendiaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were introduced in the 1950's. DTPA is now clinically accepted, but its oral activity is low, it must be injected as a Ca(II) or Zn(II) chelate to avoid toxicity, and it is structurally unsuitable for chelating U(VI) or Np(V). Actinide penetration into the mammalian iron transport and storage systems suggested that actinide ions would form stable complexes with the Fe(III)-binding units found in potent selective natural iron chelators (siderophores). Testing of that biomimetic approach began in the late 1970's with the design, production, and assessment for in vivo Pu(IV) chelation of synthetic multidentate ligands based on the backbone structures and Fe(III)-binding groups of siderophores. New efficacious actinide chelators have emerged from that program, in particular, octadentate 3,4,3-LI(1,2-HOPO) and tetradentate 5-LIO(Me-3,2-HOPO) have potential for clinical acceptance. Both are much more effective than CaNa3-DTPA for decorporation of Pu(IV), Am(III), U(VI), and Np(IV,V), they are orally active, and toxicity is acceptably low at effective dosage.

  9. Uses and limitations of serum ferritin, magnetic resonance imaging T2 and T2* in the diagnosis of iron overload and in the ferrikinetics of normalization of the iron stores in thalassemia using the International Committee on Chelation deferiprone/deferoxamine combination protocol.

    PubMed

    Kolnagou, Anita; Yazman, Dilek; Economides, Charalambos; Eracleous, Eleni; Kontoghiorghes, George J

    2009-01-01

    Excess cardiac iron deposition leads to congestive cardiac failure and accounts for more than 70% of deaths in thalassemia major patients. In three separate studies involving 145 thalassemia patients, serum ferritin and magnetic resonance imaging (MRI) relaxation times T2 and T2* have been compared for assessing iron load levels during chelation treatment. In two studies, variable levels of cardiac iron load have been detected by T2 and T2* in patients treated with deferoxamine (DFO), which, however, were unrelated to serum ferritin. In most cases, similar range levels from normal to severe cardiac iron load could be identified by both the T2 and T2* methods. However, in a few cases there were substantial differences in the levels detected between the two methods. In the third study, the ferrikinetics of the normalization of the iron stores during the International Committee on Chelation (ICOC) deferiprone (L1)/DFO combination protocol was followed up using T2 and T2* and serum ferritin. Iron deposits were found not to be proportionally distributed between the liver and the heart or uniformly distributed within each organ. Iron mobilization in each patient varied and iron deposits in each organ were cleared at different rates. Despite some limitations, the application of the MRI relaxation times T2 and T2* offers the best diagnostic methods for iron overload estimations in most organs and especially the heart. These MRI methods and serum ferritin could also be used for the ferrikinetics of iron mobilization and removal during chelation therapy and the normalization of the iron stores during the ICOC L1/DFO combination protocol. There is a need to standardize the two MRI relaxation times T2 and T2* methods and identify the factors causing the differences between them.

  10. Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD

    PubMed Central

    Jalal, Diana I.; Greco, Barbara A.; Umeukeje, Ebele M.; Reisin, Efrain; Manley, John; Zeig, Steven; Negoi, Dana G.; Hiremath, Anand N.; Blumenthal, Samuel S.; Sika, Mohammed; Niecestro, Robert; Koury, Mark J.; Ma, Khe-Ni; Greene, Tom; Lewis, Julia B.; Dwyer, Jamie P.

    2015-01-01

    Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0–28.9] versus 26.8 [13.4–47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023–9695] versus 6954 [2664–12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders. PMID:25736045

  11. Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD.

    PubMed

    Umanath, Kausik; Jalal, Diana I; Greco, Barbara A; Umeukeje, Ebele M; Reisin, Efrain; Manley, John; Zeig, Steven; Negoi, Dana G; Hiremath, Anand N; Blumenthal, Samuel S; Sika, Mohammed; Niecestro, Robert; Koury, Mark J; Ma, Khe-Ni; Greene, Tom; Lewis, Julia B; Dwyer, Jamie P

    2015-10-01

    Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4-47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders. PMID:25736045

  12. Models of the iron-only hydrogenase: a comparison of chelate and bridge isomers of Fe2(CO)4{Ph2PN(R)PPh2}(μ-pdt) as proton-reduction catalysts.

    PubMed

    Ghosh, Shishir; Hogarth, Graeme; Hollingsworth, Nathan; Holt, Katherine B; Richards, Idris; Richmond, Michael G; Sanchez, Ben E; Unwin, David

    2013-05-21

    Reactions of Fe2(CO)6(μ-pdt) (pdt = SCH2CH2CH2S) with aminodiphosphines Ph2PN(R)PPh2 (R = allyl, (i)Pr, (i)Bu, p-tolyl, H) have been carried out under different conditions. At room temperature in MeCN with added Me3NO·2H2O, dibasal chelate complexes Fe2(CO)4{κ(2)-Ph2PN(R)PPh2}(μ-pdt) are formed, while in refluxing toluene bridge isomers Fe2(CO)4{μ-Ph2PN(R)PPh2}(μ-pdt) are the major products. Separate studies have shown that chelate complexes convert to the bridge isomers at higher temperatures. Two pairs of bridge and chelate isomers (R = allyl, (i)Pr) have been crystallographically characterised together with Fe2(CO)4{μ-Ph2PN(H)PPh2}(μ-pdt). Chelate complexes adopt the dibasal diphosphine arrangement in the solid state and exhibit very small P-Fe-P bite-angles, while the bridge complexes adopt the expected cisoid dibasal geometry. Density functional calculations have been carried out on the chelate and bridge isomers of the model compound Fe2(CO)4{Ph2PN(Me)PPh2}(μ-pdt) and reveal that the bridge isomer is thermodynamically favourable relative to the chelate isomers that are isoenergetic. The HOMO in each of the three isomers exhibits significant metal-metal bonding character, supporting a site-specific protonation of the iron-iron bond upon treatment with acid. Addition of HBF4·Et2O to the Fe2(CO)4{κ(2)-Ph2PN(allyl)PPh2}(μ-pdt) results in the clean formation of the corresponding dibasal hydride complex [Fe2(CO)4{κ(2)-Ph2PN(allyl)PPh2}(μ-H)(μ-pdt)][BF4], with spectroscopic measurements revealing the intermediate formation of a basal-apical isomer. A crystallographic study reveals that there are only very small metric changes upon protonation. In contrast, the bridge isomers react more slowly to form unstable species that cannot be isolated. Electrochemical and electrocatalysis studies have been carried out on the isomers of Fe2(CO)4{Ph2PN(allyl)PPh2}(μ-pdt). Electron accession is predicted to occur at an orbital that is anti-bonding with respect to

  13. Method and apparatus for back-extracting metal chelates

    DOEpatents

    Wai, Chien M.; Smart, Neil G.; Lin, Yuehe

    1998-01-01

    A method of extracting metal and metalloid species from a solid or liquid substrate using a supercritical fluid solvent containing one or more chelating agents followed by back-extracting the metal and metalloid species from the metal and metalloid chelates formed thereby. The back-extraction acidic solution is performed utilizing an acidic solution. Upon sufficient exposure of the metal and metalloid chelates to the acidic solution, the metal and metalloid species are released from the chelates into the acid solution, while the chelating agent remains in the supercritical fluid solvent. The chelating agent is thereby regenerated and the metal and metalloid species recovered.

  14. Method and apparatus for back-extracting metal chelates

    DOEpatents

    Wai, C.M.; Smart, N.G.; Lin, Y.

    1998-08-11

    A method is described for extracting metal and metalloid species from a solid or liquid substrate using a supercritical fluid solvent containing one or more chelating agents followed by back-extracting the metal and metalloid species from the metal and metalloid chelates formed thereby. The back-extraction acidic solution is performed utilizing an acidic solution. Upon sufficient exposure of the metal and metalloid chelates to the acidic solution, the metal and metalloid species are released from the chelates into the acid solution, while the chelating agent remains in the supercritical fluid solvent. The chelating agent is thereby regenerated and the metal and metalloid species recovered. 3 figs.

  15. Silica-coated super paramagnetic iron oxide nanoparticles (SPION) as biocompatible contrast agent in biomedical photoacoustics

    PubMed Central

    Alwi, Rudolf; Telenkov, Sergey; Mandelis, Andreas; Leshuk, Timothy; Gu, Frank; Oladepo, Sulayman; Michaelian, Kirk

    2012-01-01

    In this study, we report for the first time the use of silica-coated superparamagnetic iron oxide nanoparticles (SPION) as contrast agents in biomedical photoacoustic imaging. Using frequency-domain photoacoustic correlation (the photoacoustic radar), we investigated the effects of nanoparticle size, concentration and biological media (e.g. serum, sheep blood) on the photoacoustic response in turbid media. Maximum detection depth and the minimum measurable SPION concentration were determined experimentally. The nanoparticle-induced optical contrast ex vivo in dense muscular tissues (avian pectus and murine quadricept) was evaluated and the strong potential of silica-coated SPION as a possible photoacoustic contrast agents was demonstrated. PMID:23082291

  16. Soil washing of chromium- and cadmium-contaminated sludge using acids and ethylenediaminetetra acetic acid chelating agent.

    PubMed

    Gitipour, Saeid; Ahmadi, Soheil; Madadian, Edris; Ardestani, Mojtaba

    2016-01-01

    In this research, the effect of soil washing in the removal of chromium- and cadmium-contaminated sludge samples collected from Pond 2 of the Tehran Oil Refinery was investigated. These metals are considered as hazardous substances for human health and the environment. The carcinogenicity of chromate dust has been established for a long time. Cadmium is also a potential environmental toxicant. This study was carried out by collecting sludge samples from different locations in Pond 2. Soil washing was conducted to treat the samples. Chemical agents, such as acetic acid, ethylenediaminetetra acetic acid (EDTA) and hydrochloric acid, were used as washing solutions to remove chromium and cadmium from sludge samples. The results of this study indicated that the highest removal efficiencies from the sludge samples were achieved using a 0.3 M HCl solution with 82.69% and 74.47% for chromium and cadmium, respectively. EDTA (0.1 M) in the best condition extracted 66.81% of cadmium and 72.52% of chromium from the sludges. The lowest efficiency values for the samples, however, were achieved using 3 M acetic acid with 41.7% and 46.96% removals for cadmium and chromium, respectively. The analysis of washed sludge indicated that the heavy metals removal decreased in the order of 3 M acetic acid < 0.1 M EDTA<0.3 M HCl, thus hydrochloric acid appears to offer a greater potential as a washing agent in remediating the sludge samples.

  17. Soil washing of chromium- and cadmium-contaminated sludge using acids and ethylenediaminetetra acetic acid chelating agent.

    PubMed

    Gitipour, Saeid; Ahmadi, Soheil; Madadian, Edris; Ardestani, Mojtaba

    2016-01-01

    In this research, the effect of soil washing in the removal of chromium- and cadmium-contaminated sludge samples collected from Pond 2 of the Tehran Oil Refinery was investigated. These metals are considered as hazardous substances for human health and the environment. The carcinogenicity of chromate dust has been established for a long time. Cadmium is also a potential environmental toxicant. This study was carried out by collecting sludge samples from different locations in Pond 2. Soil washing was conducted to treat the samples. Chemical agents, such as acetic acid, ethylenediaminetetra acetic acid (EDTA) and hydrochloric acid, were used as washing solutions to remove chromium and cadmium from sludge samples. The results of this study indicated that the highest removal efficiencies from the sludge samples were achieved using a 0.3 M HCl solution with 82.69% and 74.47% for chromium and cadmium, respectively. EDTA (0.1 M) in the best condition extracted 66.81% of cadmium and 72.52% of chromium from the sludges. The lowest efficiency values for the samples, however, were achieved using 3 M acetic acid with 41.7% and 46.96% removals for cadmium and chromium, respectively. The analysis of washed sludge indicated that the heavy metals removal decreased in the order of 3 M acetic acid < 0.1 M EDTA<0.3 M HCl, thus hydrochloric acid appears to offer a greater potential as a washing agent in remediating the sludge samples. PMID:26599728

  18. Combined effects of treatment with trientine, a copper-chelating agent, and x-irradiation on tumor growth in transplantation model of a murine fibrosarcoma.

    PubMed

    Hayashi, Masanobu; Hirai, Ryou; Ishihara, Yuusuke; Horiguchi, Noboru; Endoh, Daiji; Okui, Toyo

    2007-10-01

    Combined effects of treatment with trientine, a copper-chelating agent, and X-irradiation on development of fibrosarcoma using a murine transplantation model in vivo and on cellular survival in vitro were examined. Copper contents in the tumors and serum of trientine-treated mice were significantly lower than those of untreated mice. The tumor volumes of mouse fibrosarcoma QRsp-11 cells increased more slowly in the trientine-treated and the X-irradiated mice than in the control mice from 10 to 24 days postinoculation. The extent of inhibition of tumor growth by X-irradiation at 3 Gy was similar to that obtained by treatment with trientine. A combination of trientine and X-irradiation at 3 Gy showed inhibitory effects on tumor growth similar to those obtained by X-irradiation at 6 Gy. The results showed that trientine and X-irradiation interacted additively in inhibition of tumor growth. When QRsp-11 cells and mouse and bovine endothelial cells were treated with trientine after X-irradiation, the surviving fractions of the cells with combined treatments were essentially consistent with the products of the surviving fractions of trientine-treated cells and those of X-irradiated cells. When the cells were pretreated with trientine and X-irradiated, the surviving fractions of the pretreated cells were lower than those of cells without treatment.

  19. Inhibitory effects of trientine, a copper-chelating agent, on induction of DNA strand breaks in kidney cells of Long-Evans Cinnamon (LEC) rats.

    PubMed

    Hayashi, Masanobu; Miyane, Kazuhiro; Senou, Misato; Endoh, Daiji; Higuchi, Hidetoshi; Nagahata, Hajime; Nakayama, Kenji; Kon, Yasuhiro; Okui, Toyo

    2005-10-01

    The effects of treatment with trientine, a specific copper-chelating agent, on the accumulation of copper and induction of DNA strand breaks were investigated in Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson's disease. Copper accumulated in the kidneys of LEC rats in an age-dependent manner from 12 to 18 weeks of age. When LEC rats were treated with trientine from 10 weeks of age, renal copper contents did not increase and were maintained at the same levels as those in 4-week-old LEC rats. Estimation of the amounts of DNA single-strand breaks (SSBs) by comet assay showed that SSBs of DNA were induced in a substantial population of LEC rat renal cortex cells around 12 weeks of age and that the amounts of SSBs increased in an age-dependent manner from 12 to 18 weeks of age. When LEC rats were treated with trientine from 10 weeks of age, the observed number of cells with DNA damage decreased, suggesting that induction of SSBs of DNA was inhibited and/or SSBs were repaired during the period of treatment with trientine. The results show that SSBs of DNA in LEC rat kidney cells are induced prior to occurrence of clinical signs of hepatic injury and that treatment of LEC rats with trientine decreases the number of DNA strand breaks.

  20. Inhibitory effects of trientine, a copper-chelating agent, on induction of DNA strand breaks in hepatic cells of Long-Evans Cinnamon rats.

    PubMed

    Hayashi, Masanobu; Miyane, Kazuhiro; Hirooka, Takeshi; Endoh, Daiji; Higuchi, Hidetoshi; Nagahata, Hajime; Nakayama, Kenji; Kon, Yashuhiro; Okui, Toyo

    2004-11-01

    Effects of treatment with trientine, a specific copper-chelating agent, on accumulation of copper and induction of DNA strand breaks were investigated in Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson's disease. Copper accumulated in the livers of LEC rats in an age-dependent manner from 4 to 13 weeks of age. When LEC rats were treated with trientine from 10 weeks of age, hepatic copper contents did not increase and were maintained at the same levels as those in 10-week-old LEC rats. When the amounts of DNA single-strand breaks (SSBs) were estimated by a comet assay, SSBs of DNA were induced in a substantial population of LEC rat hepatic cells around 8 weeks of age and the amounts of SSBs increased in an age-dependent manner from 8 to 15 weeks of age. When LEC rats were treated with trientine from 10 weeks of age, the observed number of cells with DNA damage decreased dramatically, suggesting that induction of SSBs of DNA was inhibited and/or SSBs were repaired during the period of treatment with trientine. The results show that treatment of LEC rats with trientine decreases the number of DNA strand breaks observed, although copper contents remain high in the liver.

  1. Poisoning of a Silica-Supported Cobalt Catalyst due to Presence of Sulfur Impurities in Syngas during Fischer–Tropsch Synthesis: Effects of Chelating Agent

    SciTech Connect

    Bambal, Ashish S.; Guggilla, Vidya S.; Kugler, Edwin L.; Gardner, Todd H.; Dadyburjor, Dady B.

    2014-04-09

    The effects of sulfur impurities on the performance of cobalt-based Fischer–Tropsch catalysts are evaluated under industrially relevant operating conditions of temperature, pressure, and impurity levels. Chelating agents (CAs) were used to modify the SiO2 support, and the performances of the CA-modified catalysts are compared with conventional Co/SiO2 catalysts. For both the Co/SiO2 and CA-modified catalysts, the presence of sulfur in the inlet syngas results in a notable drop in the CO conversion, an undesired shift in the hydrocarbon selectivity toward short-chain hydrocarbons, more olefins in the products, and lower product yields. In the post-poisoning stage, i.e., after termination of sulfur introduction in the inlet syngas, the CA-modified catalysts recover activity and selectivity (to some extent at least), whereas such trends are not observed for the base-case, i.e., unmodified Co/SiO2 catalyst. Finally, the improved performance of the CA-modified catalysts in the presence of sulfur is attributed to higher densities of active sites.

  2. Release of radionuclides and chelating agents from cement-solidified decontamination low-level radioactive waste collected from the Peach Bottom Atomic Power Station Unit 3

    SciTech Connect

    Akers, D.W.; Kraft, N.C.; Mandler, J.W.

    1994-03-01

    As part of a study being performed for the Nuclear Regulatory Commission (NRC), small-scale waste-form specimens were collected during a low oxidation-state transition-metal ion (LOMI)-nitric permanganate (NP)-LOMI solidification performed in October 1989 at the Peach Bottom Atomic Power Station Unit 3. The purpose of this program was to evaluate the performance of cement-solidified decontamination waste to meet the low-level waste stability requirements defined in the NRC`s ``Technical Position on Waste Form,`` Revision 1. The samples were acquired and tested because little data have been obtained on the physical stability of actual cement-solidified decontamination ion-exchange resin waste forms and on the leachability of radionuclides and chelating agents from those waste forms. The Peach Bottom waste-form specimens were subjected to compressive strength, immersion, and leach testing in accordance with the NRC`s ``Technical Position on Waste Form,`` Revision 1. Results of this study indicate that the specimens withstood the compression tests (>500 psi) before and after immersion testing and leaching, and that the leachability indexes for all radionuclides, including {sup 14}C, {sup 99}{Tc}, and {sup 129}I, are well above the leachability index requirement of 6.0, required by the NRC`s ``Technical Position on Waste Form,`` Revision 1.

  3. Compression and immersion tests and leaching of radionuclides, stable metals, and chelating agents from cement-solidified decontamination waste collected from nuclear power stations

    SciTech Connect

    Akers, D.W.; Kraft, N.C.; Mandler, J.W.

    1994-06-01

    A study was performed for the Nuclear Regulatory Commission (NRC) to evaluate structural stability and leachability of radionuclides, stable metals, and chelating agents from cement-solidified decontamination ion-exchange resin wastes collected from seven commercial boiling water reactors and one pressurized water reactor. The decontamination methods used at the reactors were the Can-Decon, AP/Citrox, Dow NS-1, and LOMI processes. Samples of untreated resin waste and solidified waste forms were subjected to immersion and compressive strength testing. Some waste-form samples were leach-tested using simulated groundwaters and simulated seawater for comparison with the deionized water tests that are normally performed to assess waste-form leachability. This report presents the results of these tests and assesses the effects of the various decontamination methods, waste form formulations, leachant chemical compositions, and pH of the leachant on the structural stability and leachability of the waste forms. Results indicate that releases from intact and degraded waste forms are similar and that the behavior of some radionuclides such as {sup 55}Fe, {sup 60}Co, and {sup 99}Tc were similar. In addition, the leachability indexes are greater than 6.0, which meets the requirement in the NRC`s ``Technical Position on Waste Form,`` Revision 1.

  4. Cost utility analysis of reduced intensity hematopoietic stem cell transplantation in adolescence and young adult with severe thalassemia compared to hypertransfusion and iron chelation program

    PubMed Central

    2013-01-01

    Background Hematopoieticic stem cell transplantation is the only therapeutic option that can cure thalassemia disease. Reduced intensity hematopoietic stem cell transplantation (RI-HSCT) has demonstrated a high cure rate with minimal complications compared to other options. Because RI-HSCT is very costly, economic justification for its value is needed. This study aimed to estimate the cost-utility of RI-HSCT compared with blood transfusions combined with iron chelating therapy (BT-ICT) for adolescent and young adult with severe thalassemia in Thailand. Methods A Markov model was used to estimate the relevant costs and health outcomes over the patients’ lifetimes using a societal perspective. All future costs and outcomes were discounted at a rate of 3% per annum. The efficacy of RI-HSCT was based a clinical trial including a total of 18 thalassemia patients. Utility values were derived directly from all patients using EQ-5D and SF-6D. Primary outcomes of interest were lifetime costs, quality adjusted life-years (QALYs) gained, and the incremental cost-effectiveness ratio (ICER) in US ($) per QALY gained. One-way and probabilistic sensitivity analyses (PSA) were conducted to investigate the effect of parameter uncertainty. Results In base case analysis, the RI-HSCT group had a better clinical outcomes and higher lifetime costs. The incremental cost per QALY gained was US $ 3,236 per QALY. The acceptability curve showed that the probability of RI-HSCT being cost-effective was 71% at the willingness to pay of 1 time of Thai Gross domestic product per capita (GDP per capita), approximately US $ 4,210 per QALY gained. The most sensitive parameter was utility of severe thalassemia patients without cardiac complication patients. Conclusion At a societal willingness to pay of 1 GDP per capita, RI-HSCT was a cost-effective treatment for adolescent and young adult with severe thalassemia in Thailand compared to BT-ICT. PMID:23379888

  5. Novel double prodrugs of the iron chelator N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED): Synthesis, characterization, and investigation of activation by chemical hydrolysis and oxidation.

    PubMed

    Thiele, Nikki A; Abboud, Khalil A; Sloan, Kenneth B

    2016-08-01

    The development of iron chelators suitable for the chronic treatment of diseases where iron accumulation and subsequent oxidative stress are implicated in disease pathogenesis is an active area of research. The clinical use of the strong chelator N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) and its alkyl ester prodrugs has been hindered by poor oral bioavailability and lack of conversion to the parent chelator, respectively. Here, we present novel double prodrugs of HBED that have the carboxylate and phenolate donors of HBED masked with carboxylate esters and boronic acids/esters, respectively. These double prodrugs were successfully synthesized as free bases (7a-f) or as dimesylate salts (8a-c,e), and were characterized by (1)H, (13)C, and (11)B NMR; MP; MS; and elemental analysis. The crystal structure of 8a was solved. Three of the double prodrugs (8a-c) were selected for further investigation into their abilities to convert to HBED by stepwise hydrolysis and H2O2 oxidation. The serial hydrolysis of the pinacol and methyl esters of N,N'-bis(2-boronic acid pinacol ester benzyl)ethylenediamine-N,N'-diacetic acid methyl ester dimesylate (8a) was verified by LC-MS. The macro half-lives for the hydrolyses of 8a-c, measured by UV, ranged from 3.8 to 26.3 h at 37 °C in pH 7.5 phosphate buffer containing 50% MeOH. 9, the product of hydrolysis of 8a-c and the intermediate in the conversion pathway, showed little-to-no affinity for iron or copper in UV competition experiments. 9 underwent a serial oxidative deboronation by H2O2 in N-methylmorpholine buffer to generate HBED (k = 10.3 M(-1) min(-1)). The requirement of this second step, oxidation, before conversion to the active chelator is complete may confer site specificity when only localized iron chelation is needed. Overall, these results provide proof of principle for the activation of the double prodrugs by chemical hydrolysis and H2O2 oxidation, and merit further investigation into the

  6. Unsymmetrical Chelation of N-Thioether-Functionalized Bis(diphenylphosphino)amine-Type Ligands and Substituent Effects on the Nuclearity of Iron(II) Complexes: Structures, Magnetism, and Bonding.

    PubMed

    Fliedel, Christophe; Rosa, Vitor; Falceto, Andrés; Rosa, Patrick; Alvarez, Santiago; Braunstein, Pierre

    2015-07-01

    Starting from the short-bite ligands N-thioether-functionalized bis(diphenylphosphino)amine-type (Ph2P)2N(CH2)3SMe (1) and (Ph2P)2N(p-C6H4)SMe (2), the Fe(II) complexes [FeCl2(1)]n (3), [FeCl2(2)]2 (4), [Fe(OAc)(1)2]PF6 (5), and [Fe(OAc)(2)2]PF6 (6) were synthesized and characterized by Fourier transform IR, mass spectrometry, elemental analysis, and also by X-ray diffraction for 3, 4, and 6. Complex 3 is a coordination polymer in which 1 acts as a P,P-pseudochelate and a (P,P),S-bridge, whereas 4 has a chlorido-bridged dinuclear structure in which 2 acts only as a P,P-pseudochelate. Since these complexes were obtained under strictly similar synthetic and crystallization conditions, these unexpected differences were ascribed to the different spacer between the nitrogen atom and the −SMe group. In both compounds, one Fe–P bond was found to be unusually long, and a theoretical analysis was performed to unravel the electronic or steric reasons for this difference. Density functional theory calculations were performed for a set of complexes of general formula [FeCl2(SR2){R21PN(R2)P′R23}] (R = H, Me; R1, R2, and R3 = H, Me, Ph), to understand the reasons for the significant deviation of the iron coordination sphere away from tetrahedral as well as from trigonal bipyramidal and the varying degree of unsymmetry of the two Fe–P bonds involving pseudochelating PN(R)P ligands. Electronic factors nicely explain the observed structures, and steric reasons were further ruled out by the structural analysis in the solid-state of the bis-chelated complex 6, which displays usual and equivalent Fe–P bond lengths. Magnetic susceptibility studies were performed to examine how the structural differences between 3 and 4 would affect the interactions between the iron centers, and it was concluded that 3 behaves as an isolated high-spin Fe(II) mononuclear complex, while significant intra- and intermolecular ferromagnetic interactions were evidenced for 4 at low temperatures

  7. Use of paramagnetic chelated metal derivatives of polysaccharides and spin-labeled polysaccharides as contrast agents in magnetic resonance imaging

    SciTech Connect

    Bligh, S.W.; Harding, C.T.; Sadler, P.J.; Bulman, R.A.; Bydder, G.M.; Pennock, J.M.; Kelly, J.D.; Latham, I.A.; Marriott, J.A. )

    1991-02-01

    Soluble and insoluble polysaccharides were derivatized with diethylenetriaminepentaacetic acid (DTPA) and/or spin-labeled with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). Polysaccharides derivatized with DTPA were prepared via cyanogen bromide activation, coupling to a diamine linker, and to DTPA anhydride. Spin-labeled polysaccharides were also prepared via cyanogen bromide activation. The extent of derivatization for dextran (18 kDa) was about 120 glucose units per DTPA, and for cellulose and starch about 15-30 units per DTPA. For spin-labeled polysaccharides, the average loading ranged from 1 nitroxide per 16 glucose units for starch to 181 for dextran (82 kDa). These derivatized paramagnetic polysaccharides were shown to be more effective relaxants than the small paramagnetic molecules alone. Both soluble and insoluble polysaccharide-linker-DTPA-Gd(3) complexes were effectively cleared from the body (rats) after oral administration. After intravenous administration, the biodistribution of dextran-linker-DTPA-Gd(3) complexes differed significantly from that of GdDTPA. Reduction of the nitroxide by ascorbic acid was retarded in the polysaccharide derivatives, particularly in starch derivatized with both nitroxide and linker-DTPA-Cu(2). These agents showed contrast enhancement in the gastrointestinal tract of rabbits.

  8. Nanoparticle-based PARACEST agents: the quenching effect of silica nanoparticles on the CEST signal from surface-conjugated chelates.

    PubMed

    Evbuomwan, Osasere M; Merritt, Matthew E; Kiefer, Garry E; Dean Sherry, A

    2012-01-01

    Silica nanoparticles of average diameter 53 ± 3 nm were prepared using standard water-in-oil microemulsion methods. After conversion of the surface Si-OH groups to amino groups for further conjugation, the PARACEST agent, EuDOTA-(gly)₄ (-) was coupled to the amines via one or more side-chain carboxyl groups in an attempt to trap water molecules in the inner-sphere of the complex. Fluorescence and ICP analyses showed that approximately 1200 Eu(3+) complexes were attached to each silica nanoparticle, leaving behind excess protonated amino groups. CEST spectra of the modified silica nanoparticles showed that attachment of the EuDOTA-(gly)₄ (-) to the surface of the nanoparticles did not result in a decrease in water exchange kinetics as anticipated, but rather resulted in a complete elimination of the normal Eu(3+) -bound water exchange peak and broadening of the bulk water signal. This observation was traced to catalysis of proton exchange from the Eu(3+) -bound water molecule by excess positively charged amino groups on the surface of the nanoparticles.

  9. Iron oxide nanoparticles stabilized with dendritic polyglycerols as selective MRI contrast agents

    NASA Astrophysics Data System (ADS)

    Nordmeyer, Daniel; Stumpf, Patrick; Gröger, Dominic; Hofmann, Andreas; Enders, Sven; Riese, Sebastian B.; Dernedde, Jens; Taupitz, Matthias; Rauch, Ursula; Haag, Rainer; Rühl, Eckart; Graf, Christina

    2014-07-01

    Monodisperse small iron oxide nanoparticles functionalized with dendritic polyglycerol (dPG) or dendritic polyglycerol sulfate (dPGS) are prepared. They are highly stable in aqueous solutions as well as physiological media. In particular, oleic acid capped iron oxide particles (core diameter = 11 +/- 1 nm) were modified by a ligand exchange process in a one pot synthesis with dPG and dPGS bearing phosphonate as anchor groups. Dynamic light scattering measurements performed in water and different biological media demonstrate that the hydrodynamic diameter of the particles is only slightly increased by the ligand exchange process resulting in a final diameter of less than 30 nm and that the particles are stable in these media. It is also revealed by magnetic resonance studies that their magnetic relaxivity is reduced by the surface modification but it is still sufficient for high contrast magnetic resonance imaging (MRI). Additionally, incubation of dPGS functionalized iron oxide nanoparticles with human umbilical vein endothelial cells showed a 50% survival at 85 nM (concentration of nanoparticles). Surface plasmon resonance (SPR) studies demonstrate that the dPGS functionalized iron oxide nanoparticles inhibit L-selectin ligand binding whereas the particles containing only dPG do not show this effect. Experiments in a flow chamber with human myelogenous leukemia cells confirmed L-selectin inhibition of the dPGS functionalized iron oxide nanoparticles and with that the L-selectin mediated leukocyte adhesion. These results indicate that dPGS functionalized iron oxide nanoparticles are a promising contrast agent for inflamed tissue probed by MRI.Monodisperse small iron oxide nanoparticles functionalized with dendritic polyglycerol (dPG) or dendritic polyglycerol sulfate (dPGS) are prepared. They are highly stable in aqueous solutions as well as physiological media. In particular, oleic acid capped iron oxide particles (core diameter = 11 +/- 1 nm) were modified by a

  10. Correction: Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents

    NASA Astrophysics Data System (ADS)

    Hachani, Roxanne; Lowdell, Mark; Birchall, Martin; Hervault, Aziliz; Mertz, Damien; Begin-Colin, Sylvie; Thanh, Nguy&Ecirtil; N. Thi&Cmb. B. Dot; Kim

    2016-02-01

    Correction for `Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents' by Roxanne Hachani et al., Nanoscale, 2015, DOI: 10.1039/c5nr03867g.

  11. Correction: Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents.

    PubMed

    Hachani, Roxanne; Lowdell, Mark; Birchall, Martin; Hervault, Aziliz; Mertz, Damien; Begin-Colin, Sylvie; Thanh, Nguyen Thi Kim

    2016-02-21

    Correction for 'Polyol synthesis, functionalisation, and biocompatibility studies of superparamagnetic iron oxide nanoparticles as potential MRI contrast agents' by Roxanne Hachani et al., Nanoscale, 2015, DOI: 10.1039/c5nr03867g. PMID:26823197

  12. Essential trace metal excretion from rats with lead exposure and during chelation therapy.

    PubMed

    Victery, W; Miller, C R; Goyer, R A

    1986-02-01

    Urinary excretion of lead, zinc, calcium, magnesium, iron, copper, sodium, and potassium was measured in rats daily for 1 week after a 6-week exposure to 10,000 micrograms/ml lead in drinking water. Beginning on the third day, half of the lead-exposed and control rats were injected intraperitoneally with calcium disodium ethylenediaminetetraacetate (EDTA) daily for 3 days. Whole blood, plasma, and kidney metal concentrations were determined from samples obtained at the end of the experiment. Exposure to lead increased urinary excretion, not only of lead, but also of calcium, magnesium, zinc, copper, and iron. Excretion of sodium and potassium was not altered. Chelation therapy further increased excretion of lead, zinc, copper, and iron, but not magnesium. The increase in calcium excretion during chelation treatment (beyond that resulting from lead exposure per se) was accounted for by the Ca content of CaNa2-EDTA. EDTA treatment increased renal concentration of zinc but lowered renal concentration of lead, copper, and iron. These multimetal alterations may have implications for essential metal supplementation, particularly zinc, in persons being given chelation agents for excess lead exposure and in infants and children with low-level lead exposure not necessarily requiring chelation therapy.

  13. Gadolinium Nanoparticles Conjugated with Therapeutic Bifunctional Chelate as a Potential T1 Theranostic Magnetic Resonance Imaging Agent.

    PubMed

    Kang, Min-Kyoung; Lee, Gang Ho; Jung, Ki-Hye; Jung, Jae-Chang; Kim, Hee-Kyung; Kim, Yeon-Hee; Lee, Jongmin; Ryeom, Hun-Kyu; Kim, Tae-Jeong; Chang, Yongmin

    2016-05-01

    This work is directed toward the synthesis of two types of gadolinium oxide nanoparticles (Gd-oxide NPs), abbreviated as Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA, with diameters of 50-60 nm. The synthesis involves sequential coating of Gd-oxide NPs with tetraethyl orthosilicate (TEOS) and (3-aminopropyl) triethoxysilane (APTES), followed by functionalization of the aminopropylsilane group with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid conjugates of benzothiazoles (DO3A-BTA). Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA exhibit high water solubility and colloidal stability. The r1 relaxivities of both Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA are higher than those of the corresponding low-molecular-weight magnetic resonance imaging contrast agents (MRI CAs), and their r2/r1 ratios are close to 1, indicating that both can be used as potential T1 MRI CAs. Biodistribution studies demonstrated that Gd@SiO2-DO2A-BTA was excreted via both hepatobiliary and renal pathways. Gd@SiO2-DO2A-BTA exhibits a strong intracellular uptake property in a series of tumor cell lines, and has significant anticancer characteristics against cell lines such as SK-HEP-1, MDA-MB-231, HeLa, and Hep-3B.

  14. Gadolinium Nanoparticles Conjugated with Therapeutic Bifunctional Chelate as a Potential T1 Theranostic Magnetic Resonance Imaging Agent.

    PubMed

    Kang, Min-Kyoung; Lee, Gang Ho; Jung, Ki-Hye; Jung, Jae-Chang; Kim, Hee-Kyung; Kim, Yeon-Hee; Lee, Jongmin; Ryeom, Hun-Kyu; Kim, Tae-Jeong; Chang, Yongmin

    2016-05-01

    This work is directed toward the synthesis of two types of gadolinium oxide nanoparticles (Gd-oxide NPs), abbreviated as Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA, with diameters of 50-60 nm. The synthesis involves sequential coating of Gd-oxide NPs with tetraethyl orthosilicate (TEOS) and (3-aminopropyl) triethoxysilane (APTES), followed by functionalization of the aminopropylsilane group with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid conjugates of benzothiazoles (DO3A-BTA). Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA exhibit high water solubility and colloidal stability. The r1 relaxivities of both Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA are higher than those of the corresponding low-molecular-weight magnetic resonance imaging contrast agents (MRI CAs), and their r2/r1 ratios are close to 1, indicating that both can be used as potential T1 MRI CAs. Biodistribution studies demonstrated that Gd@SiO2-DO2A-BTA was excreted via both hepatobiliary and renal pathways. Gd@SiO2-DO2A-BTA exhibits a strong intracellular uptake property in a series of tumor cell lines, and has significant anticancer characteristics against cell lines such as SK-HEP-1, MDA-MB-231, HeLa, and Hep-3B. PMID:27305813

  15. Influence of chelator and near-infrared dye labeling on biocharacteristics of dual-labeled trastuzumab-based imaging agents

    PubMed Central

    Aldrich, Melissa B; Yang, Zhi; Zhou, Nina; Xie, Qing; Liu, Chen; Sevick-Muraca, Eva

    2016-01-01

    Objective To investigate the effect of fluorescent dye labeling on the targeting capabilities of 111In- (DTPA)n-trastuzumab-(IRDye 800)m. Methods Trastuzumab-based conjugates were synthesized and conjugated with diethylenetriaminepentaacetic acid (DTPA) at molar ratios of 1, 2, 3 and 5 and with a fluorescent dye (IRDye 800CW) at molar ratios of 1, 3 and 5. Immunoreactivity and internalization were assessed on SKBR-3 cells, overexpressing human epidermal growth factor receptor 2. The stability in human serum and phosphate-buffered saline (PBS) was evaluated. The biodistribution of dual-labeled conjugates was compared with that of 111In-(DTPA)2-trastuzumab in a SKBR-3 xenograft model to evaluate the effect of dye-to-protein ratio. Results All trastuzumab-based conjugates exhibited a high level of chemical and optical purity. Flow cytometry results showed that increasing dye-to-protein ratios were associated with decreased immunoreactivity. Stability studies revealed that the conjugate was stable in PBS, while in human serum, increased degradation and protein precipitation were observed with increasing dye-to-protein ratios. At 4 h, the percentages of internalization of dual-labeled conjugates normalized by dye-to-protein ratio (m) were 24.88%±2.10%, 19.99%±0.59%, and 17.47%±1.26% for "m" equal to 1, 3, and 5, respectively. A biodistribution study revealed a progressive decrease in tumor uptake with an increase in the dye-to-protein ratios. The liver, spleen and kidney showed a marked uptake with increased dye-to-protein ratios, particularly in the latter. Conclusions With non-specific-site conjugation of the fluorescent dye with a protein based on imaging agent, the increase in dye-to-protein ratios negatively impacted the immunoreactivity and stability, indicating a reduced tumor uptake. PMID:27478322

  16. Luminescent lanthanide chelates and methods of use

    DOEpatents

    Selvin, Paul R.; Hearst, John

    1997-01-01

    The invention provides lanthanide chelates capable of intense luminescence. The celates comprise a lanthanide chelator covalently joined to a coumarin-like or quinolone-like sensitizer. Exemplary sensitzers include 2- or 4-quinolones, 2- or 4-coumarins, or derivatives thereof e.g. carbostyril 124 (7-amino-4-methyl-2-quinolone), coumarin 120 (7-amino-4-methyl-2-coumarin), coumarin 124 (7-amino-4-(trifluoromethyl)-2-coumarin), aminomethyltrimethylpsoralen, etc. The chelates form high affinity complexes with lanthanides, such as terbium or europium, through chelator groups, such as DTPA. The chelates may be coupled to a wide variety of compounds to create specific labels, probes, diagnostic and/or therapeutic reagents, etc. The chelates find particular use in resonance energy transfer between chelate-lanthanide complexes and another luminescent agent, often a fluorescent non-metal based resonance energy acceptor. The methods provide useful information about the structure, conformation, relative location and/or interactions of macromolecules.

  17. Potential water-quality effects from iron cyanide anticaking agents in road salt

    SciTech Connect

    Paschka, M.G.; Ghosh, R.S.; Dzombak, D.A.

    1999-10-01

    Water-soluble iron cyanide compounds are widely used as anticaking agents in road salt, which creates potential contamination of surface and groundwater with these compounds when the salt dissolves and is washed off roads in runoff. This paper presents a summary of available information on iron cyanide use in road salt and its potential effects on water quality. Also, estimates of total cyanide concentrations in snow-melt runoff from roadways are presented as simple mass-balance calculations. Although available information does not indicate a widespread problem, it also is clear that the water-quality effects of cyanide in road salt have not been examined much. Considering the large, and increasing, volume of road salt used for deicing, studies are needed to determine levels of total and free cyanide in surface and groundwater adjacent to salt storage facilities and along roads with open drainage ditches. Results could be combined with current knowledge of the fate and transport of cyanide to assess water-quality effects of iron cyanide anticaking agents used in road salt.

  18. Neuroprotective and neurorestorative activities of a novel iron chelator-brain selective monoamine oxidase-A/monoamine oxidase-B inhibitor in animal models of Parkinson's disease and aging.

    PubMed

    Bar-Am, Orit; Amit, Tamar; Kupershmidt, Lana; Aluf, Yuval; Mechlovich, Danit; Kabha, Hoda; Danovitch, Lena; Zurawski, Vincent R; Youdim, Moussa B H; Weinreb, Orly

    2015-03-01

    Recently, we have designed and synthesized a novel multipotent, brain-permeable iron-chelating drug, VAR10303 (VAR), possessing both propargyl and monoamine oxidase (MAO) inhibitory moieties. The present study was undertaken to determine the multiple pharmacological activities of VAR in neurodegenerative preclinical models. We demonstrate that VAR affords iron chelating/iron-induced lipid-peroxidation inhibitory potency and brain selective MAO-A and MAO-B inhibitory effects, with only limited tyramine-cardiovascular potentiation of blood pressure. The results show that in 6-hydroxydopamine rat (neuroprotection) and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse (neurorescue) Parkinson's disease models, VAR significantly attenuated the loss of striatal dopamine levels, markedly reduced dopamine turnover, and increased tyrosine-hydroxylase levels. Furthermore, chronic systemic treatment of aged rats with VAR improved cognitive behavior deficits and enhanced the expression levels of neurotrophic factors (e.g., brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and nerve growth factor), Bcl-2 family members and synaptic plasticity in the hippocampus. Our study indicates that the multitarget compound VAR exerted neuroprotective and neurorestorative effects in animal models of Parkinson's disease and aging, further suggesting that a drug that can regulate multiple brain targets could be an ideal treatment-strategy for age-associated neurodegenerative disorders.

  19. Carbon-coated iron oxide nanoparticles as contrast agents in magnetic resonance imaging.

    PubMed

    Bae, Hongsub; Ahmad, Tanveer; Rhee, Ilsu; Chang, Yongmin; Jin, Seong-Uk; Hong, Sungwook

    2012-01-01

    Coprecipitated ferrite nanoparticles were coated with carbon using a hydrothermal method. From transmission electron microscope pictures, we could see that the coated iron oxide nanoparticles were spherical in shape with an average diameter of 90 nm. The strong bonding of carbon on the nanoparticle surfaces was checked by noting the C = O and C = C vibrations in Fourier transform infrared spectra. The spin-lattice relaxation process [T1] and spin-spin relaxation process [T2] relaxivities of hydrogen protons in the aqueous solution of coated nanoparticles were determined to be 1.139 (mM·s)-1 and 1.115 (mM·s)-1, respectively. These results showed that the carbon-coated iron oxide nanoparticles are applicable as both T1 and T2 contrast agents in magnetic resonance imaging.PACS: 81.05.y; 76.60.Es; 61.46; 75.50.k; 87.61.

  20. Terephthalamide-containing ligands: fast removal of iron from transferrin.

    PubMed

    Abergel, Rebecca J; Raymond, Kenneth N

    2008-02-01

    The mechanism and effectiveness of iron removal from transferrin by three series of new potential therapeutic iron sequestering agents have been analyzed with regard to the structures of the chelators. All compounds are hexadentate ligands composed of a systematically varied combination of methyl-3,2-hydroxypyridinone (Me-3,2-HOPO) and 2,3-dihydroxyterephthalamide (TAM) binding units linked to a polyamine scaffold through amide linkers; each series is based on a specific backbone: tris(2-aminoethyl)amine, spermidine, or 5-LIO(TAM), where 5-LIO is 2-(2-aminoethoxy)ethylamine. Rates of iron removal from transferrin were determined spectrophotometrically for the ten ligands, which all efficiently acquire ferric ion from diferric transferrin with a hyperbolic dependence on ligand concentration (saturation kinetics). The effect of the two iron-binding subunits Me-3,2-HOPO and TAM and of the scaffold structures on iron removal ability is discussed. At the low concentrations corresponding to therapeutic dose, TAM-containing ligands exhibit the fastest rates of iron removal, which correlates with their high affinity for ferric ion and suggests the insertion of such binding units into future therapeutic chelating agents. In addition, urea polyacrylamide gel electrophoresis was used to measure the individual microscopic rates of iron removal from the three iron-bound transferrin species (diferric transferrin, N-terminal monoferric transferrin, C-terminal monoferric transferrin) by the representative chelators 5-LIO(Me-3,2-HOPO)(2)(TAM) and 5-LIO(TAMmeg)(2)(TAM), where TAMmeg is 2,3-dihydroxy-1-(methoxyethylcarbamoyl)terephthalamide. Both ligands show preferential removal from the C-terminal site of the iron-binding protein. However, cooperative effects between the two binding sites differ with the chelator. Replacement of hydroxypyridinone moieties by terephthalamide groups renders the N-terminal site more accessible to the ligand and may represent an advantage for iron

  1. Regulation of platelet count by erythropoiesis-stimulating agentsiron axis in hemodialysis patients

    PubMed Central

    Koike, Kiyomi; Fukami, Kei; Kawaguchi, Atsushi; Shimamatsu, Kazumasa; Yamagishi, Sho-ichi; Okuda, Seiya

    2016-01-01

    Higher doses of erythropoiesis-stimulating agents (ESAs) contribute to atherothrombotic cardiovascular disease in hemodialysis (HD) patients. Thrombocytosis is associated with increased mortality in ESA-treated HD patients. We investigated variables affecting platelet count and its variability (platelet count increment [Δplatelet count]) in HD patients. This retrospective longitudinal and observational study of HD outpatients was carried out over 3 years. The outcome was independent determinants of platelet count and Δplatelet count, which were associated with iron indices, ESA dose, and C-reactive protein. In univariate regression analysis, V-shaped relationship was observed between platelet count and transferrin saturation (TSAT), ferritin, serum iron, and hemoglobin (Hb) with the bottom of 0.21, 330 ng/mL, 49 µg/dL, and 10.3 g/dL, respectively. Mixed-effect multivariate regression analysis revealed that TSAT (inversely), Hb ≤10.3 g/dL (inversely), C-reactive protein, and ESA dose were independently associated with platelet count. Δplatelet count was independently and inversely correlated with ΔTSAT and directly correlated with Δferritin. TSAT was independently and inversely associated with ESA dose. ESA dose was directly correlated with iron dose and inversely correlated with TSAT, ferritin ≤330 ng/mL, and Hb ≤10.3 g/dL. ESA dose and TSAT were correlated in determining platelet count and Δplatelet count. Targets of iron indices that reflect iron supply sufficient to avoid platelet count increment and variability may be >21% of TSAT and 300 ng/mL of serum ferritin for appropriate ESA therapy in HD patients. PMID:27099526

  2. Hydroxypyri(mi)dine-based chelators as antidotes of toxicity due to aluminum and actinides.

    PubMed

    Santos, M A; Esteves, M A; Chaves, S

    2012-01-01

    This review is focused on recent developments on hydroxypyri(mi)dines, as aluminum and actinide chelating agents to combat the toxicity due to accumulations of these metal ions in human body resulting from excessive metal exposure. After a brief update revision of the most common processes of aluminum (Al) exposure, as well as the associated toxicities and pathologies, we will focus on the current available Al chelators and future perspective as potential antidotes of Al toxicity. Due to the similarity between Al and Fe, a major emphasis is given to the hydroxypyridinone and hydroxypyrimidinone chelators, since they are analogues of the current iron chelators in clinical use (DFP and DFO). This review includes issues such as molecular design strategies and corresponding effects on the associated physico-chemical properties, lipo-hydrophilic balance, toxicity, in vivo bioassays and current clinical applications. The hydroxypyri(mi)dine chelators are also suitable for other hard metal ions, such as the radiotoxic actinides, and so a brief review is included on the applications of these chelators in actinides scavenging.

  3. Effects of solvent and chelating agent on synthesis of solid oxide fuel cell perovskite, La{sub 0.8}Sr{sub 0.2}CrO{sub 3-{delta}}

    SciTech Connect

    Lee, Byoung I.; Gupta, Ravindra K.; Whang, Chin M.

    2008-02-05

    Effects of solvent and chelating agent on synthesis of La{sub 0.8}Sr{sub 0.2}CrO{sub 3-{delta}} perovskite are reported. Samples are synthesized using a solvent (ethylene glycol or 2-methoxyethanol) and a chelating agent (acetylacetone, citric acid or ethylene diamine tetraacetic acid) by polymeric-gel method, and characterized by X-ray diffractometry and Fourier-transform infrared spectroscopy. Citric acid to metal cations molar ratio (Rc) is varied for ethylene glycol-citric acid system. Samples are mainly orthorhombic perovskite. SrCrO{sub 4} is appeared as a secondary phase and found to be the lowest for ethylene glycol-citric acid combination with Rc equal to 7. Crystallographic parameters of perovskite phase are determined and compared with those of LaCrO{sub 3}. A mechanism employing a partial-charge model, chelating effect and solvent-cage effect is proposed to explain the results. Effect of sintering temperature on phase, relative density and morphology of samples prepared using ethylene glycol and citric acid (Rc = 7) is also reported.

  4. TREG coated iron oxide nanoparticles as contrast agent for MRI in-vivo use

    NASA Astrophysics Data System (ADS)

    Gutierrez-Garcia, Eric; Hidalgo-Tobon, Silvia; Lopez, Ciro; Gonzalez-Rodriguez, Roberto; Coffer, Jeffery; De Celis Alonso, Benito; Dies Suarez, Pilar; Obregon, Manuel; Perez-Pena, Mario; Platas-Neri, Diana; Mendez-Rojas, Miguel

    2014-11-01

    Super-paramagnetic iron oxide nanoparticles (SPIONs) are of interest due to their great potential applications in diverse fields such as biomedicine. In this work we have prepared SPION nanoparticles using the polyol technique and characterized the magnetic properties of them for MRI in-vivo use. Nanoparticle preparation: All reagents were purchased from commercial sources (Sigma-Aldrich, St. Louis, USA) Iron (III) acetylacetonate, [Fe(acac)3], was used as the iron oxide precursor and thermally decomposed at high temperatures in triethyleneglycol (TREG). Nano-sized magnetite particles were prepared by an adaptation of the method proposed by Wei Cai et al[1-3]. A healthy rabbit was scanned on a clinical 1.5 T Philips MR scanner. Images were taken in 2D mode with a mFFE sequence. Relaxation time T2 was obtained from the MR images using a Matlab algorithm where the signal intensity decay was calculated at each image and then adjusted to a mono-exponential curve. Images were obtained before contrast injection, 24 hours and 36 hours following SPIONs administration. Signal decay at different Echo times for the prepared magnetic SPIONs, before and after contrast injection was measured. It was visualized a concentration of the agent contrast in brain and liver and the results were compared with images obtained from histopathology.

  5. Membrane permeability of redox active metal chelators: an important element in reducing hydroxyl radical induced NAD+ depletion in neuronal cells.

    PubMed

    Jayasena, T; Grant, R S; Keerthisinghe, N; Solaja, I; Smythe, G A

    2007-03-01

    There is substantial evidence implicating increased production of the hydroxyl radical and oxidative stress in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Significant amounts of hydroxyl radicals will be produced in the presence of hydrogen peroxide and redox active iron via Fenton chemistry. Increased iron levels within the cytoplasm of vulnerable neurons suggest that this may also be an important site of oxidative activity. We investigated the likelihood that intracellular, rather than extracellular chelation of ferrous or ferric iron may be more effective in reducing hydroxyl radical induced cell damage and preserving NAD(+) levels and cell viability. Using intracellular NAD(H) measurements as an indicator of cell viability we found that membrane permeable ferrous chelators were most efficient in preserving cellular NAD(+) levels. Hydrophilic, ferrous or ferric chelators and lipophilic ferric chelators were essentially ineffective in preventing cell