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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. Pharmacogenetic Study of Deferasirox, an Iron Chelating Agent

    PubMed Central

    Lee, Ji Won; Kang, Hyoung Jin; Choi, Ji-Yeob; Kim, Nam Hee; Jang, Mi Kyung; Yeo, Chang-Woo; Lee, Sang Seop; Kim, Hyery; Park, June Dong; Park, Kyung Duk; Shin, Hee Young; Shin, Jae-Gook; Ahn, Hyo Seop

    2013-01-01

    Transfusion-associated iron overload induces systemic toxicity. Deferasirox, a convenient long acting oral agent, has recently been introduced in clinical practice with a promising efficacy. But there are some patients who experience drug-related toxicities and cannot tolerate it. To investigate effect of genetic variations on the toxicities and find optimal target population, we analyzed the genetic polymorphisms of UDP-glucuronosyltransferase 1A (UGT1A) subfamily, multi-drug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). A total of 20 functional genetic polymorphisms were analyzed in 98 patients who received deferasirox to reduce transfusion-induced iron overload. We retrospectively reviewed the medical records to find out the drug-related toxicities. Fifteen (15.3%) patients developed hepatotoxicity. Patients without wild-type allele carrying two MRP2 haplotypes containing −1774 del and/or −24T were at increased risk of developing hepatotoxicity compared to patients with the wild-type allele on multivariate analysis (OR = 7.17, 95% CI = 1.79–28.67, P = 0.005). Creatinine elevation was observed in 9 patients (9.2%). Body weight ≥40 kg and homozygosity for UGT1A1*6 were risk factors of creatinine elevation (OR = 8.48, 95% CI = 1.7–43.57, P = 0.010 and OR = 14.17, 95% CI = 1.34–150.35, P = 0.028). Our results indicate that functional genetic variants of enzymes to metabolize and transport deferasirox are associated with drug-related toxicities. Further studies are warranted to confirm the results as the pharmacogenetic biomarkers of deferasirox. PMID:23737969

  4. Use of Iron Chelating Agents in Transfusion Dependent Thalassaemia Major Patients.

    PubMed

    Santra, S; Bhattacharya, A; Mukhopadhyay, T; Agrawal, D; Kumar, S; Das, P; Chakrabarty, P

    2015-10-01

    This cross-sectional study was done to find and investigate the utilization pattern of iron chelating agents among 73 transfusion-dependent thalassaemia major patients with continuous enrolment for at least 1 year in a day care treatment centre run by The Thalassaemia Society of India, Kolkata from November 2014 to January 2015. Transfusion dependent thalassaemia major patients above the age of 2 years managed by various haematologists and Thalassaemia specialists were studied. The administration of iron chelators namely Desferrioxamine (DFO), Deferiprone (DFP) and Deferasirox (DFX) were evaluated. Forty seven (64%) of the thalassaemics had serum ferritin level below 2500 ng/dl, of whom 20(27%) patients have ferritin level below 1000ng/dl. A number of 55(75%) of 73 patients who were treated with a single chelating agent consisted 50 patients only on DFX. Exact 8(67%) patients were on DFO+DFP and 4(33%) are treated with DFX+DFP. The mean age was 19 and mean serum ferritin level was 2280 ng/dl among the thalassaemia major patients. DFX was used 68% of patients as monotherapy and 5% patients in combination therapy with DFP. DFX in the dose of 30-40 mg/kg/day was prescribed in 52% of patients. Mean dose of 15 mg/kg/day of DFX was been administered in combination with DFP (75 mg/kg/day) in 5% patients. DFO+DFP were preferred by 8 patients, out of which 6 were aged above 25. Cost of monotherapy is twice that of combination therapy. These data demonstrates the ferritin status and present scenario of utilization of chelating agents among thalassaemia major patients on repeated transfusions. The dosing of new drug, Deferasirox and the cost analysis of various chelating regimen has also been dealt. Individualization rather than rationalization of chelation therapy should be focussed upon in managing iron overload in thalassaemia.

  5. 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.

  6. Iron-chelating agent desferrioxamine stimulates formation of neutrophil extracellular traps (NETs) in human blood-derived neutrophils

    PubMed Central

    Völlger, Lena; Akong-Moore, Kathryn; Cox, Linda; Goldmann, Oliver; Wang, Yanming; Schäfer, Simon T.; Naim, Hassan Y.; Nizet, Victor; von Köckritz-Blickwede, Maren

    2016-01-01

    Neutrophil extracellular trap (NET) formation is a significant innate immune defense mechanism against microbial infection that complements other neutrophil functions including phagocytosis and degranulation of antimicrobial peptides. NETs are decondensed chromatin structures in which antimicrobial components (histones, antimicrobial peptides and proteases) are deployed and mediate immobilization of microbes. Here we describe an effect of iron chelation on the phenotype of NET formation. Iron-chelating agent desferrioxamine (DFO) showed a modest but significant induction of NETs by freshly isolated human neutrophils as visualized and quantified by immunocytochemistry against histone–DNA complexes. Further analyses revealed that NET induction by iron chelation required NADPH-dependent production of reactive oxygen species (ROS) as well as protease and peptidyl-arginine-deiminase 4 (PAD4) activities, three key mechanistic pathways previously linked to NET formation. Our results demonstrate that iron chelation by DFO contributes to the formation of NETs and suggest a target for pharmacological manipulation of NET activity. PMID:27129288

  7. The iron-chelating agent picolinic acid enhances transferrin receptors expression in human erythroleukaemic cell lines.

    PubMed

    Testa, U; Louache, F; Titeux, M; Thomopoulos, P; Rochant, H

    1985-07-01

    Picolinic acid, a metal chelating molecule, was administered to human erythroleukaemic cell lines (K 562 and HEL) that were grown in serum-containing media. Picolinic acid inhibited both iron uptake and cell growth. Furthermore, picolinic acid was shown to markedly decrease the level of ferritin in the cells. In spite of the inhibition of cell growth, picolinic acid induced a marked increase in the transferrin-binding capacity of the cells. This phenomenon was due to a two-five-fold enhancement of the rate of transferrin receptor biosynthesis. Other iron-chelating compounds, capable of reducing the level of intracellular iron, also elicited a marked enhancement of the transferrin-binding capacity of the cells. However, the addition of iron, as ferric ammonium citrate, in the culture medium elicited a marked increase in the level of ferritin and a strong decrease in the transferrin-binding capacity of the cells. On the basis of these data we propose that a feed-back mechanism is involved in the regulation of transferrin receptors: when the cells accumulate iron they decrease the number of transferrin receptors in order to prevent further accumulation of iron; when no or low iron is available to the cells, the number of transferrin receptors markedly increases as a compensatory mechanism.

  8. Comparison of various iron chelators used in clinical practice as protecting agents against catecholamine-induced oxidative injury and cardiotoxicity.

    PubMed

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

    2011-11-18

    Catecholamines are stress hormones and sympathetic neurotransmitters essential for control of cardiac function and metabolism. However, pathologically increased catecholamine levels may be cardiotoxic by mechanism that includes iron-catalyzed formation of reactive oxygen species. In this study, five iron chelators used in clinical practice were examined for their potential to protect cardiomyoblast-derived cell line H9c2 from the oxidative stress and toxicity induced by catecholamines epinephrine and isoprenaline and their oxidation products. Hydroxamate iron chelator desferrioxamine (DFO) significantly reduced oxidation of catecholamines to more toxic products and abolished redox activity of the catecholamine-iron complex at pH 7.4. However, due to its hydrophilicity and large molecule, DFO was able to protects cells only at very high and clinically unachievable concentrations. Two newer chelators, deferiprone (L1) and deferasirox (ICL670A), showed much better protective potential and were effective at one or two orders of magnitude lower concentrations as compared to DFO that were within their clinically relevant plasma levels. Ethylenediaminetetraacetic acid (EDTA), dexrazoxane (ICRF-187, clinically approved cardioprotective agent against anthracycline-induced cardiotoxicity) as well as selected beta adrenoreceptor antagonists and calcium channel blockers exerted no effect. Hence, results of the present study indicate that small, lipophilic and iron-specific chelators L1 and ICL670A can provide significant protection against the oxidative stress and cardiomyocyte damage exerted by catecholamines and/or their reactive oxidation intermediates. This potential new application of the clinically approved drugs L1 and ICL670A warrants further investigation, preferably using more complex in vivo animal models. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  9. Iron Chelators as Potential Therapeutic Agents for Parkinson’s Disease

    PubMed Central

    Perez, Carlos A.; Tong, Yong; Guo, Maolin

    2009-01-01

    Parkinson’s disease (PD) is a neurological disorder characterized by the progressive impairment of motor skills in patients. Growing evidence suggests that abnormal redox-active metal accumulation, caused by dysregulation, plays a central role in the neuropathology of PD. Redox-active metals (e.g. Fe and Cu) catalyze essential reactions for brain function. However, these metals can also participate in the generation of highly toxic free radicals that can cause oxidative damage to cells and ultimately lead to the death of dopamine-containing neurons. The emergence of redox-active metals as key players in the pathogenesis of PD strongly suggests that metal-chelators could be beneficial in the treatment of this condition. This mini-review summarizes major recent developments on natural, synthetic iron chelating compounds and hydrogen peroxide-triggered prochelators as potential candidates for PD treatment. PMID:19809592

  10. Liposome encapsulation of chelating agents

    DOEpatents

    Rahman, Yueh Erh

    1976-01-13

    A method for transferring a chelating agent across a cellular membrane by encapsulating the charged chelating agent within liposomes and carrying the liposome-encapsulated chelating agent to the cellular membrane where the liposomes containing the chelating agent will be taken up by the cells, thereby transferring the chelating agent across the cellular membrane. A chelating agent can be introduced into the interior of a cell of a living organism wherein the liposomes will be decomposed, releasing the chelating agent to the interior of the cell. The released chelating agent will complex intracellularly deposited toxic heavy metals, permitting the more soluble metal complex to transfer across the cellular membrane from the cell and subsequently be removed from the living organism.

  11. 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.

  12. 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.

  13. 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.

  14. The effect of iron-chelating agents on Magnetospirillum magneticum strain AMB-1: stimulated growth and magnetosome production and improved magnetosome heating properties.

    PubMed

    Alphandéry, Edouard; Amor, Matthieu; Guyot, François; Chebbi, Imène

    2012-11-01

    The introduction of various iron-chelating agents to the Magnetospirillum magneticum strain AMB-1 bacterial growth medium stimulated the growth of M. magneticum strain AMB-1 magnetotactic bacteria and enhanced the production of magnetosomes. After 7 days of growth, the number of bacteria and the production of magnetosomes were increased in the presence of iron-chelating agents by factors of up to ∼2 and ∼6, respectively. The presence of iron-chelating agents also produced an increase in magnetosome size and chain length and yielded improved magnetosome heating properties. The specific absorption rate of suspensions of magnetosome chains isolated from M. magneticum strain AMB-1 magnetotactic bacteria, measured under the application of an alternating magnetic field of average field strength ∼20 mT and frequency 198 kHz, increased from ∼222 W/g(Fe) in the absence of iron-chelating agent up to ∼444 W/g(Fe) in the presence of 4 μM rhodamine B and to ∼723 W/g(Fe) in the presence of 4 μM EDTA. These observations were made at an iron concentration of 20 μM and iron-chelating agent concentrations below 40 μM.

  15. Synthesis and biological evaluation of bidentate 3-hydroxypyridin-4-ones iron chelating agents

    PubMed Central

    Saghaie, L.; Sadeghi-aliabadi, H.; Kafiri, M.

    2011-01-01

    A series of 3-hydroxypyridin-4-one derivatives (HPOs) were synthesized and their partition coefficient values (Kpart) were determined. The cytotoxic effects of these iron chelators against Hela cancer cells were also evaluated. The IC50 of HPOs was determined using MTT assay. Among these ligands, compound 4e (Kpart=5.02) with an IC50 of 30 μM and 4f (Kpart=0.1) with an IC50 of 700 μM showed the lowest and highest IC50s, respectively. In conclusion, the introduction of a more hydrophobic functional group (such as butyl in compound 4e) on the nitrogen of pyridinone ring resulted in higher cytotoxic activity of ligands. PMID:22224095

  16. 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.

  17. 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.

  18. Benzyl and Methyl Fatty Hydroxamic Acids Based on Palm Kernel Oil as Chelating Agent for Liquid-Liquid Iron(III) Extraction

    PubMed Central

    Haron, Md Jelas; Jahangirian, Hossein; Silong, Sidik; Yusof, Nor Azah; Kassim, Anuar; Rafiee-Moghaddam, Roshanak; Mahdavi, Behnam; Peyda, Mazyar; Abdollahi, Yadollah; Amin, Jamileh

    2012-01-01

    Liquid-liquid iron(III) extraction was investigated using benzyl fatty hydroxamic acids (BFHAs) and methyl fatty hydroxamic acids (MFHAs) as chelating agents through the formation of iron(III) methyl fatty hydroxamate (Fe-MFHs) or iron(III) benzyl fatty hydroxamate (Fe-BFHs) in the organic phase. The results obtained under optimized conditions, showed that the chelating agents in hexane extract iron(III) at pH 1.9 were realized effectively with a high percentage of extraction (97.2% and 98.1% for MFHAs and BFHAs, respectively). The presence of a large amount of Mg(II), Ni(II), Al(III), Mn(II) and Co(II) ions did affect the iron(III) extraction. Finally stripping studies for recovering iron(III) from organic phase (Fe-MFHs or Fe-BFHs dissolved in hexane) were carried out at various concentrations of HCl, HNO3 and H2SO4. The results showed that the desired acid for recovery of iron(III) was 5 M HCl and quantitative recovery of iron(III) was achieved from Fe(III)-MFHs and Fe(III)-BFHs solutions in hexane containing 5 mg/L of Fe(III). PMID:22408444

  19. 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

  20. Profound Morphological Changes in the Erythrocytes and Fibrin Networks of Patients with Hemochromatosis or with Hyperferritinemia, and Their Normalization by Iron Chelators and Other Agents

    PubMed Central

    Pretorius, Etheresia; Bester, Janette; Vermeulen, Natasha; Lipinski, Boguslaw; Gericke, George S.; Kell, Douglas B.

    2014-01-01

    It is well-known that individuals with increased iron levels are more prone to thrombotic diseases, mainly due to the presence of unliganded iron, and thereby the increased production of hydroxyl radicals. It is also known that erythrocytes (RBCs) may play an important role during thrombotic events. Therefore the purpose of the current study was to assess whether RBCs had an altered morphology in individuals with hereditary hemochromatosis (HH), as well as some who displayed hyperferritinemia (HF). Using scanning electron microscopy, we also assessed means by which the RBC and fibrin morphology might be normalized. An important objective was to test the hypothesis that the altered RBC morphology was due to the presence of excess unliganded iron by removing it through chelation. Very striking differences were observed, in that the erythrocytes from HH and HF individuals were distorted and had a much greater axial ratio compared to that accompanying the discoid appearance seen in the normal samples. The response to thrombin, and the appearance of a platelet-rich plasma smear, were also markedly different. These differences could largely be reversed by the iron chelator desferal and to some degree by the iron chelator clioquinol, or by the free radical trapping agents salicylate or selenite (that may themselves also be iron chelators). These findings are consistent with the view that the aberrant morphology of the HH and HF erythrocytes is caused, at least in part, by unliganded (‘free’) iron, whether derived directly via raised ferritin levels or otherwise, and that lowering it or affecting the consequences of its action may be of therapeutic benefit. The findings also bear on the question of the extent to which accepting blood donations from HH individuals may be desirable or otherwise. PMID:24416376

  1. 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.

  2. Biological activities of pyochelins: iron-chelating agents of Pseudomonas aeruginosa.

    PubMed Central

    Liu, P V; Shokrani, F

    1978-01-01

    Strains of Pseudomonas aeruginosa able to grow readily in serum (serum resistant) produce siderophores in large quantity, enabling them to extract iron from transferrins. The term pyochelin has been proposed for this group of compounds. Pyochelin extractable with ethyl acetate and designated pyochelin A appears to be a mixture of catechols and other phenolates. The structures of water-soluble siderophores, designated pyochelin B, have not been determined. Pyochelins enabled growth in serum of strains of serum-sensitive P. aeruginosa and other gram-negative bacilli. Serum-resistant strains of P. aeruginosa tended to be more virulent than equally toxigenic strains of the serum-sensitive group. However, incorporation of pyochelins into the inocula of serum-sensitive strains could reduce, rather than enhance, their virulence. Utilization of pyochelins by serum-sensitive strains of P. aeruginosa rendered some of these organisms resistant to pyocins which were otherwise lethal to them. Images PMID:103839

  3. 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. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. 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

  5. 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.

  6. 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.

  7. Novel chelating agents for iron, manganese, zinc, and copper mixed fertilisation in high pH soil-less cultures.

    PubMed

    López-Rayo, Sandra; Nadal, Paloma; Lucena, Juan J

    2016-03-15

    Studies about simultaneous fertilisation with several micronutrients have increased in recent years, as Fe, Mn and Zn deficiencies may appear in the same culture conditions. In fertigation, the replacement of sulfates by synthetic chelates is essential in areas with high pH irrigation water and substrates. Ethylenediamine-N-(2-hydroxyphenylacetic acid)-N'-(4-hydroxyphenylacetic acid) (o,p-EDDHA) and ethylenediamine disuccinic acid (EDDS) are novel chelating agents whose efficacy in simultaneous fertilisation of Zn, Mn and Cu is unknown. This work evaluates the effectiveness of both ligands compared to traditional ligands (EDTA, HEEDTA and DTPA) applied as micronutrient chelate mixtures to soybean and navy bean plants grown in soil-less cultures at high pH by analysing the SPAD and micronutrient nutritional status, including the Composition Nutritional Diagnosis (CND) analysis tool. The application of micronutrients using o,p-EDDHA was more effective in providing Mn and Zn than traditional ligands or sulfates. The application using EDDS increased the Zn nutrition. The results are well correlated with the chemical stability of the formulations. The combined application of Mn and Zn as o,p-EDDHA chelates can represent a more effective source than traditional chelates in micronutrient fertiliser mixtures in soil-less cultures at a high pH. © 2015 Society of Chemical Industry.

  8. Quantitative Analysis of the Anti-Proliferative Activity of Combinations of Selected Iron-Chelating Agents and Clinically Used Anti-Neoplastic Drugs

    PubMed Central

    Potuckova, Eliska; Jansova, Hana; Machacek, Miloslav; Vavrova, Anna; Haskova, Pavlina; Tichotova, Lucie; Richardson, Vera; Kalinowski, Danuta S.; Richardson, Des R.; Simunek, Tomas

    2014-01-01

    Recent studies have demonstrated that several chelators possess marked potential as potent anti-neoplastic drugs and as agents that can ameliorate some of the adverse effects associated with standard chemotherapy. Anti-cancer treatment employs combinations of several drugs that have different mechanisms of action. However, data regarding the potential interactions between iron chelators and established chemotherapeutics are lacking. Using estrogen receptor-positive MCF-7 breast cancer cells, we explored the combined anti-proliferative potential of four iron chelators, namely: desferrioxamine (DFO), salicylaldehyde isonicotinoyl hydrazone (SIH), (E)-N′-[1-(2-hydroxy-5-nitrophenyl)ethyliden] isonicotinoyl hydrazone (NHAPI), and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), plus six selected anti-neoplastic drugs. These six agents are used for breast cancer treatment and include: paclitaxel, 5-fluorouracil, doxorubicin, methotrexate, tamoxifen and 4-hydroperoxycyclophosphamide (an active metabolite of cyclophosphamide). Our quantitative chelator-drug analyses were designed according to the Chou-Talalay method for drug combination assessment. All combinations of these agents yielded concentration-dependent, anti-proliferative effects. The hydrophilic siderophore, DFO, imposed antagonism when used in combination with all six anti-tumor agents and this antagonistic effect increased with increasing dose. Conversely, synergistic interactions were observed with combinations of the lipophilic chelators, NHAPI or Dp44mT, with doxorubicin and also the combinations of SIH, NHAPI or Dp44mT with tamoxifen. The combination of Dp44mT with anti-neoplastic agents was further enhanced following formation of its redox-active iron and especially copper complexes. The most potent combinations of Dp44mT and NHAPI with tamoxifen were confirmed as synergistic using another estrogen receptor-expressing breast cancer cell line, T47D, but not estrogen receptor-negative MDA

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

    USDA-ARS?s Scientific Manuscript database

    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...

  10. A Review on Iron Chelators in Treatment of Iron Overload Syndromes

    PubMed Central

    Mobarra, Naser; Shanaki, Mehrnoosh; Ehteram, Hassan; Nasiri, Hajar; Sahmani, Mehdi; Saeidi, Mohsen; Goudarzi, Mehdi; Pourkarim, Hoda; Azad, Mehdi

    2016-01-01

    Iron chelation therapy is used to reduce iron overload development due to its deposition in various organs such as liver and heart after regular transfusion. In this review, different iron chelators implicated in treatment of iron overload in various clinical conditions have been evaluated using more up-to-date studies focusing on these therapeutic agents. Deferoxamine, Deferiprone and Deferasirox are the most important specific US FDA-approved iron chelators. Each of these chelators has their own advantages and disadvantages, various target diseases, levels of deposited iron and clinical symptoms of the afflicted patients which may affect their selection as the best modality. Taken together, in many clinical disorders, choosing a standard chelator does not have an accurate index which requires further clarifications. The aim of this review is to introduce and compare the different iron chelators regarding their advantages and disadvantages, usage dose and specific applications. PMID:27928480

  11. A Review on Iron Chelators in Treatment of Iron Overload Syndromes.

    PubMed

    Mobarra, Naser; Shanaki, Mehrnoosh; Ehteram, Hassan; Nasiri, Hajar; Sahmani, Mehdi; Saeidi, Mohsen; Goudarzi, Mehdi; Pourkarim, Hoda; Azad, Mehdi

    2016-10-01

    Iron chelation therapy is used to reduce iron overload development due to its deposition in various organs such as liver and heart after regular transfusion. In this review, different iron chelators implicated in treatment of iron overload in various clinical conditions have been evaluated using more up-to-date studies focusing on these therapeutic agents. Deferoxamine, Deferiprone and Deferasirox are the most important specific US FDA-approved iron chelators. Each of these chelators has their own advantages and disadvantages, various target diseases, levels of deposited iron and clinical symptoms of the afflicted patients which may affect their selection as the best modality. Taken together, in many clinical disorders, choosing a standard chelator does not have an accurate index which requires further clarifications. The aim of this review is to introduce and compare the different iron chelators regarding their advantages and disadvantages, usage dose and specific applications.

  12. Low-Molecular-Weight Iron Chelates May Be an Alternative to Gadolinium-based Contrast Agents for T1-weighted Contrast-enhanced MR Imaging.

    PubMed

    Boehm-Sturm, Philipp; Haeckel, Akvile; Hauptmann, Ralf; Mueller, Susanne; Kuhl, Christiane K; Schellenberger, Eyk A

    2017-01-07

    Purpose To synthesize two low-molecular-weight iron chelates and compare their T1 contrast effects with those of a commercial gadolinium-based contrast agent for their applicability in dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging. Materials and Methods The animal experiments were approved by the local ethics committee. Two previously described iron (Fe) chelates of pentetic acid (Fe-DTPA) and of trans-cyclohexane diamine tetraacetic acid (Fe-tCDTA) were synthesized with stability constants several orders of magnitude higher than those of gadolinium-based contrast agents. The T1 contrast effects of the two chelates were compared with those of gadopentetate dimeglumine in blood serum phantoms at 1.5 T, 3 T, and 7 T. For in vivo studies, a human breast cancer cell line (MDA-231) was implanted in five mice per group. The dynamic contrast effects of the chelates were compared by performing DCE MR imaging with intravenous application of Fe-DTPA or Fe-tCDTA on day 1 and DCE MR imaging in the same tumors with gadopentetate dimeglumine on day 2. Quantitative DCE maps were generated with software and were compared by means of a one-tailed Pearson correlation test. Results Relaxivities in serum (0.94 T at room temperature) of Fe-tCDTA (r1 = 2.2 mmol(-1) · sec(-1), r2 = 2.5 mmol(-1) · sec(-1)) and Fe-DTPA (r1 = 0.9 mmol(-1) · sec(-1), r2 = 0.9 mmol(-1) · sec(-1)) were approximately twofold and fivefold lower, respectively, compared with those of gadopentetate dimeglumine (r1 = 4.1 mmol(-1) · sec(-1), r2 = 4.8 mmol(-1) · sec(-1)). Used at moderately higher concentrations, however, iron chelates generated similar contrast effects at T1-weighted MR imaging in vitro in serum, in vivo in blood, and for DCE MR imaging of breast cancer xenografts. The volume transfer constant values for Fe-DTPA and Fe-tCDTA in the same tumors correlated well with those observed for gadopentetate dimeglumine (Fe-tCDTA Pearson R, 0.99; P = .0003; Fe-DTPA Pearson R, 0

  13. 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

  14. The Effect of Different Tea Varieties on Iron Chelation

    NASA Astrophysics Data System (ADS)

    Truong, S. K.; Karim, R.

    2016-12-01

    bond to iron. Among the teas being tested in this experiment, blackberry pomegranate green tea absorbed the most iron, thus acting as the superior chelating agent. Our experiment opens up new opportunities for investigations in chelation therapy and heavy metal poisoning through the knowledge of biological chelating agents.

  15. 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.

  16. Regional siderosis: a new challenge for iron chelation therapy

    PubMed Central

    Cabantchik, Zvi Ioav; Munnich, Arnold; Youdim, Moussa B.; Devos, David

    2013-01-01

    The traditional role of iron chelation therapy has been to reduce body iron burden via chelation of excess metal from organs and fluids and its excretion via biliary-fecal and/or urinary routes. In their present use for hemosiderosis, chelation regimens might not be suitable for treating disorders of iron maldistribution, as those are characterized by toxic islands of siderosis appearing in a background of normal or subnormal iron levels (e.g., sideroblastic anemias, neuro- and cardio-siderosis in Friedreich ataxia- and neurosiderosis in Parkinson's disease). We aimed at clearing local siderosis from aberrant labile metal that promotes oxidative damage, without interfering with essential local functions or with hematological iron-associated properties. For this purpose we introduced a conservative mode of iron chelation of dual activity, one based on scavenging labile metal but also redeploying it to cell acceptors or to physiological transferrin. The “scavenging and redeployment” mode of action was designed both for correcting aberrant iron distribution and also for minimizing/preventing systemic loss of chelated metal. We first examine cell models that recapitulate iron maldistribution and associated dysfunctions identified with Friedreich ataxia and Parkinson's disease and use them to explore the ability of the double-acting agent deferiprone, an orally active chelator, to mediate iron scavenging and redeployment and thereby causing functional improvement. We subsequently evaluate the concept in translational models of disease and finally assess its therapeutic potential in prospective double-blind pilot clinical trials. We claim that any chelator applied to diseases of regional siderosis, cardiac, neuronal or endocrine ought to preserve both systemic and regional iron levels. The proposed deferiprone-based therapy has provided a paradigm for treating regional types of siderosis without affecting hematological parameters and systemic functions. PMID:24427136

  17. A preliminary study on the interaction of ferritin single crystals with chelating agents

    NASA Astrophysics Data System (ADS)

    Domininguez-Vera, Jose M.; Rondón, Deyanira; Moreno, Abel; García-Ruiz, Juan Ma.

    1996-10-01

    The crystallization of ferritin and the subsequent in situ study of the process of iron removal from the crystals by using chelating agents is reported. The chelating agents, oxalate and acetohydroxamate, were chosen because of their high iron(III) affinity. The formation of the corresponding soluble iron(III) complexes arising from the reaction with the iron cores was detected by UV-visible spectroscopy. Furthermore, we show that for a given concentration range of the chelating agents, the iron removal process takes place without crystal destruction. This ferritin-apoferritin (or iron-depleted ferritin) conversion was followed by video-microscopy and checked by X-ray diffraction.

  18. Brazilian Thalassemia Association protocol for iron chelation therapy in patients under regular transfusion

    PubMed Central

    Veríssimo, Monica Pinheiro de Almeida; Loggetto, Sandra Regina; Fabron Junior, Antonio; Baldanzi, Giorgio Roberto; Hamerschlak, Nelson; Fernandes, Juliano Lara; Araujo, Aderson da Silva; Lobo, Clarisse Lopes de Castro; Fertrin, Kleber Yotsumoto; Berdoukas, Vasilios Antonios; Galanello, Renzo

    2013-01-01

    In the absence of an iron chelating agent, patients with beta-thalassemia on regular transfusions present complications of transfusion-related iron overload. Without iron chelation therapy, heart disease is the major cause of death; however, hepatic and endocrine complications also occur. Currently there are three iron chelating agents available for continuous use in patients with thalassemia on regular transfusions (desferrioxamine, deferiprone, and deferasirox) providing good results in reducing cardiac, hepatic and endocrine toxicity. These practice guidelines, prepared by the Scientific Committee of Associação Brasileira de Thalassemia (ABRASTA), presents a review of the literature regarding iron overload assessment (by imaging and laboratory exams) and the role of T2* magnetic resonance imaging (MRI) to control iron overload and iron chelation therapy, with evidence-based recommendations for each clinical situation. Based on this review, the authors propose an iron chelation protocol for patients with thalassemia under regular transfusions. PMID:24478610

  19. Iron-chelating compound from Mycobacterium avium.

    PubMed Central

    McCullough, W G; Merkal, R S

    1976-01-01

    A iron-chelating monohydroxamate was isolated from cultures of Mycobacterium avium grown on an iron-limiting medium. The hydroxyamate metabolite was characterized by chemical degradation and spectral measurements as L-alpha-asparaginyl-L-alpha-(N-hydroxy)-asparagine. PMID:185194

  20. 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.

  1. Objectives and Methods of Iron Chelation Therapy

    PubMed Central

    Hershko, C.; Abrahamov, A.; Konijn, A. M.; Breuer, W.; Cabantchik, I. Z.; Pootrakul, P.; Link, G.

    2003-01-01

    Recent developments in the understanding of the molecular control of iron homeostasis provided novel insights into the mechanisms responsible for normal iron balance. However in chronic anemias associated with iron overload, such mechanisms are no longer sufficient to offer protection from iron toxicity, and iron chelating therapy is the only method available for preventing early death caused mainly by myocardial and hepatic damage. Today, long-term deferoxamine (DFO) therapy is an integral part of the management of thalassemia and other transfusion-dependent anemias, with a major impact on well-being and survival. However, the high cost and rigorous requirements of DFO therapy, and the significant toxicity of deferiprone underline the need for the continued development of new and improved orally effective iron chelators. Within recent years more than one thousand candidate compounds have been screened in animal models. The most outstanding of these compounds include deferiprone (L1); pyridoxal isonicotinoyl hydrazone (PIH) and; bishydroxy- phenyl thiazole. Deferiprone has been used extensively as a substitute for DFO in clinical trials involving hundreds of patients. However, L1 treatment alone fails to achieve a negative iron balance in a substantial proportion of subjects. Deferiprone is less effective than DFO and its potential hepatotoxicity is an issue of current controversy. A new orally effective iron chelator should not necessarily be regarded as one displacing the presently accepted and highly effective parenteral drug DFO. Rather, it could be employed to extend the scope of iron chelating strategies in a manner analogous with the combined use of medications in the management of other conditions such as hypertension or diabetes. Coadministration or alternating use of DFO and a suitable oral chelator may allow a decrease in dosage of both drugs and improve compliance by decreasing the demand on tedious parenteral drug administration. Combined use of DFO

  2. Myelodysplastic Syndromes and Iron Chelation Therapy

    PubMed Central

    Angelucci, Emanuele; Urru, Silvana Anna Maria; Pilo, Federica; Piperno, Alberto

    2017-01-01

    Over recent decades we have been fortunate to witness the advent of new technologies and of an expanded knowledge and application of chelation therapies to the benefit of patients with iron overload. However, extrapolation of learnings from thalassemia to the myelodysplastic syndromes (MDS) has resulted in a fragmented and uncoordinated clinical evidence base. We’re therefore forced to change our understanding of MDS, looking with other eyes to observational studies that inform us about the relationship between iron and tissue damage in these subjects. The available evidence suggests that iron accumulation is prognostically significant in MDS, but levels of accumulation historically associated with organ damage (based on data generated in the thalassemias) are infrequent. Emerging experimental data have provided some insight into this paradox, as our understanding of iron-induced tissue damage has evolved from a process of progressive bulking of organs through high-volumes iron deposition, to one of ‘toxic’ damage inflicted through multiple cellular pathways. Damage from iron may, therefore, occur prior to reaching reference thresholds, and similarly, chelation may be of benefit before overt iron overload is seen. In this review, we revisit the scientific and clinical evidence for iron overload in MDS to better characterize the iron overload phenotype in these patients, which differs from the classical transfusional and non-transfusional iron overload syndrome. We hope this will provide a conceptual framework to better understand the complex associations between anemia, iron and clinical outcomes, to accelerate progress in this area. PMID:28293409

  3. Chelating agent-assisted heat treatment of a carbon-supported iron oxide nanoparticle catalyst for PEMFC.

    PubMed

    Liu, Shyh-Jiun; Huang, Chia-Hung; Huang, Chun-Kai; Hwang, Weng-Sing

    2009-08-28

    Iron complexes were supported on commercial carbon black and heat treated to create FeO(x)/C catalysts that showed a larger normalized current density and normalized power density than commercial Pt/C catalysts; the coordination number of the iron complexes used affected the formation of the active site for oxygen reduction in PEMFC.

  4. 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

  5. Iron chelation therapy in thalassemia syndromes.

    PubMed

    Cianciulli, Paolo

    2009-12-29

    Transfusional hemosiderosis is a frequent complication in patients with transfusion dependent chronic diseases such as thalassemias and severe type of sickle cell diseases. As there are no physiological mechanisms to excrete the iron contained in transfused red cells (1 unit of blood contains approximately 200 mg of iron) the excess of iron is stored in various organs. Cardiomyopathy is the most severe complication covering more than 70% of the causes of death of thalassemic patients. Although the current reference standard iron chelator deferoxamine (DFO) has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Despite poor compliance, because of the inconvenience of subcutaneous infusion, DFO improved considerably the survival and quality of life of patients with thalassemia. Deferiprone since 1998 and Deferasirox since 2005 were licensed for clinical use. The oral chelators have a better compliance because of oral use, a comparable efficacy to DFO in iron excretion and probably a better penetration to myocardial cells. Considerable increase in iron excretion was documented with combination therapy of DFO and Deferiprone. The proper use of the three chelators will improve the prevention and treatment of iron overload, it will reduce complications, and improve survival and quality of life of transfused patients.

  6. Iron Chelation Therapy in Thalassemia Syndromes

    PubMed Central

    Cianciulli, Paolo

    2009-01-01

    Transfusional hemosiderosis is a frequent complication in patients with transfusion dependent chronic diseases such as thalassemias and severe type of sickle cell diseases. As there are no physiological mechanisms to excrete the iron contained in transfused red cells (1 unit of blood contains approximately 200 mg of iron) the excess of iron is stored in various organs. Cardiomyopathy is the most severe complication covering more than 70% of the causes of death of thalassemic patients. Although the current reference standard iron chelator deferoxamine (DFO) has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Despite poor compliance, because of the inconvenience of subcutaneous infusion, DFO improved considerably the survival and quality of life of patients with thalassemia. Deferiprone since 1998 and Deferasirox since 2005 were licensed for clinical use. The oral chelators have a better compliance because of oral use, a comparable efficacy to DFO in iron excretion and probably a better penetration to myocardial cells. Considerable increase in iron excretion was documented with combination therapy of DFO and Deferiprone. The proper use of the three chelators will improve the prevention and treatment of iron overload, it will reduce complications, and improve survival and quality of life of transfused patients. PMID:21415999

  7. 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.

  8. 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.

  9. Modulation of iron metabolism by iron chelation regulates intracellular calcium and increases sensitivity to doxorubicin

    PubMed Central

    Yalcintepe, Leman; Halis, Emre

    2016-01-01

    Increased intracellular iron levels can both promote cell proliferation and death, as such; iron has a “two-sided effect” in the delicate balance of human health. Though the role of iron in the development of cancer remains unclear, investigations of iron chelators as anti-tumor agents have revealed promising results. Here, we investigated the influence of iron and desferrioxamine (DFO), the iron chelating agent on intracellular calcium in a human leukemia cell line, K562. Iron uptake is associated with increased reactive oxygen species (ROS) generation. Therefore, we showed that iron also caused dose-dependent ROS generation in K562 cells. The measurement of intracellular calcium was determined using Furo-2 with a fluorescence spectrophotometer. The iron delivery process to the cytoplasmic iron pool was examined by monitoring the fluorescence of cells loaded with calcein-acetoxymethyl. Our data showed that iron increased intracellular calcium, and this response was 8 times higher when cells were incubated with DFO. K562 cells with DFO caused a 3.5 times increase of intracellular calcium in the presence of doxorubicin (DOX). In conclusion, DFO induces intracellular calcium and increases their sensitivity to DOX, a chemotherapeutic agent. PMID:26773173

  10. 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.

  11. 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.

  12. Effect of trace iron levels and iron withdrawal by chelation on the growth of Candida albicans and Candida vini.

    PubMed

    Holbein, Bruce E; Mira de Orduña, Ramón

    2010-06-01

    The iron requirements of the opportunistic pathogenic yeast, Candida albicans, and the related nonpathogenic spoilage yeast Candida vini were investigated along with their responses to various exogenous iron chelators. The influence of iron as well as the exogenous chelating agents lactoferrin, EDTA, deferiprone, desferrioxamine, bathophenanthroline sulphonate and a novel carried chelator with a hydroxypyridinone-like Fe-ligand functionality, DIBI, on fungal growth was studied in a chemically defined medium deferrated to trace iron levels (<1.2 microg L(-1) or 0.02 microM of Fe). Candida albicans competed better at low iron levels compared with C. vini, which was also more susceptible to most added chelators. Candida albicans was resistant to lactoferrin at physiologically relevant concentrations, but was inhibited by low concentrations of DIBI. Candida vini was sensitive to lactoferrin as well as to DIBI, whose inhibitory activity was shown to be Fe reversible. The pathogenic potential of C. albicans and the nonpathogenic nature of C. vini were consistent with their differing abilities to grow under iron-limiting conditions and in the presence of exogenous iron chelators. Both yeasts could be controlled by appropriately strong chelators. This work provides the first evidence of the iron requirements of the spoilage organism C. vini and its response to exogenous chelators. Efficient iron withdrawal has the potential to provide the basis for new fungal growth control strategies.

  13. 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.

  14. Chromatographic methods for the separation of biocompatible iron chelators from their synthetic precursors and iron chelates.

    PubMed

    Kovaríková, Petra; Mokrý, Milan; Klime, Jirí; Vávrová, Katerina

    2004-12-01

    Chromatographic methods have been developed for the separation of the three novel biocompatible iron chelators pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), and pyridoxal 2-chlorobenzoyl hydrazone (o-108) from their synthetic precursors and iron chelates. The chromatographic analyses were achieved using analytical columns packed with 5 microm Nucleosil 120-5 C18. For the evaluation of all chelators in the presence of the synthetic precursors, EDTA was added to the mobile phase at a concentration of 2 mM. The best separation of PIH and its synthetic precursors was achieved using a mixture of phosphate buffer (0.01 M NaH2PO4, 5 mM 1-heptanesulfonic acid sodium salt; pH 3.0) and methanol (55:45, v/v). For separation of SIH and its synthetic precursors, the mobile phase was composed of 0.01 M phosphate buffer (pH 6.0) and methanol (60:40, v/v). o-108 was analyzed employing a mixture of 0.01 M phosphate buffer (pH 7.0), methanol, and acetonitrile (60:20:20, v/v/v). These mobile phases were slightly modified to separate each chelator from its iron chelate. Furthermore, a RP-TLC method has also been developed for fast separation of all compounds. The chromatographic methods described herein could be applied in the evaluation of purity and stability of these drug candidates.

  15. 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.

  16. 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.

  17. 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

  18. Ironing iron out in Parkinson's disease and other neurodegenerative diseases with iron chelators: a lesson from 6-hydroxydopamine and iron chelators, desferal and VK-28.

    PubMed

    Youdim, Moussa B H; Stephenson, Galia; Ben Shachar, Dorit

    2004-03-01

    In Parkinson's disease (PD) and its neurotoxin-induced models, 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), significant accumulation of iron occurs in the substantia nigra pars compacta. The iron is thought to be in a labile pool, unbound to ferritin, and is thought to have a pivotal role to induce oxidative stress-dependent neurodegeneration of dopamine neurons via Fenton chemistry. The consequence of this is its interaction with H(2)O(2) to generate the most reactive radical oxygen species, the hydroxyl radical. This scenario is supported by studies in both human and neurotoxin-induced parkinsonism showing that disposition of H(2)O(2) is compromised via depletion of glutathione (GSH), the rate-limiting cofactor of glutathione peroxide, the major enzyme source to dispose H(2)O(2) as water in the brain. Further, radical scavengers have been shown to prevent the neurotoxic action of the above neurotoxins and depletion of GSH. However, our group was the first to demonstrate that the prototype iron chelator, desferal, is a potent neuroprotective agent in the 6-OHDA model. We have extended these studies and examined the neuroprotective effect of intracerebraventricular (ICV) pretreatment with the prototype iron chelator, desferal (1.3, 13, 134 mg), on ICV induced 6-OHDA (250 micro g) lesion of striatal dopamine neurons. Desferal alone at the doses studied did not affect striatal tyrosine hydroxylase (TH) activity or dopamine (DA) metabolism. All three pretreatment (30 min) doses of desferal prevented the fall in striatal and frontal cortex DA, dihydroxyphenylacetic acid, and homovalinic acid, as well as the left and right striatum TH activity and DA turnover resulting from 6-OHDA lesion of dopaminergic neurons. A concentration bell-shaped neuroprotective effect of desferal was observed in the striatum, with 13 micro g being the most effective. Neither desferal nor 6-OHDA affected striatal serotonin, 5-hydroxyindole acetic acid, or

  19. The effect of ferrous-chelating hairtail peptides on iron deficiency and intestinal flora in rats.

    PubMed

    Lin, Hui-Min; Deng, Shang-Gui; Huang, Sai-Bo; Li, Ying-Jie; Song, Ru

    2016-06-01

    Chelating agents, such as small peptides, can decrease free iron content and increase iron bioavailability. They may have promising therapeutic potential and may prevent the pro-oxidant effects of low molecular weight iron. Hairtail is a species of fish that is rich in easily digestible proteins. We extended this strategy for iron delivery by using an enzymatic hydrolysate of hairtail as the chelating agent and found that the ferrous-chelating hairtail peptides have anti-anaemic activity in Sprague-Dawley rats with anaemia. The anti-anaemic activity of ferrous-chelating hairtail peptides prepared by enzymatic hydrolysis of the hairtail and ferrous chelation was studied in rat models of iron deficiency anaemia. After the end of the 35 d experiment, we noted significant differences in haemoglobin, mean corpuscular volume, haemoglobin distribution width, and ferritin concentrations between those animals supplemented with ferrous-chelating hairtail peptides and FeSO4 and healthy animals. There were no negative side effects on the animals' growth or behaviour. There was no obvious inflammation in the intestinal mucosa lamina propria and no unbalance of intestinal flora. The novel ferrous-chelating hairtail peptides may be a suitable fortificant for improving iron-deficiency status. Our findings demonstrated that this multi-tracer technique has many applications in nutritional research. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

  20. Piperazine derivatives as iron chelators: a potential application in neurobiology.

    PubMed

    Abdelsayed, S; Duong, N T Ha; Bureau, C; Michel, P P; Hirsch, E C; Chahine, J M El Hage; Serradji, N

    2015-12-01

    Polysubstituted piperazine derivatives, designed as new iron chelators, were synthesized and fully characterized by nuclear magnetic resonance and mass spectroscopy. Their potential to prevent iron-induced neurotoxicity was assessed using a cellular model of Parkinson disease. We demonstrated their ability to provide sustained neuroprotection to dopaminergic neurons that are vulnerable in this pathology. The iron chelating properties of the new compounds were determined by spectrophotometric titration illustrating that high affinity for iron is not associated with important neuroprotective effects.

  1. Iron release and uptake by plant ferritin: effects of pH, reduction and chelation.

    PubMed Central

    Laulhere, J P; Briat, J F

    1993-01-01

    Ferritins are iron-storage proteins that accumulate in plastids during seed formation, and also in leaves during senescence or iron overload. Iron release from ferritins occurs during growth of seedlings and greening of plastids. Depending on the concentration of the reducing agent ascorbate, either an overall iron release or uptake by ferritins from iron(III) citrate may occur. We have designed methods to measure these simultaneous and independent uptake and release fluxes. Each individual step of the exchange was studied using different iron chelates and an excess of ligand. It is shown that: (i) the chelated form of iron, and not ionic Fe3+, is the substrate for iron reduction, which controls the subsequent uptake by ferritin; (ii) iron uptake by ferritins is faster at pH 8.4 than at pH 7 or 6 and is inhibited by an excess of strongly binding free ligands; and (iii) strongly binding free ligands are inhibitory during iron release by ascorbate. When reactions are allowed to proceed simultaneously, the iron chelating power is shown to be a key factor in the overall exchange. The interactions of iron chelating power, reducing capacity and pH are discussed with regard to their influence on the biochemical mobilization of iron. Images Figure 1 Figure 6 Figure 7 PMID:8457196

  2. 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

  3. 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

  4. Iron chelators target both proliferating and quiescent cancer cells

    PubMed Central

    Fryknäs, Mårten; Zhang, Xiaonan; Bremberg, Ulf; Senkowski, Wojciech; Olofsson, Maria Hägg; Brandt, Peter; Persson, Ingmar; D’Arcy, Padraig; Gullbo, Joachim; Nygren, Peter; Schughart, Leoni Kunz; Linder, Stig; Larsson, Rolf

    2016-01-01

    Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells. PMID:27924826

  5. Iron chelators reduce chromosomal breaks in ataxia-telangiectasia cells.

    PubMed

    Shackelford, Rodney E; Fu, Yumei; Manuszak, Ryan P; Brooks, Torrie C; Sequeira, Adrian P; Wang, Suming; Lowery-Nordberg, Mary; Chen, Anping

    2006-11-08

    Ataxia-telangiectasia (A-T) is characterized by ataxia, genomic instability, and increased cancer incidence. Previously, iron chelator concentrations which suppressed normal cell colony formation increased A-T cell colony formation. Similarly, iron chelators preferentially increased A-T cell colony formation following peroxide exposure compared to normal cells. Last, A-T cells exhibited increased short-term sensitivity to labile iron exposure compared to normal cells, an event corrected by recombinant ATM (rATM) expression. Since chromosomal damage is important in A-T pathology and iron chelators exert beneficial effects on A-T cells, we hypothesized that iron chelators would reduce A-T cell chromosomal breaks. We treated A-T, normal, and A-T cells expressing rATM with labile iron, iron chelators, antioxidants, and t-butyl hydroperoxide, and examined chromosomal breaks and ATM activation. Additionally, the effect of ATM-deficiency on transferrin receptor (TfR) expression and TfR activity blockage in A-T and syngeneic A-T cells expressing rATM was examined. We report that (1) iron chelators and iron-free media reduce spontaneous and t-butyl hydroperoxide-induced chromosomal breaks in A-T, but not normal, or A-T cells expressing rATM; (2) labile iron exposure induces A-T cell chromosomal breaks, an event lessened with rATM expression; (3) desferal, labile iron, and copper activate ATM; (4) A-T cell TfR expression is lowered with rATM expression and (5) blocking TfR activity with anti-TfR antibodies increases A-T cell colony formation, while lowering chromosomal breaks. ATM therefore functions in iron responses and the maintenance of genomic stability following labile iron exposure.

  6. 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.

  7. 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.

  8. 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

  9. Synthesis, characterization and in vitro anticancer evaluations of two novel derivatives of deferasirox iron chelator.

    PubMed

    Salehi, Samie; Saljooghi, Amir Sh; Shiri, Ali

    2016-06-15

    Iron (Fe) chelation therapy was initially designed to alleviate the toxic effects of excess Fe evident in Fe-overload diseases. However, the novel toxicological properties of some Fe chelator-metal complexes have shifted significant attention to their application in cancer chemotherapy. The present study investigates the new role of deferasirox as an anticancer agent due to its ability to chelate with iron. Because of aminoacids antioxidant effect, deferasirox and its two novel amino acid derivatives have been synthesized through the treatment of deferasirox with DCC as well as glycine or phenylalanine methyl ester. All new compounds have been characterized by elemental analysis, FT-IR NMR and mass spectrometry. Therefore, the cytotoxicity of these compounds was screened for antitumor activity against some cell lines using cisplatin as a comparative standard by MTT assay and Flow cytometry. The impact of iron in the intracellular generation of reactive oxygen species was assessed on HT29 and MDA-MB-231 cells. The potential of the synthesized iron chelators for their efficacy to protect cells against model oxidative injury induced was compared. The reactive oxygen species intracellular fluorescence intensity were measured and the result showed that the reactive oxygen species intensity after iron incubation increased while after chelators incubation the reactive oxygen species intensity were decreased significantly. Besides, the effect of the synthesized compounds on mouse fibroblast cell line (L929) was simultaneously evaluated as control. The pharmacological results showed that deferasirox and its two novel aminoacid derivatives were potent anticancer agents.

  10. 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.

  11. Hydroxyurea Could Be a Good Clinically Relevant Iron Chelator

    PubMed Central

    Italia, Khushnooma; Colah, Roshan; Ghosh, Kanjaksha

    2013-01-01

    Our previous study showed a reduction in serum ferritin of β-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum-ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl’s Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination. PMID:24349400

  12. Hydroxyurea could be a good clinically relevant iron chelator.

    PubMed

    Italia, Khushnooma; Colah, Roshan; Ghosh, Kanjaksha

    2013-01-01

    Our previous study showed a reduction in serum ferritin of β-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum-ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl's Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination.

  13. 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

  14. Function of the iron-binding chelator produced by Coriolus versicolor in lignin biodegradation.

    PubMed

    Wang, Lu; Yan, WenChao; Chen, JiaChuan; Huang, Feng; Gao, PeiJi

    2008-03-01

    An ultrafiltered low-molecular-weight preparation of chelating compounds was isolated from a wood-containing culture of the white-rot basidiomycete Coriolus versicolor. This preparation could chelate Fe3+ and reduce Fe3+ to Fe2+, demonstrating that the substance may serve as a ferric chelator, oxygen-reducing agent, and redox-cycling molecule, which would include functioning as the electron transport carrier in Fenton reaction. Lignin was treated with the iron-binding chelator and the changes in structure were investigated by 1H-NMR, 13C-NMR, difference spectrum caused by ionization under alkaline conditions and nitrobenzene oxidation. The results indicated that the iron-binding chelator could destroy the beta-O-4 bonds in etherified lignin units and insert phenolic hydroxyl groups. The low-molecular-weight chelator secreted by C. versicolor resulted in new phenolic substructures in the lignin polymer, making it susceptible to attack by laccase or manganese peroxidase. Thus, the synergic action of the iron-binding chelator and the lignocellulolytic enzymes made the substrate more accessible to degradation.

  15. Oxidation-Induced Degradable Nanogels for Iron Chelation

    NASA Astrophysics Data System (ADS)

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

    2016-02-01

    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.

  16. 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

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

    USDA-ARS?s Scientific Manuscript database

    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...

  18. Methyl and ethyl ketone analogs of salicylaldehyde isonicotinoyl hydrazone: novel iron chelators with selective antiproliferative action.

    PubMed

    Macková, Eliška; Hrušková, Kateřina; Bendová, Petra; Vávrová, Anna; Jansová, Hana; Hašková, Pavlína; Kovaříková, Petra; Vávrová, Kateřina; Simůnek, Tomáš

    2012-05-30

    Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, orally-active tridentate iron chelator providing both effective protection against various types of oxidative stress-induced cellular injury and anticancer action. However, the major limitation of SIH is represented by its labile hydrazone bond that makes it prone to plasma hydrolysis. Recently, nine new SIH analogues derived from aromatic ketones with improved hydrolytic stability were developed. Here we analyzed their antiproliferative potential in MCF-7 breast adenocarcinoma and HL-60 promyelocytic leukemia cell lines. Seven of the tested substances showed greater selectivity than the parent agent SIH towards the latter cancer cell lines compared to non-cancerous H9c2 cardiomyoblast-derived cells. The tested chelators induced a dose-dependent dissipation of the inner mitochondrial membrane potential, an induction of apoptosis as evidenced by Annexin V positivity or significant increases of activities of caspases 3, 7, 8 and 9 and cell cycle arrest. With the exception of nitro group-bearing NHAPI, the studies of iron complexes of the chelators confirmed the crucial role of iron in the mechanism of their antiproliferative action. Finally, all the assayed chelators inhibited the oxidation of ascorbate by iron ions indicating lack of redox activity of the chelator-iron complexes. In conclusion, this study identified several important design criteria for improvement of the antiproliferative selectivity of the aroylhydrazone iron chelators. Several of the novel compounds--in particular the ethylketone-derived HPPI, NHAPI and acetyl-substituted A2,4DHAPI--merit deeper investigation as promising potent and selective anticancer agents. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  19. 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

  20. Nanoparticle and iron chelators as a potential novel Alzheimer therapy.

    PubMed

    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.

  1. 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.

  2. 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.

  3. Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression

    PubMed Central

    Mertens, Christina; Akam, Eman Abureida; Rehwald, Claudia; Brüne, Bernhard; Tomat, Elisa

    2016-01-01

    A growing body of evidence suggests that macrophage polarization dictates the expression of iron-regulated genes. Polarization towards iron sequestration depletes the microenvironment, whereby extracellular pathogen growth is limited and inflammation is fostered. In contrast, iron release contributes to cell proliferation, which is important for tissue regeneration. Moreover, macrophages constitute a major component of the infiltrates in most solid tumors. Considering the pivotal role of macrophages for iron homeostasis and their presence in association with poor clinical prognosis in tumors, we approached the possibility to target macrophages with intracellular iron chelators. Analyzing the expression of iron-regulated genes at mRNA and protein level in primary human macrophages, we found that the iron-release phenotype is a characteristic of polarized macrophages that, in turn, stimulate tumor cell growth and progression. The application of the intracellular iron chelator (TC3-S)2 shifted the macrophage phenotype from iron release towards sequestration, as determined by the iron-gene profile and atomic absorption spectroscopy (AAS). Moreover, whereas the addition of macrophage supernatants to tumor cells induced tumor growth and metastatic behavior, the supernatant of chelator-treated macrophages reversed this effect. Iron chelators demonstrated potent anti-neoplastic properties in a number of cancers, both in cell culture and in clinical trials. Our results suggest that iron chelation could affect not only cancer cells but also the tumor microenvironment by altering the iron-release phenotype of tumor-associated macrophages (TAMs). The study of iron chelators in conjunction with the effect of TAMs on tumor growth could lead to an improved understanding of the role of iron in cancer biology and to novel therapeutic avenues for iron chelation approaches. PMID:27806101

  4. Chelating agents used for plutonium and uranium removal in radiation emergency medicine.

    PubMed

    Fukuda, Satoshi

    2005-01-01

    The prospects of using chelating agents for increasing the excretion of actinides are reviewed. The removal of plutonium by chelating agents is of great importance because plutonium is extremely dangerous and induces cancer due to radiation toxicity. Similarly, uranium is a radionuclide, which causes severe renal dysfunction within a short time period due to chemical toxicity. It may also induce cancers such as leukemia and osteosarcoma in cases of long-term internal radiation exposure. Investigations on chelating agents for the removal of plutonium were initiated in the 1960's and 1970's. Diethylenetriaminepentaacetic acid (DTPA) is recognized as a chelating agent that accelerates the excretion of plutonium in early treatment after an accident. Thereafter, there has long been an interest in finding new chelating agents with radionuclide removal properties for use in therapy, and many chelating agents such as 3,4,3-LIHOPO and CBMIDA have been studied for their ability to remove plutonium and uranium. Recently, the focus has turned to drugs that have been used successfully in the treatment of a variety of other diseases, for example the iron chelating drug deferiprone or 1,2-dimethyl-3-hydroxypyrid-4-one (L1), which is used in thalassaemia and ethane-1-hydroxy-1,1-bisphosphonate (EHBP), which is used in osteoporosis. Within this context, it is important to examine the clinical use of these two drugs as well as the properties of the experimental chelators 3,4,3-LIHOPO and CBMIDA in order to identify possible uses in the treatment of radiation workers contaminated with plutonium and uranium.

  5. Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator.

    PubMed

    Vlachodimitropoulou, Evangelia; Chen, Yu-Lin; Garbowski, Maciej; Koonyosying, Pimpisid; Psaila, Bethan; Sola-Visner, Martha; Cooper, Nichola; Hider, Robert; Porter, John

    2017-09-01

    Eltrombopag (ELT) is a thrombopoietin receptor agonist, also reported to decrease labile iron in leukemia cells. Here we examine the previously undescribed iron(III)-coordinating and cellular iron-mobilizing properties of ELT. We find a high binding constant for iron(III) (log β2=35). Clinically achievable concentrations (1μM) progressively mobilised cellular iron from hepatocyte, cardiomyocyte and pancreatic cell lines, rapidly decreasing intracellular ROS and also restoring insulin secretion in pancreatic cells. Decrements in cellular ferritin paraleled total cellular iron removal, particularly in hepatocytes. Iron mobilisation from cardiomyocytes exceeded that obtained with deferiprone, desferrioxamine or deferasirox at similar iron-binding equivalents. When combined with these chelators, ELT enhanced cellular iron mobilisation, this being greater than additive (synergistic) with deferasirox. Iron-binding speciation plots are consistent with ELT donating iron to deferasirox at clinically relevant concentrations. ELT scavenges iron citrate species faster than deferasirox, but rapidly donates the chelated iron to deferasirox, consistent with a shuttling mechanism. Shuttling is also suggested by enhanced cellular iron mobilisation by ELT when combined with the otherwise ineffective extracellular hydroxypyridinone chelator, CP40. We conclude that ELT is a powerful iron chelator that decreases cellular iron and further enhances iron mobilisation when combined with clinically available chelators. Copyright © 2017 American Society of Hematology.

  6. Assessment of iron chelates efficiency for photo-Fenton at neutral pH.

    PubMed

    De Luca, Antonella; Dantas, Renato F; Esplugas, Santiago

    2014-09-15

    In this study, homogeneous photo-Fenton like at neutral pH was applied to remove sulfamethoxazole from water. The process was performed using different chelating agents in order to solubilize iron in a neutral water solution. The chelating agents tested were: ethylenediaminetetraacetic acid (EDTA); nitrilotriacetic acid (NTA); oxalic acid (OA) and tartaric acid (TA). The iron leaching was monitored over reaction time to evaluate the chelates stability and their resistance to HO· and UV-A radiation. Chelates of EDTA and NTA presented more stability than OA and TA, which also confirmed their higher efficiency. Total Organic Carbon (TOC) analyses were also performed to evaluate the contribution in terms of solution contamination related to the use of chelating agents. The better properties of biodegradability in respect of EDTA combined with better efficiency in terms of microcontaminant removal and the smallest TOC contribution indicate that NTA could represent a useful option to perform photo-Fenton processes at neutral pH. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. 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

  8. Comparison of clinically used and experimental iron chelators for protection against oxidative stress-induced cellular injury.

    PubMed

    Bendova, Petra; Mackova, Eliska; Haskova, Pavlina; Vavrova, Anna; Jirkovsky, Eduard; Sterba, Martin; Popelova, Olga; Kalinowski, Danuta S; Kovarikova, Petra; Vavrova, Katerina; Richardson, Des R; Simunek, Tomas

    2010-06-21

    Iron imbalance plays an important role in oxidative stress associated with numerous pathological conditions. Therefore, iron chelation may be an effective therapeutic approach, but progress in this area is hindered by the lack of effective ligands. Also, the potential favorable effects of chelators against oxidative injury have to be balanced against their own toxicity due to iron depletion and the ability to generate redox-active iron complexes. In this study, we compared selected iron chelators (both drugs used in clinical practice as well as experimental agents) for their efficacy to protect cells against model oxidative injury induced by tert-butyl hydroperoxide (t-BHP). In addition, intracellular chelation efficiency, redox activity, and the cytotoxicity of the chelators and their iron complexes were assayed. Ethylenediaminetetraacetic acid failed to protect cells against t-BHP cytotoxicity, apparently due to the redox activity of the formed iron complex. Hydrophilic desferrioxamine exerted some protection but only at very high clinically unachievable concentrations. The smaller and more lipophilic chelators, deferiprone, deferasirox, and pyridoxal isonicotinoyl hydrazone, were markedly more effective at preventing oxidative injury of cells. The most effective chelator in terms of access to the intracellular labile iron pool was di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone. However, overall, the most favorable properties in terms of protective efficiency against t-BHP and the chelator's own inherent cytotoxicity were observed with salicylaldehyde isonicotinoyl hydrazone. This probably relates to the optimal lipophilicity of this latter agent and its ability to generate iron complexes that do not induce marked redox activity.

  9. Steam iron cleaner poisoning

    MedlinePlus

    Chelating agent poisoning; Mineral deposit remover poisoning ... harmful chemicals in steam iron cleaner are: Chelating agents Hydroxyacetic acid Phosphoric acid Sodium hydroxide (dilute) Sulfuric ...

  10. 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.

  11. 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.

  12. 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.

  13. Cardioprotective effects of iron chelator HAPI and ROS-activated boronate prochelator BHAPI against catecholamine-induced oxidative cellular injury.

    PubMed

    Hašková, Pavlína; Jansová, Hana; Bureš, Jan; Macháček, Miloslav; Jirkovská, Anna; Franz, Katherine J; Kovaříková, Petra; Šimůnek, Tomáš

    2016-09-14

    Catecholamines may undergo iron-promoted oxidation resulting in formation of reactive intermediates (aminochromes) capable of redox cycling and reactive oxygen species (ROS) formation. Both of them induce oxidative stress resulting in cellular damage and death. Iron chelation has been recently shown as a suitable tool of cardioprotection with considerable potential to protect cardiac cells against catecholamine-induced cardiotoxicity. However, prolonged exposure of cells to classical chelators may interfere with physiological iron homeostasis. Prochelators represent a more advanced approach to decrease oxidative injury by forming a chelating agent only under the disease-specific conditions associated with oxidative stress. Novel prochelator (lacking any iron chelating properties) BHAPI [(E)-Ń-(1-(2-((4-(4,4,5,5-tetramethyl-1,2,3-dioxoborolan-2-yl)benzyl)oxy)phenyl)ethylidene) isonicotinohydrazide] is converted by ROS to active chelator HAPI with strong iron binding capacity that efficiently inhibits iron-catalyzed hydroxyl radical generation. Our results confirmed redox activity of oxidation products of catecholamines isoprenaline and epinephrine, that were able to activate BHAPI to HAPI that chelates iron ions inside H9c2 cardiomyoblasts. Both HAPI and BHAPI were able to efficiently protect the cells against intracellular ROS formation, depletion of reduced glutathione and toxicity induced by catecholamines and their oxidation products. Hence, both HAPI and BHAPI have shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. XAS studies of the effectiveness of iron chelating treatments of Mary Rose timbers

    NASA Astrophysics Data System (ADS)

    Berko, A.; Smith, A. D.; Jones, A. M.; Schofield, E. J.; Mosselmans, J. F. W.; Chadwick, A. V.

    2009-11-01

    The oxidation of sulfur in marine archaeological timbers under museum storage conditions is a recently identified problem, particularly for major artefacts such as historic ships excavated from the seabed. Recent work on the Vasa has stressed the role of iron in catalysing the oxidative degradation of the wood cellulose and the polyethylene glycols used to restore mechanical integrity to the timbers. In developing new treatment protocols for the long term preservation of Henry VIII of England's flagship, the Mary Rose, we are investigating the potential of chelating agents to neutralise and remove the iron products from the ships timbers. We have explored the use of aqueous solutions of chelating agents of calcium phytate, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) and ammonium citrate to extract the iron compounds. All of these solutions exhibit some level of iron removal; however the key is to find the most effective concentration at pH of around 7 of the reagent solution, to minimise the treatment time and find the most cost-effective treatment for the whole of the Mary Rose hull. Fe K-edge XAFS data from samples of Mary Rose timbers, before and after treatment by the chelating agents mentioned has been collected. The data collected provide valuable insights into the effectiveness of the treatment solutions.

  15. Iron chelation therapy in the management of thalassemia: the Asian perspectives.

    PubMed

    Viprakasit, Vip; Lee-Lee, Chan; Chong, Quah Thuan; Lin, Kai-Hsin; Khuhapinant, Archrob

    2009-11-01

    Worldwide, thalassemia is the most commonly inherited hemolytic anemia, and it is most prevalent in Asia and the Middle East. Iron overload represents a significant problem in patients with transfusion-dependent beta-thalassemia. Chelation therapy with deferoxamine has traditionally been the standard therapeutic option but its usage is tempered by suboptimal patient compliance due to the discomfort and demands associated with the administration regimen. Therefore, a great deal of attention has been focused on the development of oral chelating agents. Deferiprone, even though available for nearly two decades in Asia with recent encouraging data on cardiac iron removal and long-term efficacy, has serious adverse effects including agranulocytosis and neutropenia which has impeded it from routine clinical practice. A novel oral chelator; deferasirox is effective throughout a 24 h dosing period and both preclinical and clinical data indicate that it successfully removes both hepatic and cardiac iron. In Asia, optimal management of severe thalassemia patients and the availability and access to oral iron chelators still presents a major challenge in many countries. In this regard, the development and implementation of consensus guidelines for management of Asian patients with transfusion-dependent thalassemia will be a major step towards improving and maintaining the continuity of patient care.

  16. Characterization of cytoprotective and toxic properties of iron chelator SIH, prochelator BSIH and their degradation products

    PubMed Central

    Jansová, Hana; Bureš, Jan; Macháček, Miloslav; Hašková, Pavlína; Jirkovská, Anna; Roh, Jaroslav; Wang, Qin; Franz, Katherine J.; Kovaříková, Petra; Šimůnek, Tomáš

    2016-01-01

    Free cellular iron catalyzes the formation of toxic hydroxyl radicals and therefore chelation of iron could be a promising therapeutic approach in pathological states associated with oxidative stress. Salicylaldehyde isonicotinoyl hydrazone (SIH) is a strong intracellular iron chelator with well documented potential to protect against oxidative damage both in vitro and in vivo. Due to the short biological half-life of SIH and risk of toxicity due to iron depletion, boronate prochelator BSIH has been designed. BSIH cannot bind iron until it is activated by certain reactive oxygen species to active chelator SIH. The aim of this study was to examine the toxicity and cytoprotective potential of BSIH, SIH, and their decomposition products against hydrogen peroxide-induced injury of H9c2 cardiomyoblast cells. Using HPLC, we observed that salicylaldehyde was the main decomposition products of SIH and BSIH, although a small amount of salicylic acid was also detected. In the case of BSIH, the concentration of formed salicylaldehyde consistently exceeded that of SIH. Isoniazid and salicylic acid were not toxic nor did they provide any antioxidant protective effect in H9c2 cells. In contrast, salicylaldehyde was able to chelate intracellular iron and significantly preserve cellular viability and mitochondrial inner membrane potential induced by hydrogen peroxide. However it was consistently less effective than SIH. The inherent toxicities of salicylaldehyde and SIH were similar. Hence, although SIH - the active chelating agent formed following the BSIH activation - undergoes rapid hydrolysis, its principal decomposition product salicylaldehyde accounts markedly for both cytoprotective and toxic properties. PMID:27046792

  17. Characterization of cytoprotective and toxic properties of iron chelator SIH, prochelator BSIH and their degradation products.

    PubMed

    Jansová, Hana; Bureš, Jan; Macháček, Miloslav; Hašková, Pavlína; Jirkovská, Anna; Roh, Jaroslav; Wang, Qin; Franz, Katherine J; Kovaříková, Petra; Šimůnek, Tomáš

    2016-03-28

    Free cellular iron catalyzes the formation of toxic hydroxyl radicals and therefore chelation of iron could be a promising therapeutic approach in pathological states associated with oxidative stress. Salicylaldehyde isonicotinoyl hydrazone (SIH) is a strong intracellular iron chelator with well documented potential to protect against oxidative damage both in vitro and in vivo. Due to the short biological half-life of SIH and risk of toxicity due to iron depletion, boronate prochelator BSIH has been designed. BSIH cannot bind iron until it is activated by certain reactive oxygen species to active chelator SIH. The aim of this study was to examine the toxicity and cytoprotective potential of BSIH, SIH, and their decomposition products against hydrogen peroxide-induced injury of H9c2 cardiomyoblast cells. Using HPLC, we observed that salicylaldehyde was the main decomposition products of SIH and BSIH, although a small amount of salicylic acid was also detected. In the case of BSIH, the concentration of formed salicylaldehyde consistently exceeded that of SIH. Isoniazid and salicylic acid were not toxic nor did they provide any antioxidant protective effect in H9c2 cells. In contrast, salicylaldehyde was able to chelate intracellular iron and significantly preserve cellular viability and mitochondrial inner membrane potential induced by hydrogen peroxide. However it was consistently less effective than SIH. The inherent toxicities of salicylaldehyde and SIH were similar. Hence, although SIH - the active chelating agent formed following the BSIH activation - undergoes rapid hydrolysis, its principal decomposition product salicylaldehyde accounts markedly for both cytoprotective and toxic properties. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. 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. © 2013.

  19. Chelate assisted phytoextraction of heavy metals from soil. Effect, mechanism, toxicity, and fate of chelating agents.

    PubMed

    Evangelou, Michael W H; Ebel, Mathias; Schaeffer, Andreas

    2007-06-01

    The low-cost, plant-based phytoextraction technique has often been described as a promising technique to remediate heavy metal contaminated agricultural land. The application of chelating agents has shown positive effects in increasing the solubility of heavy metals in soil and therefore in enhancing phytoextraction. This paper gives an overview of the chelating agents applied in recent studies. Various synthetic aminopolycarboxylic acids, such as ethylene diamine tetraacetic acid, and natural ones such as, ethylene diamine disuccinate and nitrilotriacetic acid, are described. Additionally, results of the application of natural low molecular weight organic acids, such as citric and tartaric acid are given. The effectiveness of these different chelating agents varies according to the plant and the heavy metals used. Furthermore, a focus is laid on the chelating agents fate after application and on its toxicity to plants and soil microorganisms, as well as it degradation. The rate of degradation is of great importance for the future of chelate assisted phytoextraction as it has a direct impact on the leaching probability. An effective prevention of leaching will be crucial for the acceptance and the economic breakthrough of enhanced phytoextraction, but a satisfactory solution to this key issue has so far not been found. Possibly further experiments in the field of enhanced phytoextraction will be able to solve this major problem, but over decades various greenhouse experiments and recently field experiments have resulted in different observations. Therefore, it is questionable if further research in this direction will lead to a promising solution. Phytoextraction has possibly reached a turning point in which it should distance itself from chelate assisted phytoextraction and focus on alternative options.

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

    PubMed Central

    Eybl, V; Sýkora, J; Koutenský, J; Caisová, D; Schwartz, A; Mertl, F

    1984-01-01

    The influence of several chelating agents (CaDTPA, ZnDTPA, CaEDTA, ZnEDTA, DMSA, D-penicillamine and DMPS, DMP and DDC) on the acute toxicity of CdCl2 and on the whole body retention and tissue distribution of cadmium after the IV application of 115mCdCl2 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 treatment 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 of the retention and distribution of Cd in mice, it was demonstrated that the combined 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 CdCl2 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 115mCd-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. PMID:6734561

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. Liver iron stores in patients with secondary haemosiderosis under iron chelation therapy with deferoxamine or deferiprone.

    PubMed

    Nielsen, P; Fischer, R; Engelhardt, R; Tondüry, P; Gabbe, E E; Janka, G E

    1995-12-01

    Total body iron stores including liver and spleen iron were assessed by non-invasive SQUID biomagnetometry. The liver iron concentration was measured in groups of patients with beta-thalassaemia major or other posttransfusional siderosis under treatment with the oral iron chelator deferiprone (n = 19) and/or with parenteral deferoxamine (n = 33). An interquartile range for liver iron concentrations of 1680-4470 micrograms/g liver was found in these patients. In both groups a poor correlation between liver iron and serum ferritin values was observed. Repeated measurements of liver and spleen iron concentrations as well as determination of liver and spleen volume by sonography were performed in six patients under continuous deferiprone treatment for 3-15 months. In this group detailed information was obtained on the whole body iron store (5-36g) and the iron excretion rates (14-34 mg/d) for each patient. As indicated by decreasing liver iron concentrations, five out of six subjects showed a negative iron balance (2-13 mg/d). Conventional measurements of both serum ferritin and urine iron excretion gave fluctuating results, thus being only of limited use in the control of iron depletion therapy. The non-invasive biomagnetic liver iron quantification is a precise and clinically verified technique which offers more direct information on the long-term efficacy of an iron depletion therapy than the hitherto used methods. This technique may be of use in the clinical evaluation of new oral iron chelators.

  6. Combined Therapy of Iron Chelator and Antioxidant Completely Restores Brain Dysfunction Induced by Iron Toxicity

    PubMed Central

    Sripetchwandee, Jirapas; Pipatpiboon, Noppamas; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2014-01-01

    Background Excessive iron accumulation leads to iron toxicity in the brain; however the underlying mechanism is unclear. We investigated the effects of iron overload induced by high iron-diet consumption on brain mitochondrial function, brain synaptic plasticity and learning and memory. Iron chelator (deferiprone) and antioxidant (n-acetyl cysteine) effects on iron-overload brains were also studied. Methodology Male Wistar rats were fed either normal diet or high iron-diet consumption for 12 weeks, after which rats in each diet group were treated with vehicle or deferiprone (50 mg/kg) or n-acetyl cysteine (100 mg/kg) or both for another 4 weeks. High iron-diet consumption caused brain iron accumulation, brain mitochondrial dysfunction, impaired brain synaptic plasticity and cognition, blood-brain-barrier breakdown, and brain apoptosis. Although both iron chelator and antioxidant attenuated these deleterious effects, combined therapy provided more robust results. Conclusion In conclusion, this is the first study demonstrating that combined iron chelator and anti-oxidant therapy completely restored brain function impaired by iron overload. PMID:24400127

  7. Iron chelators in photodynamic therapy revisited: synergistic effect by novel highly active thiosemicarbazones.

    PubMed

    Mrozek-Wilczkiewicz, Anna; Serda, Maciej; Musiol, Robert; Malecki, Grzegorz; Szurko, Agnieszka; Muchowicz, Angelika; Golab, Jakub; Ratuszna, Alicja; Polanski, Jaroslaw

    2014-04-10

    In photodynamic therapy (PDT), a noninvasive anticancer treatment, visible light, is used as a magic bullet selectively destroying cancer cells by a photosensitizer that is nontoxic in the dark. Protoporphyrin IX (PpIX) is a natural photosensitizer synthesized in the cell, which is also a chelating agent that if bonded to Fe(2+) forms heme, a central component of hemoglobin. Therefore, xenobiotic iron chelators can disturb iron homeostasis, increasing the accumulation of PpIX, obstructing the last step of heme biosynthesis, and enhancing PDT efficiency. However, the attempts to use this promising idea have not proved to be hugely successful. Herein, we revisited this issue by analyzing the application of iron chelators highly toxic in the dark, which should have higher Fe(2+) affinity than the nontoxic chelators used so far. We have designed and prepared thiosemicarbazones (TSC) with the highest dark cellular cytotoxicity among TSCs ever reported. We demonstrate that compound 2 exerts powerful PDT enhancement when used in combination with 5-aminolevulinic acid (ALA), a precursor of PpIX.

  8. Iron Chelators in Photodynamic Therapy Revisited: Synergistic Effect by Novel Highly Active Thiosemicarbazones

    PubMed Central

    2014-01-01

    In photodynamic therapy (PDT), a noninvasive anticancer treatment, visible light, is used as a magic bullet selectively destroying cancer cells by a photosensitizer that is nontoxic in the dark. Protoporphyrin IX (PpIX) is a natural photosensitizer synthesized in the cell, which is also a chelating agent that if bonded to Fe2+ forms heme, a central component of hemoglobin. Therefore, xenobiotic iron chelators can disturb iron homeostasis, increasing the accumulation of PpIX, obstructing the last step of heme biosynthesis, and enhancing PDT efficiency. However, the attempts to use this promising idea have not proved to be hugely successful. Herein, we revisited this issue by analyzing the application of iron chelators highly toxic in the dark, which should have higher Fe2+ affinity than the nontoxic chelators used so far. We have designed and prepared thiosemicarbazones (TSC) with the highest dark cellular cytotoxicity among TSCs ever reported. We demonstrate that compound 2 exerts powerful PDT enhancement when used in combination with 5-aminolevulinic acid (ALA), a precursor of PpIX. PMID:24900837

  9. 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

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

    PubMed

    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

    2015-08-20

    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 (59)Fe 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

  11. ATMP-stabilized iron nanoparticles: chelator-controlled nanoparticle synthesis

    NASA Astrophysics Data System (ADS)

    Greenlee, Lauren F.; Rentz, Nikki S.

    2014-11-01

    In this study, we characterize iron nanoparticles synthesized in water in the presence of a phosphonate chelator, amino tris(methylene phosphonic acid) (ATMP) for a range of molar ratios of ATMP to iron. An increase in the molar ratio from 0.05 to 0.8 decreases nanoparticle size from approximately 150 nm to less than 10 nm. Zeta potential measurements were used to evaluate colloidal stability. Zeta potential values varied as a function of pH, and zeta potential values decreased with increasing pH. At lower molar ratios of ATMP to iron, the zeta potential varied between 15 and -40 mV, passing through an isoelectric point at pH 7.5. At higher ratios, the zeta potential was negative across the measured pH range of 2-12 and varied from -2 to -55 mV. Diffraction analysis indicates that ATMP-stabilized iron nanoparticles may have a nano-crystalline structure, potentially with regions of amorphous iron. Characterization results of ATMP-stabilized iron nanoparticles are compared to results obtained for carboxymethyl cellulose (CMC)-stabilized iron nanoparticles. CMC stabilization caused similar peak broadening in diffraction spectra as for ATMP, suggesting similar nano-crystalline/amorphous structure; however, an increase in the molar ratio of CMC to iron did not cause the same reduction in nanoparticle size as was observed for ATMP-stabilized iron nanoparticles.

  12. Oral iron chelation and the treatment of iron overload in a pediatric hematology center.

    PubMed

    Raphael, Jean L; Bernhardt, M Brooke; Mahoney, Donald H; Mueller, Brigitta U

    2009-05-01

    Recent advances have led to the development of oral iron chelators, which have changed clinical practice. The objective of this study was to descriptively assess the use of one such agent, deferasirox, as standard of care treatment in a large pediatric hematology center. We retrospectively studied all patients at the Texas Children's Hematology Center who were previously or currently treated with deferasirox. We gathered data on demographics, clinical diagnoses, length of time on chronic transfusions, previous use of deferoxamine, adherence to therapy, and reasons for discontinuation. We also assessed changes in serum ferritin, liver function tests, and creatinine for those on deferasirox for a minimum of 12 months. Fifty-nine patients were studied. Eighty-one percent of patients treated with deferasirox had a diagnosis of sickle cell disease. The mean baseline ferritin level for our study population was 2,117 ng/ml (range 754-7,211). Fifty-three percent of patients had been previously treated with deferoxamine. Adherence to oral therapy was documented in 76% of patients. For those on deferasirox for a minimum of 12 months, serum ferritin decreased in 30% of patients (44% of compliant patients, 11% of poorly compliant patients). Changes in creatinine and liver function tests were mild and did not result in long-term discontinuation of deferasirox in any cases. Outside of controlled clinical trials, deferasirox can be utilized safely as an oral iron chelator in children although adherence to therapy and the complex interaction of factors that contribute to iron overload still present challenges for clinicians. (c) 2009 Wiley-Liss, Inc.

  13. Proteomic profiling reveals that collismycin A is an iron chelator

    PubMed Central

    Kawatani, Makoto; Muroi, Makoto; Wada, Akira; Inoue, Gyo; Futamura, Yushi; Aono, Harumi; Shimizu, Kenshirou; Shimizu, Takeshi; Igarashi, Yasuhiro; Takahashi-Ando, Naoko; Osada, Hiroyuki

    2016-01-01

    Collismycin A (CMA), a microbial product, has anti-proliferative activity against cancer cells, but the mechanism of its action remains unknown. Here, we report the identification of the molecular target of CMA by ChemProteoBase, a proteome-based approach for drug target identification. ChemProteoBase profiling showed that CMA is closely clustered with di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, an iron chelator. CMA bound to both Fe(II) and Fe(III) ions and formed a 2:1 chelator-iron complex with a redox-inactive center. CMA-induced cell growth inhibition was completely canceled by Fe(II) and Fe(III) ions, but not by other metal ions such as Zn(II) or Cu(II). Proteomic and transcriptomic analyses showed that CMA affects the glycolytic pathway due to the accumulation of HIF-1α. These results suggest that CMA acts as a specific iron chelator, leading to the inhibition of cancer cell growth. PMID:27922079

  14. Triphenylphosphonium-desferrioxamine as a candidate mitochondrial iron chelator.

    PubMed

    Alta, Roxana Y P; Vitorino, Hector A; Goswami, Dibakar; Terêsa Machini, M; Espósito, Breno P

    2017-08-02

    Cell-impermeant iron chelator desferrioxamine (DFO) can have access to organelles if appended to suitable vectors. Mitochondria are important targets for the treatment of iron overload-related neurodegenerative diseases. Triphenylphosphonium (TPP) is a delocalized lipophilic cation used to ferry molecules to mitochondria. Here we report the synthesis and characterization of the conjugate TPP-DFO as a mitochondrial iron chelator. TPP-DFO maintained both a high affinity for iron and the antioxidant activity when compared to parent DFO. TPP-DFO was less toxic than TPP alone to A2780 cells (IC50 = 135.60 ± 1.08 and 4.34 ± 1.06 μmol L(-1), respectively) and its native fluorescence was used to assess its mitochondrial localization (Rr = +0.56). These results suggest that TPP-DFO could be an interesting alternative for the treatment of mitochondrial iron overload e.g. in Friedreich's ataxia.

  15. Experimental animal model to study iron overload and iron chelation and review of other such models.

    PubMed

    Italia, Khushnooma; Colah, Roshan; Ghosh, Kanjaksha

    2015-10-01

    The disorders of iron overload due to primary or secondary cause are one of the important human diseases leading to high mortality if untreated. To understand this, an animal model has been extensively studied. The source of iron administered to the mode of iron administration that can mimic the iron overload in humans has been studied. A safe and orally active iron chelator is still needed as many of the existing compounds have different types of complications and toxicity associated. Hence having a simple animal model which can be availed quickly and can be used to study various compounds for its iron chelating activity would likely to have immense utility for pharmacological studies. In this review we have shown how, using a simple procedure, a large number of small iron overloaded animals can be produced easily for various studies. Copyright © 2015. Published by Elsevier Inc.

  16. The iron chelator deferasirox protects mice from mucormycosis through iron starvation

    USDA-ARS?s Scientific Manuscript database

    Clinical and animal model data indicate that the presence of elevated available serum iron predisposes the host to mucormycosis. Here we demonstrate that deferasirox, an iron chelator recently approved for use in humans by the United States (US) Food and Drug Administration (FDA), is a highly effec...

  17. Influence of polycarboxylic acid chelating agents on the kinetics of the dissolution of metal oxides

    SciTech Connect

    Dyatlova, N.M.; Gorichev, I.G.; Dukhanin, V.S.; Malov, L.V.

    1986-11-01

    The factors influencing the rate of dissolution of metal oxides in aqueous solutions of acids in the presence of polycarboxylic acid chelating agents and other complexing agents have been quantitatively compared in this review, and the decisive role of the gradient of protons and electrons in the realization of this process has been revealed. The main hypotheses of the proposed conceptions of the electron-proton theory for the dissolution of metal oxides have been stated: 1) The rate-limiting step is charge transfer (first hypothesis); 2) The rate limiting step is the desorption of the dissolution products (second hypothesis). The applicability of the proposed electron-proton theory to the theoretical substantiation of all the experimentally observed kinetic features of the influence of various factors has been demonstrated. Practical recommendations for the effective utilization of the chelating agents considered for removing iron oxide surface deposits have been given.

  18. 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

  19. Iron reverses impermeable chelator inhibition of DNA synthesis in CCl 39 cells.

    PubMed

    Alcain, F J; Löw, H; Crane, F L

    1994-08-16

    Treatment of Chinese hamster lung fibroblasts (CCl 39 cells) with the impermeable iron(II) chelator bathophenanthroline disulfonate (BPS) inhibits DNA synthesis when cell growth is initiated with growth factors including epidermal growth factor plus insulin, thrombin, or ceruloplasmin, but not with 10% fetal calf serum. The BPS treatment inhibits transplasma membrane electron transport. The treatment leads to release of iron from the cells as determined by BPS iron(II) complex formation over 90 min. Growth factor stimulation of DNA synthesis and electron transport are restored by addition of di- or trivalent iron to the cells in the form of ferric ammonium citrate, ferrous ammonium sulfate, or diferric transferrin. The effect with BPS differs from the inhibition of growth by hydroxyurea, which acts on the ribonucleotide reductase, or diethylenetriaminepentaacetic acid, which is another impermeable chelating agent, in that these agents inhibit growth in 10% fetal calf serum. The BPS effect is consistent with removal of iron from a site on the cell surface that controls DNA synthesis.

  20. Iron Reverses Impermeable Chelator Inhibition of DNA Synthesis in CCl39 Cells

    NASA Astrophysics Data System (ADS)

    Alcain, Francisco J.; Low, Hans; Crane, Frederick L.

    1994-08-01

    Treatment of Chinese hamster lung fibro-blasts (CCl 39 cells) with the impermeable iron(II) chelator bathophenanthroline disulfonate (BPS) inhibits DNA synthesis when cell growth is initiated with growth factors including epidermal growth factor plus insulin, thrombin, or ceruloplasmin, but not with 10% fetal calf serum. The BPS treatment inhibits transplasma membrane electron transport. The treatment leads to release of iron from the cells as determined by BPS iron(II) complex formation over 90 min. Growth factor stimulation of DNA synthesis and electron transport are restored by addition of di- or trivalent iron to the cells in the form of ferric ammonium citrate, ferrous ammonium sulfate, or diferric transferrin. The effect with BPS differs from the inhibition of growth by hydroxyurea, which acts on the ribonucleotide reductase, or diethylenetriaminepentaacetic acid, which is another impermeable chelating agent, in that these agents inhibit growth in 10% fetal calf serum. The BPS effect is consistent with removal of iron from a site on the cell surface that controls DNA synthesis.

  1. Neurodegenerative diseases and therapeutic strategies using iron chelators.

    PubMed

    Ward, Roberta J; Dexter, David T; Crichton, Robert R

    2015-01-01

    This review will summarise the current state of our knowledge concerning the involvement of iron in various neurological diseases and the potential of therapy with iron chelators to retard the progression of the disease. We first discuss briefly the role of metal ions in brain function before outlining the way by which transition metal ions, such as iron and copper, can initiate neurodegeneration through the generation of reactive oxygen and nitrogen species. This results in protein misfolding, amyloid production and formation of insoluble protein aggregates which are contained within inclusion bodies. This will activate microglia leading to neuroinflammation. Neuroinflammation plays an important role in the progression of the neurodegenerative diseases, with activated microglia releasing pro-inflammatory cytokines leading to cellular cell loss. The evidence for metal involvement in Parkinson's and Alzheimer's disease as well as Friedreich's ataxia and multiple sclerosis will be presented. Preliminary results from trials of iron chelation therapy in these neurodegenerative diseases will be reviewed. Copyright © 2015 Elsevier GmbH. All rights reserved.

  2. 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

  3. 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

  4. Efficacy of reversal of aortic calcification by chelating agents

    PubMed Central

    Lei, Yang; Sinha, Aditi; Vyavahare, Naren

    2013-01-01

    Elastin specific medial vascular calcification, termed Monckeberg’s sclerosis has been recognized as a major risk factor for various cardiovascular events. We hypothesize that chelating agents, such as disodium ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA) and sodium thiosulfate (STS) might reverse elastin calcification by directly removing calcium (Ca) from calcified tissues into soluble calcium complexes. We assessed the chelating ability of EDTA, DTPA, and STS on removal of calcium from hydroxyapatite (HA) powder, calcified porcine aortic elastin, and calcified human aorta in vitro. We show that both EDTA and DTPA could effectively remove calcium from HA and calcified tissues, while STS was not effective. The tissue architecture was not altered during chelation. In the animal model of aortic elastin-specific calcification, we further show that local periadventitial delivery of EDTA loaded in to poly (lactic-co-glycolic acid) (PLGA) nanoparticles regressed elastin specific calcification in the aorta. Collectively, the data indicate that elastin-specific medial vascular calcification could be reversed by chelating agents. PMID:23963635

  5. Efficacy of reversal of aortic calcification by chelating agents.

    PubMed

    Lei, Yang; Grover, Arjun; Sinha, Aditi; Vyavahare, Naren

    2013-11-01

    Elastin-specific medial vascular calcification, termed "Monckeberg's sclerosis," has been recognized as a major risk factor for various cardiovascular events. We hypothesize that chelating agents, such as disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), and sodium thiosulfate (STS) might reverse elastin calcification by directly removing calcium from calcified tissues into soluble calcium complexes. We assessed the chelating ability of EDTA, DTPA, and STS on removal of calcium from hydroxyapatite (HA) powder, calcified porcine aortic elastin, and calcified human aorta in vitro. We show that both EDTA and DTPA could effectively remove calcium from HA and calcified tissues, while STS was not effective. The tissue architecture was not altered during chelation. In the animal model of aortic elastin-specific calcification, we further show that local periadventitial delivery of EDTA loaded in to poly(lactic-co-glycolic acid) nanoparticles regressed elastin-specific calcification in the aorta. Collectively, the data indicate that elastin-specific medial vascular calcification could be reversed by chelating agents.

  6. 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. Copyright © 2010 Elsevier Inc. All rights reserved.

  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. Archetypes for actinide-specific chelating agents

    SciTech Connect

    Smith, W.L.

    1980-01-01

    The complexes of uranium and thorium with monomeric hydroxamic acids can serve as archetypes for an optimized macrochelate designed for tetravalent actinides. The eight-coordinate complexes, Th(i-PrN(O)C(O)R)/sub 4/, where R = tert-butyl or R = neopentyl, have been synthesized and their structures have been determined by x-ray diffraction. The bulky alkyl substituents impart remarkable volatility and hydrocarbon solubility to these complexes, and the steric interactions of these substituents largely determine the structures. When R = tert-butyl, the substituents occupy the corners of a tetrahedron and force the complex into a distorted cubic geometry with crystallographic S/sub 4/ symmetry. Insertion of a methylene group between the carbonyl carbon and the tert-butyl group relaxes the steric requirements, and the coordination polyhedron of the neopentyl derivative is close to the mmmm isomer of the trigonal-faced dodecahedron. Uranium tetrachloride was quantitatively oxidized via an oxygen transfer reaction with two equivalents of N-phenylbenzohydroxamic acid anion (PBHA) in tetrahydrofuran (THF) to form UO/sub 2/ Cl(PBHA)(THF)/sub 2/ and benzanilide. The structure of the uranyl complex has been determined from x-ray diffraction data; the linear uranyl ion is surrounded by a planar pentagonal array composed of two hydroxamate oxygen atoms, a chloride ion and two THF oxygens, such that the chloride ion is opposite the hydroxamate group. That the THF and phenyl rings are twisted from this equatorial plane limits the molecular geometry to that of the C/sub 1/ point group. Some aspects of the chemistry of hydroxamic acids and of their incorporation into molecules that may serve as precursors of tetravalent actinide specific sequestering agents have also been investigated.

  9. Abiotic reductive extraction of arsenic from contaminated soils enhanced by complexation: arsenic extraction by reducing agents and combination of reducing and chelating agents.

    PubMed

    Kim, Eun Jung; Lee, Jae-Cheol; Baek, Kitae

    2015-01-01

    Abiotic reductive extraction of arsenic from contaminated soils was studied with various reducing agents and combinations of reducing and chelating agents in order to remediate arsenic-contaminated soils. Oxalate and ascorbic acid were effective to extract arsenic from soil in which arsenic was associated with amorphous iron oxides, but they were not effective to extract arsenic from soils in which arsenic was bound to crystalline oxides or those in which arsenic was mainly present as a scorodite phase. An X-ray photoelectron spectroscopy study showed that iron oxides present in soils were transformed to Fe(II,III) or Fe(II) oxide forms such as magnetite (Fe3O4, Fe(II)Fe2(III)O4) by reduction with dithionite. Thus, arsenic extraction by dithionite was not effective due to the re-adsorption of arsenic to the newly formed iron oxide phase. Combination of chelating agents with reducing agents greatly improved arsenic extraction from soil samples. About 90% of the total arsenic could be extracted from all soil samples by using a combination of dithionite and EDTA. Chelating agents form strong complexation with iron, which can prevent precipitation of a new iron oxide phase and also enhance iron oxide dissolution via a non-reductive dissolution pathway. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Iron and iron chelators: a review on potential effects on skin aging.

    PubMed

    Pouillot, Anne; Polla, Ada; Polla, Barbara S

    2013-12-01

    Similar to oxygen, iron is essential for aerobic life and energy production. Akin to oxygen, iron can be toxic and accelerate the aging process. Indeed, via the Fenton and Haber Weiss reactions, iron potentiates the generation of highly reactive oxygen free radicals such as hydroxyl radical, thus stimulating oxidative damage. The possibility that women's longer life span relates to a lower iron status due to iron loss during reproductive life has been considered as a valid hypothesis, while hemochromatosis has been proposed as a model of iron overload to examine the effects of iron on the aging process. Iron plays an aggravating role in many diseases in which iron deprivation has been shown to be beneficial including ischaemia-reperfusion injury, neurological disorders and muscle diseases such as Duchenne's muscular dystrophy. In the skin, excess iron combined with UV radiation exerts pro-oxidant effects while scavenging of free iron prevents or inhibits the toxic effects of UV radiation on both nude mice and human skin. In this review, we propose that iron chelators and/or iron deprivation might play a significant role in the prevention of aging- associated diseases and conditions, in particular in the skin, and increase quality of life. Controlled iron deprivation might be achieved by regular blood donation in which case the quality of life of both the donor and the recipient is improved. Increasing the frequency of blood donation may thus significantly contribute to both individual and social wellbeing. Furthermore, we propose the skin as an accessible model for the study of aging and the effects of iron / iron deprivation on the aging mechanisms. Finally, we suggest that the development of topical iron chelators might represent a novel and simple approach to prevent skin aging, when such prevention has proven an important factor in increasing an aging populations' quality of life.

  11. 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.

  12. Antimalarial action of hydroxamate-based iron chelators and potentiation of desferrioxamine action by reversed siderophores.

    PubMed Central

    Golenser, J; Tsafack, A; Amichai, Y; Libman, J; Shanzer, A; Cabantchik, Z I

    1995-01-01

    Hydroxamate-based chelators of iron are potent inhibitors of in vitro growth of Plasmodium falciparum. Two types of such chelators, the natural desferrioxamine and the synthetic reversed siderophore RSFileum2, are prototypes of antimalarial agents whose action spectra differ in the speed of action, stage dependence, and degree of reversibility of effects. This work explores the possibility of improving the antimalarial efficacy of these agents by using them in various combinations on in vitro cultures of P. falciparum. Growth assessment was based both on total nucleic acid synthesis and on parasitemia. The results indicate that the synthetic reversed siderophore more than complements the antimalarial action of desferrioxamine when applied during either ring, trophozoite, or mixed stages. The combined drug effects were significantly higher than the additive effect of the individual drugs. Qualitatively similar results were obtained for both reversible effects and irreversible (i.e., sustained) effects. Following an 8-h window of exposure the combined drug treatment caused parasite growth arrest and prevented its recovery, even 3 days after the treatment. The fact that such a combination of iron chelators displays a wider action spectrum than either drug alone has implications for the design of chemotherapy regimens. PMID:7695330

  13. The oral iron chelator ICL670A (deferasirox) does not protect myocytes against doxorubicin.

    PubMed

    Hasinoff, Brian B; Patel, Daywin; Wu, Xing

    2003-12-01

    The oral iron chelating agent ICL670A (deferasirox) and the clinically approved cardioprotective agent dexrazoxane (ICRF-187) were compared for their ability to protect neonatal rat cardiac myocytes from doxorubicin-induced damage. Doxorubicin is thought to induce oxidative stress on the heart muscle through iron-mediated oxygen radical damage. While dexrazoxane was able to protect myocytes from doxorubicin-induced lactate dehydrogenase release, ICL670A, in contrast, depending upon the concentration, synergistically increased or did not affect the cytotoxicity of doxorubicin. This occurred in spite of the fact that ICL670A quickly and efficiently removed iron(III) from its complex with doxorubicin, and rapidly entered myocytes and displaced iron from a fluorescence-quenched trapped intracellular iron-calcein complex. Continuous exposure of ICL670A to either myocytes or Chinese hamster ovary (CHO) cells resulted in cytotoxicity while treatment of CHO cells with the ferric complex of ICL670A did not. These results suggest that ICL670A was cytotoxic either by removing or withholding iron from critical iron-containing proteins. Electron paramagnetic resonance spectroscopy was used to show that neither ICL670A nor its ferric complex were able to generate free radicals in either oxidizing or reducing systems suggesting that its cytotoxicity is not due to radical generation.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  15. Oral deferiprone for iron chelation in people with thalassaemia.

    PubMed

    Fisher, Sheila A; Brunskill, Susan J; Doree, Carolyn; Chowdhury, Onima; Gooding, Sarah; Roberts, David J

    2013-08-21

    Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through red blood cell transfusions.Repeated transfusions result in an excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. A commonly used iron chelator, deferiprone, has been found to be pharmacologically efficacious. However, important questions exist about the efficacy and safety of deferiprone compared to another iron chelator, desferrioxamine. To summarise data from trials on the clinical efficacy and safety of deferiprone and to compare the clinical efficacy and safety of deferiprone with desferrioxamine for thalassaemia. We searched the Cochrane Cystic fibrosis and Genetic Disorders Group's Haemoglobinopathies trials Register and MEDLINE, EMBASE, CENTRAL (The Cochrane Library), LILACS and other international medical databases, plus registers of ongoing trials and the Transfusion Evidence Library (www.transfusionevidencelibrary.com). We also contacted the manufacturers of deferiprone and desferrioxamine.All searches were updated to 05 March 2013. Randomised controlled trials comparing deferiprone with another iron chelator; or comparing two schedules or doses of deferiprone, in people with transfusion-dependent thalassaemia. Two authors independently assessed trials for risk of bias and extracted data. Missing data were requested from the original investigators. A total of 17 trials involving 1061 participants (range 13 to 213 participants per trial) were included. Of these, 16 trials compared either deferiprone alone with desferrioxamine alone, or a combined therapy of deferiprone and desferrioxamine with either deferiprone alone or desferrioxamine alone; one compared different schedules of deferiprone. There was little consistency between outcomes and limited information to fully assess the risk of bias of most of the included trials.Four trials reported

  16. Iron chelation therapy in myelodysplastic syndromes: where do we stand?

    PubMed Central

    Mitchell, Mhairi; Gore, Steven D; Zeidan, Amer M

    2014-01-01

    Anemia leading to transfusion dependency (TD) and iron overload (IO) is commonly observed in patients with myelodysplastic syndromes (MDS). In MDS, TD and IO have been retrospectively associated with inferior survival and worse clinical outcomes, including cardiac, hepatic and endocrine dysfunction, and, in some analyses, with leukemic progression and infectious complications. Although suggested by retrospective analyses, clear prospective documentation of the beneficial effects of iron chelation therapy (ICT) on organ function and survival in MDS patients with TD and IO is currently lacking. Consequently, the role of ICT in MDS patients with TD and IO remains a very controversial aspect in the management of MDS. In this review, the authors summarize the current knowledge regarding IO in MDS and the role of ICT. PMID:23991926

  17. Ability to determine the desferrioxamine-chelatable iron fractions of nontransferrin-bound iron using HPLC.

    PubMed

    Koba, Marcin; Słomka, Artur; Bączek, Tomasz; Marszałł, Michał P; Zekanowska, Ewa

    2013-02-01

    Iron is an essential element in human development. It is imperative for oxygen and electron transport and also for DNA and neurotransmitters synthesis. On the other hand, this metal is able to participate in Fenton's reaction that in turn leads to free radical damage. The most toxic fraction of iron - nontransferrin-bound iron and its part desferrioxamine-chelatable iron - can serve as an exquisite biomarker in the identification of iron imbalance. The goal of the present study was to devise a simple, repeatable, and inexpensive method for the determination of desferrioxamine-chelatable iron in serum blood samples. The assay procedure is based on desferrioxamine complex formation with iron ions followed to ferrioxamine and its quantitative measurement using RP-HPLC method. The desferrioxamine-chelatable iron was extracted from blood by centrifugation and SPE method. Chromatographic separation was performed at 40°C by step-form gradient elution using Cadenza CD-C18 column (150 × 4.6 mm id, particle size of 3.0 μm) connected with precolumn for contaminants removal. Gradient HPLC elution has been carried out with solvent A (10 mM Tris-HCl, pH 5.5) and solvent B (ACN). The flow rate was 1.2 mL/min, and the total separation time was 5 min. The linear quantitation range was 2.5-500 μM (r = 0.9973), and the LOD and LOQ were 0.42 and 1.29 μM, respectively. Proposed HPLC method allowed for the determination of desferrioxamine-chelatable iron fraction's of nontransferrin-bound iron, both in the buffer and the serum supplemented with iron ions as well as in the patients' serum samples with good results of precision and recovery. The developed method found to be sufficiently precise and reproducible for established conditions and after validation and may be used for routine assay of desferrioxamine-chelatable iron in biological samples. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Iron overload in thalassemia and related conditions: therapeutic goals and assessment of response to chelation therapies.

    PubMed

    Porter, John B; Shah, Farrukh T

    2010-12-01

    Transfusional iron loading inevitably results in hepatic iron accumulation, with variable extrahepatic distribution that is typically less pronounced in sickle cell disease than in thalassemia disorders. Iron chelation therapy has the goal of preventing iron-mediated tissue damage through controlling tissue iron levels, without incurring chelator-mediated toxicity. Historically, target levels for tissue iron control have been limited by the increased frequency of deferoxamine-mediated toxicity and low levels of iron loading. With newer chelation regimes, these limitations are less evident. The reporting of responses to chelation therapies has typically focused on average changes in serum ferritin in patient populations. This approach has three limitations. First, changes in serum ferritin may not reflect trends in iron balance equally in all patients or for all chelation regimens. Second, this provides no information about the proportion of patients likely respond. Third, this gives insufficient information about iron trends in tissues such as the heart. Monitoring of iron overload has advanced with the increasing use of MRI techniques to estimate iron balance (changes in liver iron concentration) and extrahepatic iron distribution (myocardial T2*). The term nonresponder has been increasingly used to describe individuals who fail to show a downward trend in one or more of these variables. Lack of a response of an individual may result from inadequate dosing, high transfusion requirement, poor treatment adherence, or unfavorable pharmacology of the chelation regime. This article scrutinizes evidence for response rates to deferoxamine, deferiprone (and combinations), and deferasirox.

  19. Improving clinical outcome in patients with myelodysplastic syndrome and iron overload using iron chelation therapy.

    PubMed

    Leitch, Heather A

    2007-12-01

    Until recently, little information on the benefits of iron chelation therapy (ICT) in patients with myelodysplastic syndrome (MDS) and iron overload was known. A recent retrospective study showed improved survival in transfusion-dependent patients with MDS (Low or Intermediate-1 risk IPSS) receiving ICT, compared with those not receiving ICT; median overall survival was not reached at 160 months versus 40 months, respectively. Significantly more patients receiving ICT survived to 4 years (80% versus 44%; p < 0.03), suggesting that MDS patients with iron overload might benefit from ICT. Prospective studies to confirm the benefit of ICT in MDS are warranted.

  20. 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.

  1. 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

  2. Effects of iron chelators, iron salts, and iron oxide nanoparticles on the proliferation and the iron content of oligodendroglial OLN-93 cells.

    PubMed

    Hohnholt, Michaela; Geppert, Mark; Dringen, Ralf

    2010-08-01

    The oligodendroglial cell line OLN-93 was used as model system to investigate the consequences of iron deprivation or iron excess on cell proliferation. Presence of ferric or ferrous iron chelators inhibited the proliferation of OLN-93 cells in a time and concentration dependent manner, while the application of a molar excess of ferric ammonium citrate (FAC) prevented the inhibition of proliferation by the chelator deferoxamine. Proliferation of OLN-93 cells was not affected by incubation with 300 microM iron that was applied in the form of FAC, FeCl(2), ferrous ammonium sulfate or iron oxide nanoparticles, although the cells efficiently accumulated iron during exposure to each of these iron sources. The highest specific iron content was observed for cells that were exposed to the nanoparticles. These data demonstrate that the proliferation of OLN-93 cells depends strongly on the availability of iron and that these cells efficiently accumulate iron from various extracellular iron sources.

  3. Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome.

    PubMed

    Shenoy, Niraj; Vallumsetla, Nishanth; Rachmilewitz, Eliezer; Verma, Amit; Ginzburg, Yelena

    2014-08-07

    Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, and potential for malignant transformation. Lower/intermediate-risk MDSs are associated with longer survival and high red blood cell (RBC) transfusion requirements resulting in secondary iron overload. Recent data suggest that markers of iron overload portend a relatively poor prognosis, and retrospective analysis demonstrates that iron chelation therapy is associated with prolonged survival in transfusion-dependent MDS patients. New data provide concrete evidence of iron's adverse effects on erythroid precursors in vitro and in vivo. Renewed interest in the iron field was heralded by the discovery of hepcidin, the main serum peptide hormone negative regulator of body iron. Evidence from β-thalassemia suggests that regulation of hepcidin by erythropoiesis dominates regulation by iron. Because iron overload develops in some MDS patients who do not require RBC transfusions, the suppressive effect of ineffective erythropoiesis on hepcidin may also play a role in iron overload. We anticipate that additional novel tools for measuring iron overload and a molecular-mechanism-driven description of MDS subtypes will provide a deeper understanding of how iron metabolism and erythropoiesis intersect in MDSs and improve clinical management of this patient population.

  4. Effect of Iron Chelation Therapy on Glucose Metabolism in Non-Transfusion-Dependent Thalassaemia.

    PubMed

    Chuansumrit, Ampaiwan; Pengpis, Pimprae; Mahachoklertwattana, Pat; Sirachainan, Nongnuch; Poomthavorn, Preamrudee; Sungkarat, Witaya; Kadegasem, Praguywan; Khlairit, Patcharin; Wongwerawattanakoon, Pakawan

    2017-01-01

    To compare insulin sensitivity, β-cell function and iron status biomarkers in non-transfusion-dependent thalassaemia (NTDT) with iron excess during pre- and post-iron chelation. Subjects with NTDT, aged older than 10 years, with serum ferritin >300 ng/ml, were included. Iron chelation with deferasirox (10 mg/kg/day) was prescribed daily for 6 months. Ten patients with a median age of 17.4 years were enrolled. The comparison between pre- and post-chelation demonstrated significantly lower iron load: median serum ferritin (551.4 vs. 486.2 ng/ml, p = 0.047), median TIBC (211.5 vs. 233.5 µg/dl, p = 0.009) and median non-transferrin binding iron (5.5 vs. 1.4 µM, p = 0.005). All patients had a normal oral glucose tolerance test (OGTT) both pre- and post-chelation. However, fasting plasma glucose was significantly reduced after iron chelation (85.0 vs.79.5 mg/dl, p = 0.047). MRI revealed no significant changes of iron accumulation in the heart and liver after chelation, but there was a significantly lower iron load in the pancreas, assessed by higher T2* at post-chelation compared with pre-chelation (41.9 vs. 36.7 ms, p = 0.047). No adverse events were detected. A trend towards improving insulin sensitivity and β-cell function as well as a reduced pancreatic iron load was observed following 6 months of iron chelation (TCTR20160523003). © 2016 S. Karger AG, Basel.

  5. Phytic acid: an alternative root canal chelating agent.

    PubMed

    Nassar, Mohannad; Hiraishi, Noriko; Tamura, Yukihiko; Otsuki, Masayuki; Aoki, Kazuhiro; Tagami, Junji

    2015-02-01

    The objectives of this study were to investigate the effect of phytic acid, inositol hexakisphosphate (IP6), as a final rinse on the surface of instrumented root canals and smear-layered flat dentin surfaces treated with sodium hypochlorite (NaOCl) and to evaluate its effect on the viability and alkaline phosphatase activity of osteoblast-like cells (MC3T3-E1). The universally accepted chelating agent EDTA was used as the control in all conducted experiments. Root canals of human canines were instrumented with rotary files and irrigated with 5% NaOCl, followed by a final rinse of 17% EDTA (1 minute), 1% IP6 (1 minute or 30 seconds), or distilled water. NaOCl-treated flat coronal dentin surfaces were also treated with 17% EDTA (1 minute), 1% IP6 (1 minute or 30 seconds), or distilled water. The presence or absence of smear layer was evaluated with scanning electron microscopy. Cell viability and alkaline phosphatase assays were performed to evaluate the effect of IP6 and EDTA on cultured MC3T3-E1 cells. The results demonstrated the ability of IP6 to remove the smear layer from instrumented root canals and flat coronal dentin surfaces. When compared with EDTA, IP6 was less cytotoxic and did not affect the differentiation of MC3T3-E1 cells. IP6 shows the potential to be an effective and biocompatible chelating agent. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  6. 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.

  7. Chelation and determination of labile iron in primary hepatocytes by pyridinone fluorescent probes

    PubMed Central

    Ma, Yongmin; de Groot, Herbert; Liu, Zudong; Hider, Robert C.; Petrat, Frank

    2005-01-01

    A series of fluorescent iron chelators has been synthesized such that a fluorescent function is covalently linked to a 3-hydroxypyridin-4-one. In the present study, the fluorescent iron chelators were loaded into isolated rat hepatocytes. The intracellular fluorescence was not only quenched by an addition of a highly lipophilic 8-hydroxyquinoline–iron(III) complex but also was dequenched by the addition of an excess of the membrane-permeable iron chelator CP94 (1,2-diethyl-3-hydroxypyridin-4-one). The time course of uptake of iron and iron chelation in single, intact cells was recorded on-line by using digital fluorescence microscopy. Intracellular concentrations of various fluorescent iron chelators were determined by using a spectrofluorophotometer subsequent to lysis of probe-loaded cells and were found to depend on their partition coefficients; the more hydrophobic the compound, the higher the intracellular concentration. An ex situ calibration method was used to determine the chelatable iron pool of cultured rat hepatocytes. CP655 (7-diethylamino-N-[(5-hydroxy-6-methyl-4-oxo-1,4-dihydropyridin-3-yl)methyl]-N-methyl-2-oxo-2H-chromen-3-carboxamide), which is a moderately lipophilic fluorescent chelator, was found to be the most sensitive probe for monitoring chelatable iron, as determined by the intracellular fluorescence increase induced by the addition of CP94. The concentration of the intracellular chelatable iron pool in hepatocytes was determined by this probe to be 5.4±1.3 μM. PMID:16336208

  8. Synthesis and initial in vitro evaluations of novel antioxidant aroylhydrazone iron chelators with increased stability against plasma hydrolysis.

    PubMed

    Hruskova, Katerina; Kovarikova, Petra; Bendova, Petra; Haskova, Pavlina; Mackova, Eliska; Stariat, Jan; Vavrova, Anna; Vavrova, Katerina; Simunek, Tomas

    2011-03-21

    Oxidative stress is known to contribute to a number of cardiovascular pathologies. Free intracellular iron ions participate in the Fenton reaction and therefore substantially contribute to the formation of highly toxic hydroxyl radicals and cellular injury. Earlier work on the intracellular iron chelator salicylaldehyde isonicotinoyl hydrazone (SIH) has demonstrated its considerable promise as an agent to protect the heart against oxidative injury both in vitro and in vivo. However, the major limitation of SIH is represented by its labile hydrazone bond that makes it prone to plasma hydrolysis. Hence, in order to improve the hydrazone bond stability, nine compounds were prepared by a substitution of salicylaldehyde by the respective methyl- and ethylketone with various electron donors or acceptors in the phenyl ring. All the synthesized aroylhydrazones displayed significant iron-chelating activities and eight chelators showed significantly higher stability in rabbit plasma than SIH. Furthermore, some of these chelators were observed to possess higher cytoprotective activities against oxidative injury and/or lower toxicity as compared to SIH. The results of the present study therefore indicate the possible applicability of several of these novel agents in the prevention and/or treatment of cardiovascular disorders with a known (or presumed) role of oxidative stress. In particular, the methylketone HAPI and nitro group-containing NHAPI merit further in vivo investigations.

  9. 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.

  10. Isolation and characterization of iron chelators from turmeric (Curcuma longa): selective metal binding by curcuminoids.

    PubMed

    Messner, Donald J; Surrago, Christine; Fiordalisi, Celia; Chung, Wing Yin; Kowdley, Kris V

    2017-08-11

    Iron overload disorders may be treated by chelation therapy. This study describes a novel method for isolating iron chelators from complex mixtures including plant extracts. We demonstrate the one-step isolation of curcuminoids from turmeric, the medicinal food spice derived from Curcuma longa. The method uses iron-nitrilotriacetic acid (NTA)-agarose, to which curcumin binds rapidly, specifically, and reversibly. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin each bound iron-NTA-agarose with comparable affinities and a stoichiometry near 1. Analyses of binding efficiencies and purity demonstrated that curcuminoids comprise the primary iron binding compounds recovered from a crude turmeric extract. Competition of curcuminoid binding to the iron resin was used to characterize the metal binding site on curcumin and to detect iron binding by added chelators. Curcumin-Iron-NTA-agarose binding was inhibited by other metals with relative potency: (>90% inhibition) Cu(2+) ~ Al(3+) > Zn(2+) ≥ Ca(2+) ~ Mg(2+) ~ Mn(2+) (<20% inhibition). Binding was also inhibited by pharmaceutical iron chelators (desferoxamine or EDTA) or by higher concentrations of weak iron chelators (citrate or silibinin). Investigation of the physiological effects of iron binding by curcumin revealed that curcumin uptake by cultured cells was reduced >80% by addition of iron to the media; uptake was completely restored by desferoxamine. Ranking of metals by relative potencies for blocking curcumin uptake agreed with their relative potencies in blocking curcumin binding to iron-NTA-agarose. We conclude that curcumin can selectively bind toxic metals including iron in a physiological setting, and propose inhibition of curcumin binding to iron-NTA-agarose for iron chelator screening.

  11. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions

    PubMed Central

    Neufeld, Ellis J.

    2006-01-01

    For nearly 30 years, patients with transfusional iron overload have depended on nightly deferoxamine infusions for iron chelation. Despite dramatic gains in life expectancy in the deferoxamine era for patients with transfusion-dependent anemias, the leading cause of death for young adults with thalassemia major and related disorders has been cardiac disease from myocardial iron deposition. Strategies to reduce cardiac disease by improving chelation regimens have been of the highest priority. These strategies have included development of novel oral iron chelators to improve compliance, improved assessment of cardiac iron status, and careful epidemiologic assessment of European outcomes with deferiprone, an oral alternative chelator available for about a decade. Each of these strategies is now bearing fruit. The novel oral chelator deferasirox was recently approved by the Food and Drug Administration (FDA); a randomized clinical trial demonstrates that deferasirox at 20 to 30 mg/kg/d can maintain or improve hepatic iron in thalassemia as well as deferoxamine. A randomized trial based on cardiac T2* magnetic resonance imaging (MRI) suggests that deferiprone can unload myocardial iron faster than deferoxamine. Retrospective epidemiologic data suggest dramatic reductions in cardiac events and mortality in Italian subjects exposed to deferiprone compared with deferoxamine. These developments herald a new era for iron chelation, but many unanswered questions remain. PMID:16627763

  12. 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. © 2015 Institute of Food Technologists®

  13. Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

    PubMed Central

    Kontoghiorghes, G J; Aldouri, M A; Hoffbrand, A V; Barr, J; Wonke, B; Kourouclaris, T; Sheppard, L

    1987-01-01

    The main iron chelator used for transfusional iron overload is desferrioxamine, which is expensive, has toxic side effects, and has to be given subcutaneously. An orally active iron chelator is therefore required. The effects of oral 1,2-dimethyl-3-hydroxypyrid-4-one on urinary iron excretion were studied in eight patients who had received multiple transfusions: four had myelodysplasia and four beta thalassaemia major. Different daily doses of the drug up to 100 mg/kg/day, alone or in combination with ascorbic acid, were used. In three patients with thalassaemia the effect of the drug was compared with that of subcutaneous desferrioxamine at the same daily dose. In all eight patients a single dose of oral 1,2-dimethyl-3-hydroxypyrid-4-one resulted in substantial urinary iron excretion, mainly in the first 12 hours. Urinary iron excretion increased with the dose and with the degree of iron loading of the patient. Giving two or three divided doses over 24 hours resulted in higher urinary iron excretion than a single dose of the same amount over the same time. In most patients coadministration of oral ascorbic acid further increased urinary iron excretion. 1,2-Dimethyl-3-hydroxypyrid-4-one caused similar iron excretion to that achieved with subcutaneous desferrioxamine at a comparable dose. In some cases the iron excretion was sufficiently high (maximum 99 mg/day) to suggest that a negative iron balance could be easily achieved with these protocols in patients receiving regular transfusions. No evidence of toxicity was observed on thorough clinical examination or haematological and biochemical testing in any of the patients. None of the patients had any symptoms that could be ascribed to the drug. These results suggest that the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one is as effective as subcutaneous desferrioxamine in increasing urinary iron excretion in patients loaded with iron. Its cheap synthesis, oral activity, and lack of obvious toxicity at effective

  14. Targeting dysregulation of brain iron homeostasis in Parkinson's disease by iron chelators.

    PubMed

    Weinreb, Orly; Mandel, Silvia; Youdim, Moussa B H; Amit, Tamar

    2013-09-01

    Brain iron accumulation has been implicated in a host of chronic neurological diseases, including Parkinson's disease (PD). The elevated iron levels observed in the substantia nigra of PD subjects have been suggested to incite the generation of reactive oxygen species and intracellular α-synuclein aggregation, terminating in the oxidative neuronal destruction of this brain area. Thus, elucidation of the molecular mechanisms involved in iron dysregulation and oxidative stress-induced neurodegeneration is a crucial step in deciphering PD pathology and in developing novel iron-complexing compounds aimed at restoring brain iron homeostasis and attenuating neurodegeneration. This review discusses the involvement of dysregulation of brain iron homeostasis in PD pathology, with an emphasis on the potential effectiveness of naturally occurring compounds and novel iron-chelating/antioxidant therapeutic hybrid molecules, exerting a spectrum of neuroprotective interrelated activities: antioxidant/monoamine oxidase inhibition, activation of the hypoxia-inducible factor (HIF)-1 signaling pathway, induction of HIF-1 target iron-regulatory and antioxidative genes, and inhibition of α-synuclein accumulation and aggregation.

  15. The Oral Iron Chelator Deferiprone Protects against Iron Overload–Induced Retinal Degeneration

    PubMed Central

    Hadziahmetovic, Majda; Song, Ying; Wolkow, Natalie; Iacovelli, Jared; Grieco, Steven; Lee, Jennifer; Lyubarsky, Arkady; Pratico, Domenico; Connelly, John; Spino, Michael; Harris, Z. Leah

    2011-01-01

    Purpose. Iron-induced oxidative stress may exacerbate age-related macular degeneration (AMD). Ceruloplasmin/Hephaestin double-knockout (DKO) mice with age-dependent retinal iron accumulation and some features of AMD were used to test retinal protection by the oral iron chelator deferiprone (DFP). Methods. Cultured retinal pigment epithelial (ARPE-19) cells and mice were treated with DFP. Transferrin receptor mRNA (Tfrc), an indicator of iron levels, was quantified by qPCR. In mice, retinal oxidative stress was assessed by mass spectrometry, and degeneration by histology and electroretinography. Results. DFP at 60 μM decreased labile iron in ARPE-19 cells, increasing Tfrc and protecting 70% of cells against a lethal dose of H2O2. DFP 1 mg/mL in drinking water increased retinal Tfrc mRNA 2.7-fold after 11 days and also increased transferrin receptor protein. In DKOs, DFP over 8 months decreased retinal iron levels to 72% of untreated mice, diminished retinal oxidative stress to 70% of the untreated level, and markedly ameliorated retinal degeneration. DFP was not retina toxic in wild-type (WT) or DKO mice, as assessed by histology and electroretinography. Conclusions. Oral DFP was not toxic to the mouse retina. It diminished retinal iron levels and oxidative stress and protected DKO mice against iron overload–induced retinal degeneration. Further testing of DFP for retinal disease involving oxidative stress is warranted. PMID:21051716

  16. Inhibition of in vitro lymphoproliferation by three novel iron chelators of the pyridoxal and salicyl aldehyde hydrazone classes.

    PubMed

    van Reyk, D; Sarel, S; Hunt, N

    2000-08-15

    The capacity of three novel iron chelators, namely 1-[N-ethoxycarbonylmethylpyridoxylidenium]-2-[2'-pyridyl]hydrazine bromide (EPH), 1-[5'-bromosalicylidene]-2-[2"-pyridyl]hydrazine (BsPH), and 1-pyridoxylidene-2-[1'-phthalazyl]hydrazine dihydrochloride (PPhH), to inhibit the proliferation of mitogen-stimulated murine lymph node cells was examined in vitro. All three are of the aryl hydrazone class, the prototype of which is pyridoxal isonicotinoyl hydrazone. The chelators inhibited lymphoproliferation at low micromolar concentrations. EPH and PPhH had an inhibitory capacity comparable to that of desferrioxamine (IC(50): 3 and 2 microM, respectively), whereas BsPH was more potent (IC(50) < 1 microM). The inhibitory effects of the chelator were not due to cell cytotoxicity and could be abrogated by pretreating the chelator with iron. Time-course studies established a site of action for the chelators at the G(1)/S phase transition. These agents warrant further investigation for their potential as immunosuppressants.

  17. The Influence of Chelating Agents on the Kinetics of Calcite Dissolution.

    PubMed

    Fredd; Fogler

    1998-08-01

    The kinetics of calcite dissolution in the presence of calcium chelating agents was investigated over the pH range of 3.3-12 using a rotating disk apparatus. The results show that the rate of dissolution is increased significantly by the presence of chelating agents such as CDTA, DTPA, and EDTA. The rate of dissolution is influenced by the kinetics of the chelation reactions and varies considerably with pH and type of chelating agent. A surface chelation mechanism was introduced to describe the dissolution. The mechanism involves the adsorption of the chelating agent onto the calcite surface and follows Langmuir-Hinshelwood kinetics. The dissolution is different from conventional hydrogen ion attack in that the chelating agent attacks the calcium component of the lattice rather than the carbonate component. Therefore, the rate of dissolution is enhanced by the influence of hydrogen ion attack at low pH. In addition, the various ionic forms of the chelating agents react with the calcite surface at different rates depending on the number of hydrogen ions associated with the species. In general, the rate of dissolution increases with increasing protonation. The surface complexation mechanism was shown to describe the rate of calcite dissolution in the presence of chelating agents over the pH range of 4-12. Copyright 1998 Academic Press.

  18. INFLUENCE OF IRON CHELATION ON R1 AND R2 CALIBRATION CURVES IN GERBIL LIVER AND HEART

    PubMed Central

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

    2008-01-01

    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 paper 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. 33 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 upon the acuity of iron loading and unloading as well as the iron chelator administered. PMID:18581418

  19. Obligatory Reduction of Ferric Chelates in Iron Uptake by Soybeans

    PubMed Central

    Chaney, Rufus L.; Brown, John C.; Tiffin, Lee O.

    1972-01-01

    The contrasting Fe2+ and Fe3+ chelating properties of the synthetic chelators ethylenediaminedi (o-hydroxyphenylacetate) (EDDHA) and 4,7-di(4-phenylsulfonate)-1, 10-phenanthroline (bathophenanthrolinedisulfonate) (BPDS) were used to determine the valence form of Fe absorbed by soybean roots supplied with Fe3+-chelates. EDDHA binds Fe3+ strongly, but Fe2+ weakly; BPDS binds Fe2+ strongly but Fe3+ weakly. Addition of an excess of BPDS to nutrient solutions containing Fe3+-chelates inhibited soybean Fe uptake-translocation by 99+%; [Fe(II) (BPDS)3]4− accumulated in the nutrient solution. The addition of EDDHA caused little or no inhibition. These results were observed with topped and intact soybeans. Thus, separation and absorption of Fe from Fe3+-chelates appear to require reduction of Fe3+-chelate to Fe2+-chelate at the root, with Fe2+ being the principal form of Fe absorbed by soybean. PMID:16658143

  20. Iron Chelators and Exogenic Photosensitizers. Synergy through Oxidative Stress Gene Expression

    PubMed Central

    Mrozek-Wilczkiewicz, Anna; Malarz, Katarzyna; Rams-Baron, Marzena; Serda, Maciej; Bauer, Daniela; Montforts, Franz-Peter; Ratuszna, Alicja; Burley, Thomas; Polanski, Jaroslaw; Musiol, Robert

    2017-01-01

    In non-invasive anticancer photodynamic therapy (PDT), a nontoxic photosensitizer (PS), which is activated by visible light, is used as a magic bullet that selectively destroys cancer cells. Recently, we described the combined therapy of 5-aminolevulinic acid (ALA-PDT) with thiosemicarbazone (TSC), i.e. an iron-chelating agent. This resulted in a strong synergistic effect. Herein, we investigated a novel strategy using a combination of PDT consist of the xenobiotic-porphyrin type PS with TSC. We observed a synergistic effect for all of the pairs of TSC-PS. This approach can be rationalized by the fact that both chlorin and TSC can affect the generation of reactive oxygen species (ROS). In order to elucidate the plausible mechanism of action, we also combined the investigated PSs with DFO, which forms complexes that are redox inactive. We detected a slight antagonism or additivity for this combination. This may suggest that the ability of an iron chelator (IC) to participate in the production of ROS and the generation of oxidative stress is important. PMID:28819397

  1. 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.

  2. The iron chelator deferasirox protects mice from mucormycosis through iron starvation

    PubMed Central

    Ibrahim, Ashraf S.; Gebermariam, Teclegiorgis; Fu, Yue; Lin,, Lin; Husseiny, Mohamed I.; French, Samuel W.; Schwartz, Julie; Skory, Christopher D.; Edwards, John E.; Spellberg, Brad J.

    2007-01-01

    Mucormycosis causes mortality in at least 50% of cases despite current first-line therapies. Clinical and animal data indicate that the presence of elevated available serum iron predisposes the host to mucormycosis. Here we demonstrate that deferasirox, an iron chelator recently approved for use in humans by the US FDA, is a highly effective treatment for mucormycosis. Deferasirox effectively chelated iron from Rhizopus oryzae and demonstrated cidal activity in vitro against 28 of 29 clinical isolates of Mucorales at concentrations well below clinically achievable serum levels. When administered to diabetic ketoacidotic or neutropenic mice with mucormycosis, deferasirox significantly improved survival and decreased tissue fungal burden, with an efficacy similar to that of liposomal amphotericin B. Deferasirox treatment also enhanced the host inflammatory response to mucormycosis. Most importantly, deferasirox synergistically improved survival and reduced tissue fungal burden when combined with liposomal amphotericin B. These data support clinical investigation of adjunctive deferasirox therapy to improve the poor outcomes of mucormycosis with current therapy. As iron availability is integral to the pathogenesis of other infections (e.g., tuberculosis, malaria), broader investigation of deferasirox as an antiinfective treatment is warranted. PMID:17786247

  3. The Incidence of Ototoxicity in Patients Using Iron Chelators.

    PubMed

    Derin, Serhan; Azık, Fatih Mehmet; Topal, Yaşar; Topal, Hatice; Karakuş, Volkan; Çetinkaya, Petek Uzay; Şahan, Murat; Azık, Tansel Erdem; Kocabaş, Can Naci

    2017-04-01

    In this study, we aimed to detect the incidences of ototoxicity in patients with hemoglobinopathies taking deferoxamine (DFO), deferiprone, and deferasirox using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) scale to obtain more objective data. Fifty-five transfusion-dependent patients were evaluated in this study. The NCI CTCAE scale was used to assess ototoxicity levels. The average ferritin and hemoglobin levels, the type of iron chelator, and the duration of therapy of all the patients were recorded. Ototoxicity was observed in 15 patients (31.9 %), all of whom were taking DFO. The median age was 19.5 (6-43) in patients without ototoxicity and 29 (16-50) in those with ototoxicity; this difference was statistically significant (p<0.05). The median ferritin and pre-tx Hb levels were 1391 ng/mL and 9.06 mg/dL, respectively, in patients with ototoxicity and 986.7 ng/mL and 9.24 mg/dL, respectively, in those without ototoxicity; these differences were not significant (p>0.05). Ototoxicity was not observed in the eight patients who used only deferasirox and deferiprone. The ototoxicity incidence with DFO at doses below 50 mg/kg/day was 27.3%. Deferiprone and deferasirox were not associated with ototoxic effects in patients taking these drugs.

  4. Iron bioavailability in humans from breakfasts enriched with iron bis-glycine chelate, phytates and polyphenols.

    PubMed

    Layrisse, M; García-Casal, M N; Solano, L; Barón, M A; Arguello, F; Llovera, D; Ramírez, J; Leets, I; Tropper, E

    2000-09-01

    This study was conducted to determine the bioavailability of iron amino acid chelate (ferrochel) added to fortify breads prepared from either precooked corn flour or white wheat flour + cheese and margarine compared with the same basal breakfast enriched with either ferrous sulfate or iron-EDTA. The inhibitory effect of phytate and polyphenols on iron absorption from ferrochel was also tested. A total of 74 subjects were studied in five experiments. Iron absorption from ferrochel was about twice the absorption from ferrous sulfate (P: < 0.05). When ferrous sulfate and ferrochel were administered together or in different meals, absorption from ferrochel was about twice the absorption from ferrous sulfate (P: < 0.05). Polyphenols present in coffee and tea inhibited iron absorption in a dose-dependent manner. American-type coffee did not modify iron absorption significantly, whereas both espresso-type coffee and tea reduced iron absorption from ferrochel by 50% (P: < 0. 05). Ferrochel partially prevented the inhibitory effect of phytates. Because of its high solubility in aqueous solutions even at pH 6, its low interactions with food and high absorption, ferrochel is a suitable compound for food fortification.

  5. 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

  6. Influence of pH, buffers and role of quinolinic acid, a novel iron chelating agent, in the determination of hydroxyl radical scavenging activity of plant extracts by Electron Paramagnetic Resonance (EPR).

    PubMed

    Fadda, Angela; Barberis, Antonio; Sanna, Daniele

    2018-02-01

    The Fenton reaction is used to produce hydroxyl radicals for the evaluation of the antioxidant activity of plant extracts. In this paper the parameters affecting the production of hydroxyl radicals and their spin trapping with DMPO were studied. The use of quinolinic acid (Quin) as an Fe(II) ligand was proposed for antioxidant activity determination of Green tea, orange juice and asparagus extracts. Quin, buffers and pH affect the DMPO-OH signal intensity of the EPR spectra. Quin/Fe(II) and low pH enhance the OH generation. Phosphate and Tris-HCl buffers decrease the signal intensity measured in Fe(II)-sulfate and Fe(II)-Quin systems. The extracts were analyzed with Fenton systems containing Fe(II)-sulfate and Fe(II)-Quin with and without buffer. The highest activity was shown with Fe(II)-Quin without buffer, this system being less influenced by pH and chelating agents present in the extracts. This paper will help researchers to better design spin trapping experiments for food matrices. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    SciTech Connect

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

    2016-02-08

    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, ({sup 1}H, and {sup 13}C), FTIR, and MS-ESI. Data on the synthesis, characterization, and the application of the ligand as a chelating agent are presented.

  8. Targeting mitochondrial cell death pathway to overcome drug resistance with a newly developed iron chelate.

    PubMed

    Ganguly, Avishek; Basu, Soumya; Chakraborty, Paramita; Chatterjee, Shilpak; Sarkar, Avijit; Chatterjee, Mitali; Choudhuri, Soumitra Kumar

    2010-06-22

    Multi drug resistance (MDR) or cross-resistance to multiple classes of chemotherapeutic agents is a major obstacle to successful application of chemotherapy and a basic problem in cancer biology. The multidrug resistance gene, MDR1, and its gene product P-glycoprotein (P-gp) are an important determinant of MDR. Therefore, there is an urgent need for development of novel compounds that are not substrates of P-glycoprotein and are effective against drug-resistant cancer. In this present study, we have synthesized a novel, redox active Fe (II) complex (chelate), iron N- (2-hydroxy acetophenone) glycinate (FeNG). The structure of the complex has been determined by spectroscopic means. To evaluate the cytotoxic effect of FeNG we used doxorubicin resistant and/or sensitive T lymphoblastic leukemia cells and show that FeNG kills both the cell types irrespective of their MDR phenotype. Moreover, FeNG induces apoptosis in doxorubicin resistance T lymphoblastic leukemia cell through mitochondrial pathway via generation reactive oxygen species (ROS). This is substantiated by the fact that the antioxidant N-acetyl-cysteine (NAC) could completely block ROS generation and, subsequently, abrogated FeNG induced apoptosis. Therefore, FeNG induces the doxorubicin resistant T lymphoblastic leukemia cells to undergo apoptosis and thus overcome MDR. Our study provides evidence that FeNG, a redox active metal chelate may be a promising new therapeutic agent against drug resistance cancers.

  9. New synthetic approach and iron chelating studies of 1-alkyl-2-methyl-3-hydroxypyrid-4-ones.

    PubMed

    Kontoghiorghes, G J; Sheppard, L; Chambers, S

    1987-10-01

    The major diseases of iron metabolism are iron deficiency anaemia, which could be treated using Fe2+ or Fe3+ salt supplements, and iron overload, which could arise either from an increased gastrointestinal absorption of iron or from recurrent blood transfusions. While the former form of iron overload could be treated by phlebotomy the latter requires the use of a chelator. Desferrioxamine is the only clinically available chelator for the treatment of iron overload but its use worldwide is limited because it is expensive and orally inactive. Several alpha-ketohydroxy heteroaromatic chelators have been synthesised and tested for their iron binding properties at physiological pH. The synthetic route involves the benzylation of the hydroxyl group of maltol using benzyl chloride, the conversion of the benzylated maltol to the 1-alkyl benzylated pyridine derivative by introducing the corresponding alkylamine in alkaline conditions and the cleavage of the benzyl group in acid to form the 1-alkyl-2-methyl-3-hydroxypyrid-4-one. All the chelators are water soluble and stable at a wide range of pH, forming stable, water soluble, coloured iron complexes with a molar ratio of approximately 3 chelator: 1 iron at pH 7.4 and lower molar ratio of chelators to iron complexes at acidic pH. When the 1-methyl, 1-ethyl and 1-propyl, -2-methyl-3-hydroxypyrid-4-ones were mixed at pH 7.4 with transferrin, ferritin and haemosiderin substantial amounts of iron were released.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Investigation of Changing Pore Topology and Porosity During Matrix Acidizing using Different Chelating Agents

    NASA Astrophysics Data System (ADS)

    Umer Shafiq, Mian; Khaled Ben Mahmud, Hisham; Rezaee, Reza; Testamanti, Nadia

    2017-07-01

    Core flooding acidizing experiments on sandstone/carbonate formation are usually performed in the laboratory to observe different physical phenomena and to design acidizing stimulation jobs for the field. During the tests, some key parameters are analyzed such as pore volume required for breakthrough as well as pressure. Hydrochloric acid (HCl) is commonly used in the carbonate matrix acidizing while Mud acid (HF: HCl) is usually applied during the sandstone acidizing to remove damage around the well bore. However, many problems are associated with the application of these acids, such as fast reaction, corrosion and incompatibility of HCl with some minerals (illite). To overcome these problems, chelating agents (HEDTA, EDTA and GLDA) were used in this research. Colton tight sandstone and Guelph Dolomite core samples were used in this study. The experiments usually are defined in terms of porosity, permeability, dissolution and pore topology. Effluent samples were analyzed to determine dissolved iron, sodium, potassium, calcium and other positive ions using Inductively Coupled Plasma (ICP). Meanwhile Nuclear Magnetic Resonance (NMR) was employed to determine porosity and pore structure of the core sample. Core flood experiments on Berea sandstone cores and dolomite samples with dimensions of 1.5 in × 3 in were conducted at a flow rate of 1 cc/min under 150oF temperature. NMR and porosity analysis concluded that applied chemicals are effective in creating fresh pore spaces. ICP analysis concluded that HEDTA showed good ability to chelate calcium, sodium, magnesium, potassium and iron. It can be established from the analysis that HEDTA can increase more amount of permeability as compared to other chelates.

  11. Natural iron chelators: Protective role in A549 cells of flavonoids-rich extracts of Citrus juices in Fe(3+)-induced oxidative stress.

    PubMed

    Ferlazzo, Nadia; Visalli, Giuseppa; Cirmi, Santa; Lombardo, Giovanni Enrico; Laganà, Pasqualina; Di Pietro, Angela; Navarra, Michele

    2016-04-01

    Exogenous iron in particulate matter and imbalanced iron homeostasis cause deleterious effects on health. Natural and synthetic iron chelators may be of therapeutic benefit, therefore we evaluated the protective effect of Citrus flavonoids-rich extracts from bergamot and orange juices in iron overloaded human lung epithelial cells. Cytofluorimetric, biochemical and genotoxic analyses were performed in Fe2(SO4)3 exposed A549, pretreated with each extract whose chemical composition was previously detected. Chelating activity was assessed in cells by a calcein ester. Both extracts reduced the generation of reactive oxygen species and membrane lipid peroxidation, improved mitochondrial functionality, and prevented DNA-oxidative damage in iron-exposed cells. Antioxidant effects were attributed to the chelating property, blocking upstream the redox activity of iron. Flavonoid-rich extracts also induced antioxidant catalase. The bergamot and orange juice extracts had a broad-spectrum protective effect. Their use prevents iron oxidative injury and these natural iron chelators could be used as therapeutic agents.

  12. Role of lipid oxidation, chelating agents, and antioxidants in metallic flavor development in the oral cavity.

    PubMed

    Omür-Özbek, Pinar; Dietrich, Andrea M; Duncan, Susan E; Lee, YongWoo

    2012-03-07

    This study investigated the production of metallic flavor, which is a combination of taste and retronasal odor. Chemical reactions in the oral cavity and saliva of healthy subjects were investigated after ingesting iron and copper solutions above and near threshold levels. Significant increase in lipid oxidation (p < 0.001) occurred after metal ingestion, detected as TBARS values. Ferrous ion caused the greatest flavor sensation and lipid oxidation, followed by cupric and cuprous ions. Ferric ion did not cause metallic sensation. Occurrence of oxidation was supported by damage to salivary proteins, detected as protein-carbonyls, and by a significant increase of odorous lipid oxidation related aldehydes. Sensory evaluation demonstrated that antioxidants (vitamins E and C) minimally reduced metallic flavor but that chelating agents (EDTA and lactoferrin) removed the metallic flavor. The role of lipid oxidation is essential for the production of a metallic flavor from ingestion of ferrous, cupric, and cuprous ions.

  13. 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.

  14. Chelation Therapy with Oral Solution of Deferiprone in Transfusional Iron-Overloaded Children with Hemoglobinopathies

    PubMed Central

    Makis, Alexandros; Chaliasos, Nikolaos; Alfantaki, Sapfo; Karagouni, Paraskevi; Siamopoulou, Antigone

    2013-01-01

    Iron overload in hemoglobinopathies is secondary to blood transfusions, chronic hemolysis, and increased iron absorption and leads to tissue injury requiring the early use of chelating agents. The available agents are parenteral deferoxamine and oral deferiprone and deferasirox. There are limited data on the safety and efficacy of deferiprone at a very young age. The aim of our study was the presentation of data regarding the use of oral solution of deferiprone in 9 children (mean age 6.5, range 2–10) with transfusion dependent hemoglobinopathies (6 beta thalassemia major, 1 thalassemia intermedia, and 2 sickle cell beta thalassemia). The mean duration of treatment was 21.5 months (range 15–31). All children received the oral solution without any problems of compliance. Adverse reactions were temporary abdominal discomfort and diarrhea (1 child), mild neutropenia (1 child) that resolved with no need of discontinuation of treatment, and transient arthralgia (1 child) that resolved spontaneously. The mean ferritin levels were significantly reduced at the end of 12 months (initial 2440 versus final 1420 μg/L, P < 0.001). This small study shows that oral solution of deferiprone was well tolerated by young children and its use was not associated with major safety concerns. Furthermore, it was effective in decreasing serum ferritin. PMID:24294523

  15. Safety and Pharmacokinetics of the Oral Iron Chelator SP-420 in β-thalassemia.

    PubMed

    Taher, Ali T; Saliba, Antoine N; Kuo, Kevin H; Giardina, Patricia J; Cohen, Alan R; Neufeld, Ellis J; Aydinok, Yesim; Kwiatkowski, Janet L; Jeglinski, Brenda I; Pietropaolo, Keith; Berk, Gregory; Viprakasit, Vip

    2017-09-22

    Our Phase I, open-label, multi-center, dose-escalation study evaluated the pharmacokinetics (PK) of SP-420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent β-thalassemia. SP-420 was administered as a single dose of 1.5 (n=3), 3 (n=3), 6 (n=3), 12 (n=3), and 24 (n=6) mg/kg or as a twice-daily dose of 9 mg/kg (n=6) over 14-28 days. There was a near dose-linear increase in the mean plasma SP-420 concentrations and in the mean values for Cmax and AUC0-τ over the dose range evaluated. The median tmax ranged from 0.5 - 2.25 h and was not dose-dependent. The study was prematurely terminated by the sponsor due to renal adverse events including proteinuria, increase in serum creatinine, and one case of Fanconi syndrome. Other adverse effects included hypersensitivity reactions and gastrointestinal disturbances. Based on current dose administration, the renal adverse events observed outweighed the possible benefits from chelation therapy. However, additional studies assessing efficacy and safety of lower doses or less frequent dosing of SP-420 over longer durations with close monitoring would be necessary to better explain the findings of our study and characterize the safety of the study drug. This article is protected by copyright. All rights reserved. © 2017 Wiley Periodicals, Inc.

  16. The determination of ferric iron in plants by HPLC using the microbial iron chelator desferrioxamine E.

    PubMed

    Fernández, Victoria; Winkelmann, Günther

    2005-02-01

    Common methods for plant iron determination are based on atomic absorption spectroscopy, radioactive measurements or extraction with subsequent spectrophotometry. However, accuracy is often a problem due to background, contamination and interfering compounds. We here describe a novel method for the easy determination of ferric iron in plants by chelation with a highly effective microbial siderophore and separation by high performance liquid chromatography (HPLC). After addition of colourless desferrioxamine E (DFE) to plant fluids, the soluble iron is trapped as a brown-red ferrioxamine E (FoxE) complex which is subsequently separated by HPLC on a reversed phase column. The formed FoxE complex can be identified due to its ligand-to-metal charge transfer band at 435 nm. Alternatively, elution of both, DFE and FoxE can be followed as separate peaks at 220 nm wavelength with characteristic retention times. The extraordinarily high stability constant of DFE with ferric iron of K = 10(32) enables extraction of iron from a variety of ferrous and ferric iron compounds and allows quantitation after separation by HPLC without interference by coloured by-products. Thus, iron bound to protein, amino acids, citrate and other organic acid ligands and even insoluble ferric hydroxides and phosphates can be solubilized in the presence desferrioxamine E. The "Ferrioxamine E method" can be applied to all kinds of plant fluids (apoplasmic, xylem, phloem, intracellular) either at physiological pH or even at acid pH values. The FoxE complex is stable down to pH 1 allowing protein removal by perchloric acid treatment and HPLC separation in the presence of trifluoroacetic acid containing eluents.

  17. Fate of labeled hydroxamates during iron transport from hydroxamate-ion chelates.

    PubMed

    Arceneaux, J E; Davis, W B; Downer, D N; Haydon, A H; Byers, B R

    1973-09-01

    The fate of the hydroxamic acid-iron transport cofactors during iron uptake from the (59)Fe(3+) chelates of the (3)H-labeled hydroxamates schizokinen and aerobactin was studied by assay of simultaneous incorporation of both (59)Fe(3+) and (3)H. In the schizokinen-producing organism Bacillus megaterium ATCC 19213 transport of (59)Fe(3+) from the (3)H-schizokinen-(59)Fe(3+) chelate at 37 C was accompanied by rapid uptake and release (within 2 min) of (3)H-schizokinen, although (3)H-schizokinen discharge was temperature-dependent and did not occur at 0 C. In the schizokinen-requiring strain B. megaterium SK11 similar release of (3)H-schizokinen occurred only at elevated concentrations of the double-labeled chelate; at lower chelate concentrations, (3)H-schizokinen remained cell-associated. Temperature-dependent uptake of deferri (iron-free) (3)H-schizokinen to levels equivalent to those incorporated from the chelate form was noted in strain SK11, but strain ATCC 19213 showed only temperature-independent binding of low concentrations of deferri (3)H-schizokinen. These results indicate an initial temperature-independent binding of the ferric hydroxamate which is followed rapidly by temperature-dependent transport of the chelate into the cell and an enzyme catalyzed separation of iron from the chelate. The resulting deferri hydroxamate is discharged from the cell only when a characteristic intracellular concentration of the hydroxamate is exceeded, which happens in the schizokinen-requiring strain only at elevated concentrations of the chelate. This strain also appears to draw the deferri hydroxamate into the cell by a temperature-dependent mechanism. The aerobactin-producing organism Aerobacter aerogenes 62-1 also demonstrated rapid initial uptake and temperature-dependent discharge of (3)H-aerobactin during iron transport from (3)H-aerobactin-(59)Fe(3+), suggesting a similar ferric hydroxamate transport system in this organism.

  18. 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

  19. 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.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  1. Comparison of oral and subcutaneous iron chelation therapies in the prevention of major endocrinopathies in beta-thalassemia major patients.

    PubMed

    Wang, Chung-Hsing; Wu, Kang-Hsi; Tsai, Fuu-Jen; Peng, Ching-Tien; Tsai, Chang-Hai

    2006-01-01

    While hypertransfusion and subcutaneous iron chelation therapy have increased longevity of patients with beta-thalassemia (thal) major, endocrinopathies have become more common and impair the quality of their lives. Additionally, subcutaneous iron chelation therapy is an uncomfortable experience and can prevent patients from regular compliance with iron chelation therapy. We compared the efficacy of oral deferiprone (L1) to subcutaneous desferrioxamine (DFO) chelation therapy for the prevention of major endocrinopathies (growth hormone insufficiency, diabetes mellitus and gonadal dysfunction) among patients with beta-thal major to see if we could offer these patients an easier and more painless way to reduce their body iron load and related endocrine complications.

  2. The role of antioxidants and iron chelators in the treatment of oxidative stress in thalassemia.

    PubMed

    Fibach, Eitan; Rachmilewitz, Eliezer A

    2010-08-01

    On the basis of all the presented data, one can conclude that oxidative stress plays a major role in the pathophysiology of thalassemia and other congenital and acquired hemolytic anemias. Free extracellular (labile plasma iron, LPI) and intracellular (labile iron pool, LIP) iron species that have been identified in thalassemic blood cells are responsible for generation of oxidative stress by catalyzing formation of oxygen radicals over the antioxidant capacity of the cell. Consequently, there is a rationale for iron chelation to eliminate the free-iron species, which in this respect, act like antioxidants. In addition, antioxidants such as vitamin E and polyphenols are also capable of ameliorating increased oxidative stress parameters and, given together with iron chelators, may provide a substantial improvement in the pathophysiology of hemolytic anemias and particularly in thalassemia.

  3. 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)

  4. 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)

  5. Iron Oxide Nanoparticle Based Contrast Agents for Magnetic Resonance Imaging.

    PubMed

    Shen, Zheyu; Wu, Aiguo; Chen, Xiaoyuan

    2017-05-01

    Magnetic iron oxide nanoparticles (MIONs) have attracted enormous attention due to their wide applications, including for magnetic separation, for magnetic hyperthermia, and as contrast agents for magnetic resonance imaging (MRI). This review article introduces the methods of synthesizing MIONs, and their application as MRI contrast agents. Currently, many methods have been reported for the synthesis of MIONs. Herein, we only focus on the liquid-based synthesis methods including aqueous phase methods and organic phase methods. In addition, the MIONs larger than 10 nm can be used as negative contrast agents and the recently emerged extremely small MIONs (ES-MIONs) smaller than 5 nm are potential positive contrast agents. In this review, we focus on the ES-MIONs because ES-MIONs avoid the disadvantages of MION-based T2- and gadolinium chelate-based T1-weighted contrast agents.

  6. The role of iron and chelators on infections in iron overload and non iron loaded conditions: prospects for the design of new antimicrobial therapies.

    PubMed

    Kontoghiorghes, George J; Kolnagou, Annita; Skiada, Anna; Petrikkos, George

    2010-06-01

    Iron overload is known to exacerbate many infectious diseases. Infectious complications are considered to be the second main cause of morbidity and mortality in iron loaded thalassemia patients. Effective chelation therapy leading to the normalization of the iron stores could reduce the incidence of related infections. Microbial pathogens could obtain growth-essential iron from healthy hosts. Conversely, iron withholding and/or removal is an important defense strategy for mammalian hosts, which is primarily accomplished by the iron chelating proteins transferrin and lactoferrin. Chelating drugs could prevent microbial growth and play an essential role in antimicrobial therapeutic strategies. Specific mechanisms and interactions apply in the transfer or withholding of iron between the chelating drugs deferoxamine (DFO), deferiprone (L1) and deferasirox (DFRA) with microbial pathogens such as bacteria, fungi and protozoa. In some cases, chelators and in particular DFO, could act as a siderophore for the microbe and exacerbate infections such as yersiniasis and mucormycosis. Deferiprone appears to have the highest therapeutic index for long-term antimicrobial activity and the highest tissue penetration, including access to the brain. Selection of specific chelation therapy protocols could be considered in conditions where other antimicrobial therapies have failed or where resistance has developed to existing therapies.

  7. 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.

  8. 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.

  9. Chelation protocols for the elimination and prevention of iron overload in thalassaemia.

    PubMed

    Kolnagou, Annita; Kontoghiorghes, George John

    2018-01-01

    Iron overload toxicity is the main cause of mortality and morbidity in thalassaemia patients. The complete elimination and prevention of iron overload is the main aim of chelation therapy, which can be achieved by chelation protocols that can effectively remove excess iron load and maintain body iron at normal levels. Deferiprone and selected combinations with deferoxamine can be designed, adjusted and used effectively for removing all excess stored iron and for maintaining normal iron stores (NIS) in different categories of thalassaemia patients. High doses of deferiprone (75-100 mg/kg/day) and deferoxamine (50-60 mg/kg, 1-7 days/week) combinations can be used for achieving and maintaining NIS in heavily iron loaded transfused patients. In contrast, deferiprone (75-100 mg/kg/day) can be used effectively and sometimes intermittently for maintaining NIS in non heavily transfused patients. Deferasirox can in particular be used in patients not tolerating deferoxamine and deferiprone. The design of tailored made personalised protocols using deferiprone and selected combinations with deferoxamine should be considered as optimum chelation therapies for the complete treatment and the prevention of iron overload in thalassaemia.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  11. Iron-enhanced coagulation is attenuated by chelation: thrombelastographic and ultrastructural analysis.

    PubMed

    Nielsen, Vance G; Pretorius, Etheresia

    2014-12-01

    Increased circulating ferritin and free iron have been found in a variety of disease states associated with thrombophilia. When blood or plasma is exposed to iron addition, characteristic changes in thrombus formation are observed by scanning electron microscopy, which include fusion of fibrin polymers, matting, and even sheeting of fibrin. A primary mechanism posited to explain iron-mediated hypercoagulability is hydroxyl radical formation and modification of fibrinogen; however, iron has also been demonstrated to bind to fibrinogen. We have recently demonstrated that iron enhances coagulation, manifested as a decrease in the time of onset of coagulation. Using clinically encountered concentrations of iron created by addition of FeCl3 to human plasma, we demonstrated that iron-mediated changes in reaction time determined by thrombelastography or changes in thrombus ultrastructure were significantly, but not completely, reversed by iron chelation with deferoxamine. Thus, reversible iron binding to fibrinogen mechanistically explains a significant portion of coagulation kinetic and ultrastructural hypercoagulability. Further investigation is needed to determine whether residual iron binding or other iron-mediated effects is responsible for hypercoagulability observed after chelation.

  12. Cellular pool of transient ferric iron, chelatable by deferoxamine and distinct from ferritin, that is involved in oxidative cell injury.

    PubMed

    Rothman, R J; Serroni, A; Farber, J L

    1992-10-01

    A cellular pool of transient ferric iron that is chelatable by deferoxamine, distinct from ferritin, and required for oxidative cell injury has been identified in cultured rat hepatocytes labeled with 59FeCl3. Pretreatment of hepatocytes with deferoxamine depleted the cellular pool of chelatable iron and protected the cells from an oxidative injury. Incubation of deferoxamine-pretreated hepatocytes in serum-free medium restored both the chelatable iron pool and the susceptibility to oxidative injury. Furthermore, inhibition of protein degradation with chymostatin prevented the restoration of both the chelatable pool and susceptibility to oxidative injury. The deferoxamine-chelatable iron pool was distinguished kinetically and immunochemically from the larger cellular pool of ferritin iron. The labeled iron in the deferoxamine-chelatable pool was transient, unlike either the total cellular uptake of 59Fe or its incorporation into ferritin, both of which increased with time of labeling. With pulse-chase labeling, the percentage of the total uptake of 59Fe that was represented by the deferoxamine-chelatable pool decreased. At the same time, the percentage represented by radioactivity immunoprecipitable as ferritin increased. Furthermore, immunoprecipitation of ferritin from the labeled lysates enriched the resulting immunosupernatants in deferoxamine-chelatable iron. The degree of enrichment for chelatable iron correlated with the percentage of the cellular label that was immunoprecipitable as ferritin. The deferoxamine-chelatable iron appears to represent a metabolically common pool of iron that is rapidly in transit through the cell. Extracellular iron entering the pool can be utilized for heme synthesis or stored in ferritin, whereas protein degradation releases storage iron into this pool.

  13. Reducing power and iron chelating property of Terminalia chebula (Retz.) alleviates iron induced liver toxicity in mice.

    PubMed

    Sarkar, Rhitajit; Hazra, Bibhabasu; Mandal, Nripendranath

    2012-08-31

    The 70% methanol extract of Terminalia chebula Retz. fruit (TCME) was investigated for its in vitro iron chelating property and in vivo ameliorating effect on hepatic injury of iron overloaded mice. The effect of fruit extract on Fe2+-ferrozine complex formation and Fe2+ mediated pUC-18 DNA breakdown was studied in order to find the in vitro iron chelating activity. Thirty-six Swiss Albino mice were divided into six groups of: blank, patient control and treated with 50, 100, 200 mg/kg b.w. of TCME and desirox (standard iron chelator drug with Deferasirox as parent compound). Evaluations were made for serum markers of hepatic damage, antioxidant enzyme, lipid per oxidation and liver fibrosis levels. The reductive release of ferritin iron by the extract was further studied. In vitro results showed considerable iron chelation with IC50 of 27.19 ± 2.80 μg/ml, and a significant DNA protection with [P]50 of 1.07 ± 0.03 μg/ml along with about 86% retention of supercoiled DNA. Iron-dextran injection (i.p.) caused significant increase in the levels of the serum enzymes, viz., alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (ALP) and Bilirubin, which were subsequently lowered by oral administration of 200 mg/kg b.w. dose of the fruit extract by 81.5%, 105.88%, 188.08% and 128.31%, respectively. Similarly, treatment with the same dose of the extract was shown to alleviate the reduced levels of liver antioxidant enzyme superoxide dismutase, catalase, glutathione S-transferase and non-enzymatic reduced glutathione, by 49.8%, 53.5%, 35.4% and 11% respectively, in comparison to the iron overloaded mice. At the same time, the fruit extract effectively lowered the iron-overload induced raised levels of lipid per oxidation, protein carbonyl, hydroxyproline and liver iron by 49%, 67%, 67% and 26%, respectively, with oral treatment of 200 mg/kg b.w. dose of TCME. The fruit extract also showed potential activity for reductive release

  14. Inhibition of DNA synthesis in CCL 39 cells by impermeable iron chelators.

    PubMed

    Alcaín, F J; Löw, H; Crane, F L

    1997-02-01

    The synthesis of DNA in CCl 39 cells is inhibited by the presence of the Fe2+ chelator bathophenanthroline disulfonate (BPS) when growth is stimulated by thrombin EGF plus insulin, but not by fetal calf serum. The presence of transferrin and Fe3+ in fetal calf serum can be the basis for lack of BPS effect with serum. The impermeable Fe3+ chelator Tiron does not, by itself, inhibit growth factor induced DNA synthesis, but it induces together with BPS inhibition on fetal calf serum induced DNA synthesis. The combined effect of BPS and Tiron is similar to inhibition of DNA synthesis by impermeable polyvalent DTPA which can chelate both Fe2+ and Fe3+ but does not inhibit ribonucleotide reductase in intact cells. Ferrous iron that bind BPS can relieve the inhibition at stoichiometric concentration. Ferric iron also prevents the inhibition even though it does not bind BPS. BPS does not inhibit DNA synthesis in HeLa cells. BPS reacts with iron from CCl 39 cells but not from HeLa cells. Data show that iron available for impermeable external chelators is in the ferrous state, and that exogenous iron should be reduced before it reverses the inhibition.

  15. Prooxidant and antioxidant properties of salicylaldehyde isonicotinoyl hydrazone iron chelators in HepG2 cells

    PubMed Central

    Caro, Andres A.; Commissariat, Ava; Dunn, Caroline; Kim, Hyunjoo; García, Salvador Lorente; Smith, Allen; Strang, Harrison; Stuppy, Jake; Desrochers, Linda P.; Goodwin, Thomas E.

    2015-01-01

    Background Salicylaldehyde isonicotinoyl hydrazone (SIH) is an iron chelator of the aroylhydrazone class that displays antioxidant or prooxidant effects in different mammalian cell lines. Because the liver is the major site of iron storage, elucidating the effect of SIH on hepatic oxidative metabolism is critical for designing effective hepatic antioxidant therapies. Methods Hepatocyte-like HepG2 cells were exposed to SIH or to analogs showing greater stability, such as N′-[1-(2-Hydroxyphenyl)ethyliden]isonicotinoyl hydrazide (HAPI), or devoid of iron chelating properties, such as benzaldehyde isonicotinoyl hydrazone (BIH), and toxicity, oxidative stress and antioxidant (glutathione) metabolism were evaluated. Results Autoxidation of Fe2+ in vitro increased in the presence of SIH or HAPI (but not BIH), an effect partially blocked by Fe2+ chelation. Incubation of HepG2 cells with SIH or HAPI (but not BIH) was non-toxic and increased reactive oxygen species (ROS) levels, activated the transcription factor Nrf2, induced the catalytic subunit of γ-glutamate cysteine ligase (Gclc), and increased glutathione concentration. Fe2+ chelation decreased ROS and inhibited Nrf2 activation, and Nrf2 knock-down inhibited the induction of Gclc in the presence of HAPI. Inhibition of γ-glutamate cysteine ligase enzymatic activity inhibited the increase in glutathione caused by HAPI, and increased oxidative stress. Conclusions SIH iron chelators display both prooxidant (increasing the autoxidation rate of Fe2+) and antioxidant (activating Nrf2 signaling) effects. General significance Activation by SIH iron chelators of a hormetic antioxidant response contributes to its antioxidant properties and modulates the anti- and pro-oxidant balance. PMID:26275495

  16. Efficacy of Deferasirox as an Oral Iron Chelator in Paediatric Thalassaemia Patients

    PubMed Central

    Hishikar, Rajesh; Khandwal, Onkar; Agarwal, Manju; Joshi, Usha; Halwai, Ajay; Maheshwari, Basant; Sheohare, Raka

    2017-01-01

    Introduction Thalassaemia Major patients require frequent blood transfusion leading to iron overload. Excessive iron gets deposited in vital organs and leads to dysfunction of the heart, liver, anterior pituitary, pancreas, and joints. Our body has limited mechanism to excrete iron, so patients with iron overload and its complications need safe and effective iron chelation therapy. Aim To assess the efficacy of Deferasirox (DFX) as an iron chelator, with specific reference to reduction in serum ferritin level. Materials and Methods This is a prospective; observational study done in 45 multitransfused Thalassaemia Major Children receiving DFX therapy at registered Thalassaemia society Raipur Chhattisgarh. DFX was given in an initial dose of 20 mg/kg/day and according to response increased to a maximum of 40 mg/kg/day. Serum ferritin level was estimated at time of registration and at every three monthly intervals (four times during study period). The primary end point of the study was change in serum ferritin level after 12 months of DFX therapy. Results The mean serum ferritin before DFX therapy of all cases was 3727.02 ng/mL. After 12 months of mean dose of 38 mg/kg/day of DFX, the mean decline in serum ferritin was 1207.11 ng/mL (drop by 32.38%, p-value <0.001). Conclusion DFX monotherapy has a good safety profile and effectively chelates total body iron in Thalassaemia major patients. PMID:28384880

  17. Iron uptake by Caco-2 cells from NaFeEDTA and FeSO4: Effects of ascorbic acid, pH, and a Fe(II) chelating agent.

    PubMed

    Zhu, Le; Glahn, Raymond P; Yeung, Chi Kong; Miller, Dennis D

    2006-10-04

    Sodium iron(III) ethylenediaminetetraacetate (NaFeEDTA) has considerable promise as an iron fortificant because of its high bioavailability in foods containing iron absorption inhibitors. In this study, uptakes of iron from NaFeEDTA, FeSO4, and FeCl3 by Caco-2 cells were compared in the absence or presence of ascorbic acid (AA), an iron absorption enhancer; at selected pH levels; and in the absence or presence of an iron absorption inhibitor, bathophenanthroline disulfonic acid (BPDS). Ferritin formation in the cells was used as the indicator of iron uptake. Uptake from all three Fe sources was similar in the absence of AA. Adding AA at a 5:1 molar excess as compared to Fe increased uptake by 5.4-, 5.1-, and 2.8-fold for FeSO4, FeCl3, and NaFeEDTA, respectively. The smaller effect of AA on uptake from NaFeEDTA may be related to the higher solubility of NaFeEDTA and/or the strong binding affinity of EDTA for Fe3+, which may prevent AA and duodenal cytochrome b from effectively reducing EDTA-bound Fe. Uptake was inversely related to the pH of the media over a range of 5.8-7.2. Because uptake by DMT-1 is proton-coupled, the inverse relationship between pH and Fe uptake in all three iron sources suggests that they all follow the DMT-1 pathway into the cell. Adding BPDS to the media inhibited uptake from all three iron compounds equally. Because BPDS binds Fe2+ but not Fe3+ and because only Fe2+ is transported by DMT-1, the finding that BPDS inhibited uptake from NaFeEDTA suggests that at least some iron dissociates from EDTA and is reduced just as simple inorganic iron at the brush border membrane of the enterocyte. Taken together, these results suggest that uptake of iron from NaFeEDTA by intestinal enterocytes is regulated similarly to uptake from iron salts.

  18. 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

  19. [Iron chelate treatment of hereditary sideroblastic anemia complicated by hemochromatosis].

    PubMed

    Kremp, L; Girot, R; Alliot, S; Najean, Y; Douchain, F; Hongre, J F

    1983-01-01

    In a child with sideroblastic anemia complicated with hemochromatosis, iron overload was successfully treated with slow subcutaneous perfusion of deferoxamine. A 28 month-treatment resulted in the inversion of iron balance, which became negative, and the normalization of serum ferritin and abdominal CT scan. These results indicate that deferoxamine perfusion 12/24 hrs is able to restrict or even to remove the iron overload, previously responsible for hemochromatosis, a factor of mortality in this disease.

  20. Mössbauer spectroscopic study of iron-chelate trammels

    NASA Astrophysics Data System (ADS)

    Pal, Sangita; Meena, S. S.; Ningthoujam, R. S.; Goswami, D.

    2014-04-01

    Any kind of waste effluent in the Indian context and other countries contains a lot of iron in any ore. During mining, milling, extraction and purification process iron acts as contaminant towards other metal's purity. It is essential to remove iron to the maximum extent. In this case, an "IN-HOUSE" resin polyacrylamidehydroxamic acid (PHOA) has been designed and developed which is highly hydrophilic three dimensionally cross-linked. It has an excellent iron binding capacity with almost no leaching. Interaction of resin with ammonium ferrous sulphate and red-mod (Fe2O3) is studied using Mössbauer spectroscopy.

  1. Benzylidene Acylhydrazides Inhibit Chlamydial Growth in a Type III Secretion- and Iron Chelation-Independent Manner

    PubMed Central

    Bao, Xiaofeng; Gylfe, Åsa; Sturdevant, Gail L.; Gong, Zheng; Xu, Shuang; Caldwell, Harlan D.; Elofsson, Mikael

    2014-01-01

    Chlamydiae are widespread Gram-negative pathogens of humans and animals. Salicylidene acylhydrazides, developed as inhibitors of type III secretion system (T3SS) in Yersinia spp., have an inhibitory effect on chlamydial infection. However, these inhibitors also have the capacity to chelate iron, and it is possible that their antichlamydial effects are caused by iron starvation. Therefore, we have explored the modification of salicylidene acylhydrazides with the goal to uncouple the antichlamydial effect from iron starvation. We discovered that benzylidene acylhydrazides, which cannot chelate iron, inhibit chlamydial growth. Biochemical and genetic analyses suggest that the derivative compounds inhibit chlamydiae through a T3SS-independent mechanism. Four single nucleotide polymorphisms were identified in a Chlamydia muridarum variant resistant to benzylidene acylhydrazides, but it may be necessary to segregate the mutations to differentiate their roles in the resistance phenotype. Benzylidene acylhydrazides are well tolerated by host cells and probiotic vaginal Lactobacillus species and are therefore of potential therapeutic value. PMID:24914180

  2. 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

  3. Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats.

    PubMed

    Shachar, Dorit Ben; Kahana, Nava; Kampel, Vladimir; Warshawsky, Abraham; Youdim, Moussa B H

    2004-02-01

    Significant increase in iron occurs in the substantia nigra pars compacta of Parkinsonian subjects, and in 6-hydroxydopamine (6-OHDA) treated rats and monkeys. This increase in iron has been attributed to its release from ferritin and is associated with the generation of reactive oxygen species and the onset of oxidative stress-induced neurodegeneration. Several iron chelators with hydroxyquinoline backbone were synthesized and their ability to inhibit basal as well as iron-induced mitochondrial lipid peroxidation was examined. The neuroprotective potential of the brain permeable iron chelator, VK-28 (5-[4-(2-hydroxyethyl) piperazine-1-ylmethyl]-quinoline-8-ol), injected either intraventricularly (ICV) or intraperitoneally (IP), to 6-OHDA lesioned rats was investigated. VK-28 inhibited both basal and Fe/ascorbate induced mitochondrial membrane lipid peroxidation, with an IC(50) (12.7 microM) value comparable to that of the prototype iron chelator, desferal, which does not cross the blood brain barrier. At an ICV pretreatment dose as low as 1 microg, VK-28 was able to completely protect against ICV 6-OHDA (250 microg) induced striatal dopaminergic lesion, as measured by dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) levels. IP injection of rats with VK-28 (1 and 5 mg/kg) daily for 10 and 7 days, respectively, demonstrated significant neuroprotection against ICV 6-OHDA at the higher dose, with 68% protection against loss of dopamine at 5mg/kg dosage of VK-28. The present study is the first to show neuroprotection with a brain permeable iron chelator. The latter can have implications for the treatment of Parkinson's disease and other neurodegenerative diseases (Alzheimer's disease, Friedreich ataxia, aceruloplasminemia, Hallervorden Spatz syndrome) where abnormal iron accumulation in the brain is thought to be associated with the degenerative processes.

  4. Comparative effects of chelating agents on distribution, excretion, and renal toxicity of inorganic mercury in rats

    SciTech Connect

    Kojima, S.; Shimada, H.; Kiyozumi, M. )

    1989-06-01

    The effects of three chelating agents, sodium N-benzyl-D-glucamine dithiocarbamate(NBG-DTC), 2,3-dimercaptopropanol(BAL), and D-penicillamine(D-PEN), on the distribution, excretion, and renal toxicity of inorganic mercury were compared in rats exposed to HgCl2. Rats were injected i.p. with 203HgCl2 (300 micrograms of Hg and 2 microCi of 203Hg/kg) and 30 min or 24 h later they were injected with a chelating agent (a quarter of an LD50). The injection of the chelating agents significantly enhanced the biliary and urinary excretions of mercury. BAL was the most effective for removal of mercury from the body at 30 min after mercury treatment. The extent of enhancing effect of the chelating agents for removal of mercury at 24 h after mercury was in the order NBG-DTC = BAL greater than D-PEN. The injection of BAL at 24 h after mercury treatment caused the redistribution of mercury to the heart and lung. NBG-DTC did not result in the redistribution of mercury to the heart, lung, and brain. Urinary excretion of protein and AST significantly increased 24-48 h after mercury treatment and decreased to the control values 72 h after mercury. The injection of the chelating agents at 30 min after mercury treatment significantly decreased the urinary excretion of protein and AST. In rats pretreated with mercury 24 h earlier, the chelating agents significantly decreased the urinary protein at 48 h after mercury treatment, but did not decrease the urinary AST. The results of this study indicate that the chelating agents are effective in removing mercury from the body, resulting in the protective effect against the mercury-induced renal damage.

  5. Effects of chelators on mercury, iron, and lead neurotoxicity in cortical culture.

    PubMed

    Rush, Travis; Hjelmhaug, Julie; Lobner, Doug

    2009-01-01

    Chelation therapy for the treatment of acute, high dose exposure to heavy metals is accepted medical practice. However, a much wider use of metal chelators is by alternative health practitioners for so called "chelation therapy". Given this widespread and largely unregulated use of metal chelators it is important to understand the actions of these compounds. We tested the effects of four commonly used metal chelators, calcium disodium ethylenediaminetetraacetate (CaNa2EDTA), D-penicillamine (DPA), 2,3 dimercaptopropane-1-sulfonate (DMPS), and dimercaptosuccinic acid (DMSA) for their effects on heavy metal neurotoxicity in primary cortical cultures. We studied the toxicity of three forms of mercury, inorganic mercury (HgCl2), methyl mercury (MeHg), and ethyl mercury (thimerosal), as well as lead (PbCl2) and iron (Fe-citrate). DPA had the worst profile of effects, providing no protection while potentiating HgCl2, thimerosal, and Fe-citrate toxicity. DMPS and DMSA both attenuated HgCl2 toxicity and potentiated thimerosal and Fe toxicity, while DMPS also potentiated PbCl2 toxicity. CaNa2EDTA attenuated HgCl2 toxicity, but caused a severe potentiation of Fe-citrate toxicity. The ability of these chelators to attenuate the toxicity of various metals is quite restricted, and potentiation of toxicity is a serious concern. Specifically, protection is provided only against inorganic mercury, while it is lacking against the common form of mercury found in food, MeHg, and the form found in vaccines, thimerosal. The potentiation of Fe-citrate toxicity is of concern because of iron's role in oxidative stress in the body. Potentiation of iron toxicity could have serious health consequences when using chelation therapy.

  6. Chelating agents inhibit activity and prevent expression of streptococcal glucan-binding lectins.

    PubMed Central

    Lü-Lü; Singh, J S; Galperin, M Y; Drake, D; Taylor, K G; Doyle, R J

    1992-01-01

    Several of the cariogenic mutans streptococci produce cell wall-associated glucan-binding lectins (GBLs). The lectins bind alpha-1,6-linked glucans and have no affinity for other polysaccharides or anomeric linkages. When citrate or lactate was included in the growth medium, expression of the activities of the GBLs of Streptococcus cricetus and S. sobrinus was prevented. Furthermore, chelating agents, including citrate, lactate, EDTA, and acetylacetone, were able to reversibly inhibit glucan-induced aggregation of GBL+ streptococci. In addition, the chelating agents prevented sucrose-dependent streptococcal adhesion to glass surfaces and dispersed preformed adherent masses of the streptococci. Neither citrate nor other chelating agents modified the activities of glucosyltransferases. Expression of the lectin could only be achieved by the addition of manganous ion to the growth medium. Chloramphenicol and other metabolic inhibitors prevented synthesis of GBL in cells obtained from manganese-deficient medium and shifted to manganous ion-sufficient medium. The GBL may be a manganoprotein, the manganese of which may be perturbed, but not removed, by chelating agents. During synthesis of the GBL, manganous ion may be required in order for the protein to achieve an active conformation. Citrate or other chelating agents may have promise as anticaries agents. Images PMID:1500189

  7. Flavonoids function as antioxidants: By scavenging reactive oxygen species or by chelating iron?

    NASA Astrophysics Data System (ADS)

    Wuguo, Deng; Xingwang, Fang; Jilan, Wu

    1997-09-01

    Flavonoids have been reported to exhibit strong antioxidative activity. In the present work, a systematic mechanistic study has been performed on five flavonoids (baicalin, hesperidin, naringin, quercetin and rutin) selected according to their structural characteristics. The experimental results reveal that flavonoids function as antioxidant mainly by chelating iron ions and by scavenging peroxyl radicals whereas their OH radical scavenging effect is much less important.

  8. Synthesis and Thermodynamic Evaluation of Mixed Hexadentate Linear Iron Chelators Containing Hydroxypyridinone and Terephthalamide Units1

    PubMed Central

    Abergel, Rebecca J.; Raymond, Kenneth N.

    2011-01-01

    A series of new linear iron chelators containing hydroxypyridinone and terephthalamide moieties has been prepared. All are hexadentate ligands composed of a systematically varied combination of me-3,2-hydroxypyridinone and 2,3-dihydroxyterephthalamide binding units; most are based on a spermidine scaffold but one incorporates the bifunctional 2,3-dihydroxyterephthalamide unit as an integral part of the backbone. Protonation and ferric iron complex formation constants have been determined from solution thermodynamic studies giving log ε110 values of 25.7, 30.7, 36.3, 43.8, and 45.0 respectively. The ferric complexes display reversible reduction potentials from −276 mV to −1032 mV (measured relative to the normal hydrogen electrode NHE) in alkaline solution. The incremental replacement of hydroxypyridinone units by terephthalamide binding groups progressively reduces the ligand acidity, markedly increases the iron-chelate stability, and improves the selectivity for ferric ion over ferrous ion. While the majority of iron chelators forming very stable ferric complexes are based on a tripodal backbone such as TREN, the ferric 5-LIO(TAMmeg)2(TAM) complex, despite its non-tripodal scaffold, is one of the most stable iron complexes yet reported. Moreover, the high affinity for ferric ion of the discussed linear ligands strongly correlates with their ability to remove iron in vivo. PMID:16634594

  9. A Powerful Mitochondria-Targeted Iron Chelator Affords High Photoprotection against Solar Ultraviolet A Radiation.

    PubMed

    Reelfs, Olivier; Abbate, Vincenzo; Hider, Robert C; Pourzand, Charareh

    2016-08-01

    Mitochondria are the principal destination for labile iron, making these organelles particularly susceptible to oxidative damage on exposure to ultraviolet A (UVA, 320-400 nm), the oxidizing component of sunlight. The labile iron-mediated oxidative damage caused by UVA to mitochondria leads to necrotic cell death via adenosine triphosphate depletion. Therefore, targeted removal of mitochondrial labile iron via highly specific tools from these organelles may be an effective approach to protect the skin cells against the harmful effects of UVA. In this work, we designed a mitochondria-targeted hexadentate (tricatechol-based) iron chelator linked to mitochondria-homing SS-like peptides. The photoprotective potential of this compound against UVA-induced oxidative damage and cell death was evaluated in cultured primary skin fibroblasts. Our results show that this compound provides unprecedented protection against UVA-induced mitochondrial damage, adenosine triphosphate depletion, and the ensuing necrotic cell death in skin fibroblasts, and this effect is fully related to its potent iron-chelating property in the organelle. This mitochondria-targeted iron chelator has therefore promising potential for skin photoprotection against the deleterious effects of the UVA component of sunlight. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Iron chelators increase the resistance of Ataxia telangeictasia cells to oxidative stress.

    PubMed

    Shackelford, Rodney E; Manuszak, Ryan P; Johnson, Cybele D; Hellrung, Daniel J; Link, Charles J; Wang, Suming

    2004-10-05

    Ataxia telangeictasia (A-T) is an autosomal recessive disorder characterized by immune dysfunction, genomic instability, chronic oxidative damage, and increased cancer incidence. Previously, desferal was found to increase the resistance of A-T, but not normal cells to exogenous oxidative stress in the colony forming-efficiency assay, suggesting that iron metabolism is dysregulated in A-T. Since desferal both chelates iron and modulates gene expression, we tested the effects of apoferritin and the iron chelating flavonoid quercetin on A-T cell colony-forming ability. We demonstrate that apoferritin and quercetin increase the ability of A-T cells to form colonies. We also show that labile iron levels are significantly elevated in Atm-deficient mouse sera compared to syngeniec wild type mice. Our findings support a role for labile iron acting as a Fenton catalyst in A-T, contributing to the chronic oxidative stress seen in this disease. Our findings further suggest that iron chelators might promote the survival of A-T cells and hence, individuals with A-T.

  11. (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).

  12. [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).

  13. 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.

  14. Curcumin induces apoptosis and protective autophagy in castration-resistant prostate cancer cells through iron chelation.

    PubMed

    Yang, Chunguang; Ma, Xueyou; Wang, Zhihua; Zeng, Xing; Hu, Zhiquan; Ye, Zhangqun; Shen, Guanxin

    2017-01-01

    Curcumin induces apoptosis and autophagy in different cancer cells. Moreover, chemical and biological experiments have evidenced that curcumin is a biologically active iron chelator and induces cytotoxicity through iron chelation. We thus hypothesized that curcumin may induce apoptosis and autophagy in castration-resistant prostate cancer (CRPC) cells through its iron-chelating properties. CRPC cells were loaded with curcumin alone or in combination with ferric ammonium citrate (FAC). Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by flow cytometry, terminal deoxynucleotidyl transferase nick end labeling (TUNEL) assay and caspase activity. Autophagy status was analyzed by the detection of autophagosomes and light chain 3-II (LC3-II) using transmission electron microscopy and Western blot. Iron-binding activity of curcumin was assessed by spectrophotometry and MTT assay. The expression levels of transferrin receptor 1 (TfR1) and iron regulatory protein 1 (IRP1) were examined by Western blot. Curcumin induced apoptosis and autophagy in CRPC cells. Combining curcumin with autophagy inhibitors (3-methyladenine [3-MA]) synergized the apoptotic effect of curcumin. Moreover, curcumin bound to FAC at a ratio of ~1:1, as assessed by spectrophotometry and MTT assay. Apoptosis and autophagy induced by curcumin were counteracted by equal amounts of FAC. At apoptosis- and autophagy-inducing concentrations, curcumin enhanced the expression levels of TfR1 and IRP1, indicative of iron deprivation induced by curcumin. Together, our results indicate that curcumin induces apoptosis and protective autophagy in CRPC cells, which are at least partially dependent on its iron-chelating properties.

  15. Curcumin induces apoptosis and protective autophagy in castration-resistant prostate cancer cells through iron chelation

    PubMed Central

    Yang, Chunguang; Ma, Xueyou; Wang, Zhihua; Zeng, Xing; Hu, Zhiquan; Ye, Zhangqun; Shen, Guanxin

    2017-01-01

    Background Curcumin induces apoptosis and autophagy in different cancer cells. Moreover, chemical and biological experiments have evidenced that curcumin is a biologically active iron chelator and induces cytotoxicity through iron chelation. We thus hypothesized that curcumin may induce apoptosis and autophagy in castration-resistant prostate cancer (CRPC) cells through its iron-chelating properties. Materials and methods CRPC cells were loaded with curcumin alone or in combination with ferric ammonium citrate (FAC). Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by flow cytometry, terminal deoxynucleotidyl transferase nick end labeling (TUNEL) assay and caspase activity. Autophagy status was analyzed by the detection of autophagosomes and light chain 3-II (LC3-II) using transmission electron microscopy and Western blot. Iron-binding activity of curcumin was assessed by spectrophotometry and MTT assay. The expression levels of transferrin receptor 1 (TfR1) and iron regulatory protein 1 (IRP1) were examined by Western blot. Results Curcumin induced apoptosis and autophagy in CRPC cells. Combining curcumin with autophagy inhibitors (3-methyladenine [3-MA]) synergized the apoptotic effect of curcumin. Moreover, curcumin bound to FAC at a ratio of ~1:1, as assessed by spectrophotometry and MTT assay. Apoptosis and autophagy induced by curcumin were counteracted by equal amounts of FAC. At apoptosis- and autophagy-inducing concentrations, curcumin enhanced the expression levels of TfR1 and IRP1, indicative of iron deprivation induced by curcumin. Conclusion Together, our results indicate that curcumin induces apoptosis and protective autophagy in CRPC cells, which are at least partially dependent on its iron-chelating properties. PMID:28243065

  16. Ferrous iron chelating property of low-molecular weight succinoglycans isolated from Sinorhizobium meliloti.

    PubMed

    Cho, Eunae; Choi, Jae Min; Kim, Hwanhee; Tahir, Muhammad Nazir; Choi, Youngjin; Jung, Seunho

    2013-04-01

    Iron is an essential nutrient for nitrogen-fixing legume root nodules, and the chelation of ferrous iron plays an important role in the mobility and availability of iron to the legume. In the present study, we investigated the iron-binding properties of low-molecular weight succinoglycans isolated from the nitrogen-fixing bacterium, Sinorhizobium meliloti. The low-molecular weight succinoglycans comprising three monomers (M1-M3), four dimers (D1-D4), and six trimers (T1-T6) of the succinoglycan repeating unit were purified by various chromatographic techniques. Interestingly, the colorimetric ferrozine method showed that the succinoglycans T6, M3, and D3 demonstrated a ferrous iron chelating ability of 83, 63, and 38 % per mg, respectively. The individual binding constants were determined as 43703, 2313, and 760 M(-1) for succinoglycans T6, M3, and D3 using ultraviolet-visible spectroscopy. The complexation of succinoglycan and ferrous iron can cause structural changes, which were analyzed by circular dichroism spectroscopy. Furthermore, the complex could provide antioxidant activity through an anti-Fenton reaction. These results demonstrate that the low-molecular weight succinoglycans can effectively modulate iron biochemistry as a novel ferrous iron-acquisition system of S. meliloti.

  17. Iron chelation therapy as a treatment for Pythium insidiosum in an animal model.

    PubMed

    Zanette, R A; Alves, S H; Pilotto, M B; Weiblen, C; Fighera, R A; Wolkmer, P; Flores, M M; Santurio, J M

    2013-05-01

    Iron plays an important role in the pathogenesis of Pythium insidiosum. Human pythiosis frequently occurs in iron-overloaded thalassaemic patients and experimentally infected animals develop iron deficiency anaemia. Therefore, we sought to determine the in vitro and in vivo activities of the iron chelator deferasirox against P. insidiosum. In vitro, the MIC and minimum fungicidal concentration (MFC) values of deferasirox for 17 strains of P. insidiosum were determined in accordance with CLSI document M38-A2. In vivo studies were carried out in 20 inoculated rabbits divided into four groups: placebo, immunotherapy obtained from vortexed P. insidiosum cultures (14 day intervals), deferasirox (15 mg/kg/day) and a combination of immunotherapy and deferasirox. Five non-infected animals were used as controls. The MIC and MFC values of deferasirox for P. insidiosum ranged from 12.5 to 50 mg/L and from 50 to 100 mg/L, respectively. Treatment with deferasirox alone ameliorated anaemia and normalized the serum iron levels and hepatic iron concentration in the animals. However, the mean lesion size, although decreased, did not differ significantly from that in the placebo group. The results of immunotherapy plus iron chelation therapy were worse than those of immunotherapy alone. Moreover, the disease spread to the lung tissue in 5 out of 10 deferasirox-treated animals. Despite its limited in vitro and in vivo activity, deferasirox improved iron deficiency anaemia in P. insidiosum-infected rabbits. Further studies are needed to investigate the immunomodulatory properties observed in this study and the benefits and drawbacks of using iron-chelating drugs as an adjuvant therapy in pythiosis.

  18. Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment.

    PubMed

    Poli, L; Alberici, A; Buzzi, P; Marchina, E; Lanari, A; Arosio, C; Ciccone, A; Semeraro, F; Gasparotti, R; Padovani, A; Borroni, Barbara

    2017-02-01

    We report the case of a patient with hereditary ceruloplasmin deficiency due to a novel gene mutation in ceruloplasmin gene (CP), treated with fresh frozen plasma (FFP) and iron chelation therapy. A 59-year-old man with a past history of diabetes was admitted to our department due to progressive gait difficulties and cognitive impairment. Neurological examination revealed a moderate cognitive decline, with mild extrapyramidal symptoms, ataxia, and myoclonus. Brain T2-weighted MR imaging showed bilateral basal ganglia hypointensity with diffuse iron deposition. Increased serum ferritin, low serum copper concentration, undetectable ceruloplasmin, and normal urinary copper excretion were found. The genetic analysis of the CP (OMIM #604290) reported compound heterozygosity for two mutations, namely c.848G > A and c.2689_2690delCT. Treatment with FFP (500 mL i.v./once a week) and administration of iron chelator (Deferoxamine 1000 mg i.v/die for 5 days, followed by Deferiprone 500 mg/die per os) were undertaken. At the 6-month follow-up, clinical improvement of gait instability, trunk ataxia, and myoclonus was observed; brain MRI scan showed no further progression of basal ganglia T2 hypointensity. This case report suggests that the early initiation of combined treatment with FFP and iron chelation may be useful to reduce the accumulation of iron in the central nervous system and to improve the neurological symptoms.

  19. 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

  20. Reversible immobilization of invertase on Cu-chelated polyvinylimidazole-grafted iron oxide nanoparticles.

    PubMed

    Uzun, Kerem; Çevik, Emre; Şenel, Mehmet; Baykal, Abdülhadi

    2013-12-01

    Polyvinylimidazole (PVI)-grafted iron oxide nanoparticles (PVIgMNP) were prepared by grafting of telomere of PVI on the iron oxide nanoparticles. Different metal ions (Cu(2+), Zn(2+), Cr(2+), Ni(2+)) ions were chelated on polyvinylimidazole-grafted iron oxide nanoparticles, and then the metal-chelated magnetic particles were used in the adsorption of invertase. The maximum invertase immobilization capacity of the PVIgMNP-Cu(2+) beads was observed to be 142.856 mg/g (invertase/PVIgMNP) at pH 5.0. The values of the maximum reaction rate (V max) and Michaelis-Menten constant (Km) were determined for the free and immobilized enzymes. The enzyme adsorption-desorption studies, pH effect on the adsorption efficiency, affinity of different metal ions, the kinetic parameters and storage stability of free and immobilized enzymes were evaluated.

  1. Preparation, Identification and Antioxidant Properties of Black-Bone Silky Fowl (Gallus gallus domesticus Brisson) Iron(II)-Oligopeptide Chelate.

    PubMed

    Pan, Huanglei; Song, Shasha; Ma, Qiuyue; Wei, Hui; Ren, Difeng; Lu, Jun

    2016-06-01

    Black-bone silky fowl iron(II)-oligopeptide chelate was synthesized from iron(II) solution and the black-bone silky fowl oligopeptide, which was extracted from the muscle protein of black-bone silky fowl (Gallus gallus domesticus Brisson). Orthogonal array analysis was used to determine the optimal conditions for the iron(II)-oligopeptide chelate preparation. Ultraviolet-visible (UV-Vis) spectroscopy, electron microscopy, and Fourier transform infrared (FTIR) spectroscopy were used to identify the structure of iron(II)-oligopeptide chelate. 2-Diphenyl-1-picrylhydrazyl (DPPH) and superoxide radical scavenging assays were performed to compare the antioxidant abilities of the black-bone silky fowl oligopeptide and iron(II)-oligopeptide chelate. The optimal conditions for iron(II)-oligopeptide chelate preparation were 4% of the black-bone silky fowl oligopeptide and a ratio of the black- -bone silky fowl oligopeptide to FeCl2·4H2O of 5:1 at pH=4. Under these conditions, the chelation rate was (84.9±0.2) % (p<0.05), and the chelation yield was (40.3±0.1) % (p<0.05). The structures detected with UV-Vis spectroscopy, electron microscopy and FTIR spectra changed significantly after chelation, suggesting that Fe(II) ions formed coordinate bonds with carboxylate (-RCOOŻ) and amino (-NH2) groups in the oligopeptides, confirming that this is a new oligopeptide-iron chelate. The iron(II)-oligopeptide chelate had stronger scavenging activity towards DPPH and superoxide radicals than did the black-bone silky fowl oligopeptide.

  2. Preparation, Identification and Antioxidant Properties of Black-Bone Silky Fowl (Gallus gallus domesticus Brisson) Iron(II)-Oligopeptide Chelate

    PubMed Central

    Pan, Huanglei; Song, Shasha; Ma, Qiuyue; Wei, Hui; Ren, Difeng; Lu, Jun

    2016-01-01

    Summary Black-bone silky fowl iron(II)-oligopeptide chelate was synthesized from iron(II) solution and the black-bone silky fowl oligopeptide, which was extracted from the muscle protein of black-bone silky fowl (Gallus gallus domesticus Brisson). Orthogonal array analysis was used to determine the optimal conditions for the iron(II)-oligopeptide chelate preparation. Ultraviolet-visible (UV-Vis) spectroscopy, electron microscopy, and Fourier transform infrared (FTIR) spectroscopy were used to identify the structure of iron(II)-oligopeptide chelate. 2-Diphenyl-1-picrylhydrazyl (DPPH) and superoxide radical scavenging assays were performed to compare the antioxidant abilities of the black-bone silky fowl oligopeptide and iron(II)-oligopeptide chelate. The optimal conditions for iron(II)-oligopeptide chelate preparation were 4% of the black-bone silky fowl oligopeptide and a ratio of the black- -bone silky fowl oligopeptide to FeCl2·4H2O of 5:1 at pH=4. Under these conditions, the chelation rate was (84.9±0.2) % (p<0.05), and the chelation yield was (40.3±0.1) % (p<0.05). The structures detected with UV-Vis spectroscopy, electron microscopy and FTIR spectra changed significantly after chelation, suggesting that Fe(II) ions formed coordinate bonds with carboxylate (-RCOOŻ) and amino (-NH2) groups in the oligopeptides, confirming that this is a new oligopeptide-iron chelate. The iron(II)-oligopeptide chelate had stronger scavenging activity towards DPPH and superoxide radicals than did the black-bone silky fowl oligopeptide. PMID:27904406

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. Effect of novel 1-alkyl-3-hydroxy-2-methylpyrid-4-one chelators on uptake and release of iron from macrophages

    SciTech Connect

    Brock, J.H.; Liceaga, J.; Arthur, H.M.; Kontoghiorghes, G.J. )

    1990-05-01

    The effect of several iron chelators on iron uptake and release by mouse peritoneal macrophages has been investigated. The 1,2-dimethyl (L1) and 1-ethyl-2-methyl (L1NEt) derivatives of 3-hydroxypyrid-4-one markedly enhanced iron mobilisation from macrophages pulsed with 59Fe-transferrin-antitransferrin immune complexes and were more effective than desferrioxamine, maltol, or mimosine. Release increased with increasing chelator concentration. None of the chelators donated significant amounts of iron to macrophages, and none showed any cytotoxic effect. The synthetic alpha-ketohydroxypyridine chelators may therefore be active in removing iron from the reticuloendothelial system as well as from hepatocytes, and indeed may be superior to desferrioxamine.

  8. Effect of novel 1-alkyl-3-hydroxy-2-methylpyrid-4-one chelators on uptake and release of iron from macrophages.

    PubMed

    Brock, J H; Licéaga, J; Arthur, H M; Kontoghiorghes, G J

    1990-05-01

    The effect of several iron chelators on iron uptake and release by mouse peritoneal macrophages has been investigated. The 1,2-dimethyl (L1) and 1-ethyl-2-methyl (L1NEt) derivatives of 3-hydroxypyrid-4-one markedly enhanced iron mobilisation from macrophages pulsed with 59Fe-transferrin-antitransferrin immune complexes and were more effective than desferrioxamine, maltol, or mimosine. Release increased with increasing chelator concentration. None of the chelators donated significant amounts of iron to macrophages, and none showed any cytotoxic effect. The synthetic alpha-ketohydroxypyridine chelators may therefore be active in removing iron from the reticuloendothelial system as well as from hepatocytes, and indeed may be superior to desferrioxamine.

  9. Synthesis, conjugation, and radiolabeling of a novel bifunctional chelating agent for (225)Ac radioimmunotherapy applications.

    PubMed

    Chappell, L L; Deal, K A; Dadachova, E; Brechbiel, M W

    2000-01-01

    225Ac (t(1/2) = 10 days) is an alternative alpha-emitter that has been proposed for radioimmunotherapy (RIT) due to its many favorable properties, such as half-life and mode of decay. The factor limiting use of (225)Ac in RIT is the lack of an acceptably stable chelate for in vivo applications. Herein is described the first reported bifunctional chelate for (225)Ac that has been evaluated for stability for in vivo applications. The detailed synthesis of a bifunctional chelating agent 2-(4-isothiocyanatobenzyl)-1,4,7,10,13, 16-hexaazacyclohexadecane- 1,4,7,10,13,16-hexaacetic acid (HEHA-NCS) is reported. This ligand was conjugated to three monoclonal antibodies, CC49, T101, and BL-3 with chelate-to-protein ratios between 1.4 and 2. The three conjugates were radiolabeled with (225)Ac, and serum stability study of the [(225)Ac]BL-3-HEHA conjugate was performed.

  10. Australian guidelines for the assessment of iron overload and iron chelation in transfusion-dependent thalassaemia major, sickle cell disease and other congenital anaemias.

    PubMed

    Ho, P J; Tay, L; Lindeman, R; Catley, L; Bowden, D K

    2011-07-01

    Iron overload is the most important cause of mortality in patients with thalassaemia major. Iron chelation is therefore a critical issue in the management of these patients and others with transfusion-dependent haemoglobinopathies and congenital anaemias. In recent years, significant developments have been made in the assessment of iron overload, including the use of magnetic resonance imaging for measuring liver and cardiac iron. Advances in the modalities available for iron chelation, with the advent of oral iron chelators including deferiprone and deferasirox in addition to parenteral desferrioxamine, have expanded treatment options. A group of Australian haematologists has convened to formulate guidelines for managing iron overload on the basis of available evidence, and to describe best consensus practice as undertaken in major Australian Haemoglobinopathy units. The results of their discussions are described in this article, with the aim of providing guidance in the management of iron overload in these patients.

  11. 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.

  12. Therapeutic value of combined therapy with deferiprone and silymarin as iron chelators in Egyptian children with beta thalassemia major.

    PubMed

    Hagag, Adel A; Elfaragy, Mohamed S; Elrifaey, Shaymaa M; Abd El-Lateef, Amal E

    2015-01-01

    Beta Thalassemia is inherited anemia characterized by absent or reduced synthesis of β-globin chains of hemoglobin, caused by β-globin gene mutations resulting in chronic hemolytic anemia that requires 'repeated blood transfusion with resulting iron overload'. Silymarin has iron chelating activity in thalassemic patients with iron overload. was to study the therapeutic value of combined therapy of Deferiprone and silymarin as iron chelators in Egyptian children with beta thalassemia with iron overload'. 'This study was conducted on 80 beta thalassemic children with their serum ferritin more than 1000 ng/ml who were divided into two groups'. Group I included 40 patients who were treated with oral Deferiprone and silymarin for 9 months. Group II included 40 patients who were treated with oral Deferiprone and placebo for 9 months. 'There were no significant differences in serum ferritin, iron and TIBC between group I and group II before the study but after regular chelation therapy, serum ferritin and iron were significantly lower in group I than group II. No statistically significant differences in serum creatinine, blood urea, ALT, AST and bilirubin levels between Group I and Group II before and after chelation therapy were observed'. Deferiprone in combination with silymarin are better iron chelators than Deferiprone and placebo. 'Extensive multicenter studies in large number of patients with longer follow up period and more advanced methods of assessment of iron status to clarify the exact role of silymarin in reduction of iron over load in thalassemic children'.

  13. 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.

  14. Thermodynamic studies of iron chelation with doxycycline in acidic medium

    NASA Astrophysics Data System (ADS)

    Javed, Javeria; Zahir, Erum

    2017-06-01

    Doxycycline (DOX) is a broad-spectrum tetracycline antibiotic synthetically derived from oxytetracycline. The complex formation of this drug with iron(III) was studied using spectrophotometry. The thermodynamic parameters of the systems were calculated using the changes in the absorption spectra which occur due to hydrogen bond or complex formation. Thermodynamic parameters of the formation of iron(III) complex with doxycycline (Δ H, Δ G, Δ S, and stability constants) were determined spectrophotometrically at a wavelength corresponding to absorption maximum (374.5 nm) at three different temperatures (22, 35, and 45°C). The obtained data show that the complex has metal to ligand molar ratio of 1: 2 at pH 2-3. The stability constants were calculated to be 13.99 × 106, 7.06 × 105, and 1.29 × 106 by mole ratio method at 22, 35, and 45°C, respectively.

  15. 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.

  16. Neuroprotection of brain-permeable iron chelator VK-28 against intracerebral hemorrhage in mice.

    PubMed

    Li, Qian; Wan, Jieru; Lan, Xi; Han, Xiaoning; Wang, Zhongyu; Wang, Jian

    2017-09-01

    Iron overload plays a key role in the secondary brain damage that develops after intracerebral hemorrhage (ICH). The significant increase in iron deposition is associated with the generation of reactive oxygen species (ROS), which leads to oxidative brain damage. In this study, we examined the protective effects of VK-28, a brain-permeable iron chelator, against hemoglobin toxicity in an ex vivo organotypic hippocampal slice culture (OHSC) model and in middle-aged mice subjected to an in vivo, collagenase-induced ICH model. We found that the effects of VK-28 were similar to those of deferoxamine (DFX), a well-studied iron chelator. Both decreased cell death and ROS production in OHSCs and in vivo, decreased iron-deposition and microglial activation around hematoma in vivo, and improved neurologic function. Moreover, compared with DFX, VK-28 polarized microglia to an M2-like phenotype, reduced brain water content, deceased white matter injury, improved neurobehavioral performance, and reduced overall death rate after ICH. The protection of VK-28 was confirmed in a blood-injection ICH model and in aged-male and young female mice. Our findings indicate that VK-28 is protective against iron toxicity after ICH and that, at the dosage tested, it has better efficacy and less toxicity than DFX does.

  17. HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation.

    PubMed

    Bianchi, L; Tacchini, L; Cairo, G

    1999-11-01

    Treatment with iron chelators mimics hypoxic induction of the hypoxia inducible factor (HIF-1) which activates transcription by binding to hypoxia responsive elements (HRE). We investigated whether HIF-1 is involved in transcriptional activation of the transferrin receptor (TfR), a membrane protein which mediates cellular iron uptake, in response to iron deprivation. The transcription rate of the TfR gene in isolated nuclei was up-regulated by treatment of Hep3B human hepatoma cells with the iron chelator desferrioxamine (DFO). The role of HIF-1 in the activation of TfR was indicated by the following observations: (i) DFO-dependent activation of a luciferase reporter gene in transfected Hep3B cells was mediated by a fragment of the human TfR promoter containing a putative HRE sequence; (ii) mutation of this sequence prevented stimulation of luciferase activity; (iii) binding to this sequence of HIF-1alpha, identified by competition experiments and supershift assays, was induced by DFO. Furthermore, in mouse hepatoma cells unable to assemble functional HIF-1, inducibility of TfR transcription by DFO was lost and TfR mRNA up-regulation was reduced. These results, which show the role of HIF-1 in the control of TfR gene expression in conditions of iron depletion, give insights into the mechanisms of transcriptional regulation which concur with the well-characterized post-transcriptional control of TfR expression to expand the extent of response to iron deficiency.

  18. Stabilization of heavy metals in contaminated sediments using organic chelating agents.

    PubMed

    Xu, Ying; Fang, Sheng-Rong

    2015-01-01

    A stabilization treatment for heavy metals in sediments was developed using the heavy metal chelators ammonium dipropyl dithiophosphate (ADD) and potassium diisopropyl dithiophosphate (PDD). The results indicate that 7% ADD and 7% PDD achieved Pb and Cu stabilization rates of up to 99%, Cd stabilization rates of 78% and 95%, and Zn stabilization rates of 21 and 51%, respectively. At pH levels ranging from 2 to 12, the amount of heavy metals in leachate from the stabilized product using the chelating agents were significantly less than those using Na2S and Na3PO4. After treatment, the chelating agents were mainly bound to the exchangeable fraction of heavy metals in the sediment and formed stable bonds with organic matter, thus significantly reducing the biological risks of heavy metals in sediment.

  19. Iron release and membrane damage in erythrocytes exposed to oxidizing agents, phenylhydrazine, divicine and isouramil.

    PubMed Central

    Ferrali, M; Signorini, C; Ciccoli, L; Comporti, M

    1992-01-01

    Mouse erythrocytes were incubated with oxidizing agents, phenylhydrazine, divicine and isouramil. With all the oxidants a rapid release of iron in a desferrioxamine (DFO)-chelatable form was seen and it was accompanied by methaemoglobin formation. If the erythrocytes were depleted of GSH by a short preincubation with diethyl maleate, the release of iron was accompanied by lipid peroxidation and, subsequently, haemolysis. GSH depletion by itself did not induce iron release, methaemoglobin formation, lipid peroxidation or haemolysis. Rather, the fate of the cell in which iron is released depended on the intracellular availability of GSH. In addition, iron release was higher in depleted cells than in native ones, suggesting a role for GSH in preventing iron release when oxidative stress is imposed by the oxidants. Iron release preceded lipid peroxidation. The latter was prevented when the erythrocytes were preloaded with DFO in such a way (preincubation with 10 mM-DFO) that the intracellular concentration was equivalent to that of the released iron, but not when the intracellular DFO was lower (preincubation with 0.1 mM-DFO). Extracellular DFO did not affect lipid peroxidation and haemolysis, suggesting again that the observed events occur intracellularly (intracellular chelation of released iron). The relevance of iron release from iron complexes in the mechanisms of cellular damage induced by oxidative stress is discussed. PMID:1637315

  20. Ascorbate-dependent formation of hydroxyl radicals in the presence of iron chelates.

    PubMed

    Prabhu, H R; Krishnamurthy, S

    1993-10-01

    The autoxidation of L-ascorbate on incubation in saline phosphate buffer (pH 7.4) is accompanied by hydroxyl radical (.OH) generation. The metal chelator EDTA showed significant inhibition of ascorbate autoxidation and ascorbate-dependent .OH release. On the other hand, Fe2+ (EDTA) greatly augmented both ascorbate autoxidation and ascorbate-dependent .OH production. The biological iron chelating compounds such as ATP, ADP, citrate and pyrophosphate suppressed both ascorbate autoxidation and ascorbate-mediated .OH production, thereby indicating that these compounds suppress the activating effect of iron. Ascorbate autoxidation and ascorbate-dependent .OH formation, stimulated by Fe2+ (EDTA) were significantly inhibited by .OH scavengers, namely mannitol, thiourea and sodium formate, as well as by catalase and to a lesser extent by bovine serum albumin, superoxide dismutase (native and heat denatured) and heat denatured catalase.

  1. Catalytic superoxide scavenging by metal complexes of the calcium chelator EGTA and contrast agent EHPG.

    PubMed

    Fisher, Anna E O; Hague, Theresa A; Clarke, Charlotte L; Naughton, Declan P

    2004-10-08

    Metal ion chelators widely used in experimental protocols and clinical diagnosis are generally assumed to be inert. We previously reported that the ubiquitous chelator EDTA has high levels of superoxide suppressing activity. Here, we report that the common chelators calcium chelator EGTA and contrast agent EHPG have significant activities in suppressing superoxide levels depending on the nature of metal ion chelated. The most active species is Mn(II)-EGTA which exhibited an IC50 value of 0.19 microM for superoxide destruction. In addition, IC50 values for Mn(II)-EHPG and 2Cu(II)-EGTA were 0.69 and 0.60 microM, respectively. In conclusion, Mn(II) and Cu(II) complexes of the common chelators EGTA and EHPG exhibit considerable superoxide scavenging activities. Caution should be employed in their use in biological systems where superoxide has a key role and they may be useful for the development of catalytic anti-oxidants. Copyright 2004 Elsevier Inc.

  2. Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

    PubMed Central

    Fortin, Patricia M; Madgwick, Karen V; Trivella, Marialena; Hopewell, Sally; Doree, Carolyn; Estcourt, Lise J

    2016-01-01

    This is the protocol for a review and there is no abstract. The objectives are as follows: To identify and assess the effectiveness of interventions to improve adherence to iron chelation therapy compared to standard care in people with SCD or thalassaemia including: identifying and assessing the effectiveness of different types of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions);identifying and assessing the effectiveness of interventions specific to different age groups (children, adolescents, adults). PMID:27713668

  3. Iron Chelation Therapy with Deferasirox in the Management of Iron Overload in Primary Myelofibrosis

    PubMed Central

    Elli, Elena Maria; Belotti, Angelo; Aroldi, Andrea; Parma, Matteo; Pioltelli, Pietro; Pogliani, Enrico Maria

    2014-01-01

    Deferasirox (DSX) is the principal option currently available for iron-chelation-therapy (ICT), principally in the management of myelodysplastic syndromes (MDS), while in primary myelofibrosis (PMF) the expertise is limited. We analyzed our experience in 10 PMF with transfusion-dependent anemia, treated with DSX from September 2010 to December 2013. The median dose tolerated of DSX was 750 mg/day (10 mg/kg/day), with 3 transient interruption of treatment for drug-related adverse events (AEs) and 3 definitive discontinuation for grade 3/4 AEs. According to IWG 2006 criteria, erythroid responses with DSX were observed in 4/10 patients (40%), 2 of them (20%) obtaining transfusion independence. Absolute changes in median serum ferritin levels (Delta ferritin) were greater in hematologic responder (HR) compared with non-responder (NR) patients, already at 6 months of ICT respect to baseline. Our preliminary data open new insights regarding the benefit of ICT not only in MDS, but also in PMF with the possibility to obtain an erythroid response, overall in 40 % of patients. HR patients receiving DSX seem to have a better survival and a lower incidence of leukemic transformation (PMF-BP). Delta ferritin evaluation at 6 months could represent a significant predictor for a different survival and PMF-BP. However, the tolerability of the drug seems to be lower compared to MDS, both in terms of lower median tolerated dose and for higher frequency of discontinuation for AEs. The biological mechanism of action of DSX in chronic myeloproliferative setting through an independent NF-κB inhibition could be involved, but further investigations are required. PMID:24959339

  4. 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.

  5. Enhancing Potentially Plant-Available Lead Concentrations in Contaminated Residential Soils Using a Biodegradable Chelating Agent

    NASA Astrophysics Data System (ADS)

    Andra, S.; Datta, R.; Sarkar, D.; Saminathan, S.

    2007-12-01

    Chelation of heavy metals is an important factor in enhancing metal solubility and, hence, metal availability to plants to promote phytoremediation. In the present study, we compared the effects of application of a biodegradable chelating agent, namely, ethylenediaminedisuccinic acid (EDDS) on enhancing plant available form of lead (Pb) in Pb-based paint contaminated residential soils compared to that of a more commonly used, but non-biodegradable chelate, i.e., ethylenediaminetetraacetic acid (EDTA). Development of a successful phytoremediation model for metals such as Pb depends on a thorough understanding of the physical and chemical properties of the soil, along with the optimization of a chelate treatment to mobilize Pb from `unavailable' pools to potentially plant available fraction. In this context, we set out to perform batch incubation experiments to investigate the effectiveness of the two aforementioned chelates in enhancing plant available Pb at four different concentrations (0, 5, 10 and 15 mM/kg soil) and three treatment durations (0, 10 and 30 days). We selected 12 contaminated residential soils from two major metropolitan areas (San Antonio, TX and Baltimore, MD) with varying soil physico-chemical properties - the soils from San Antonio were primarily alkaline and those from Baltimore were typically acidic. Total soil Pb concentrations ranged between 256 mg/kg and 4,182 mg/kg. Our results show that both chelates increased the solubility of Pb, otherwise occluded in the complex soil matrix. For both EDTA and EDDS, the exchangeable concentrations of soil Pb also increased with increase in chelate concentration and incubation time. The most effective treatment was 15 mM chelate kg-1 soil incubated for 30 days, which caused many fold increase in potentially plant available Pb (a combination of the soluble and exchangeable fractions) relative to the unamended controls. Step wise multiple linear regression analysis using chelate-extractable Pb and soil

  6. Effect of enhanced iron chelation therapy on glucose metabolism in patients with beta-thalassaemia major.

    PubMed

    Farmaki, Kalistheni; Angelopoulos, Nicholas; Anagnostopoulos, George; Gotsis, Efstathios; Rombopoulos, Grigorios; Tolis, George

    2006-08-01

    Recently introduced chelation regimens that combine deferoxamine (DFO) and deferiprone have been shown to have greater efficacy in promoting iron excretion than either chelator alone and have been associated with rapid reduction of the iron load in the heart and liver, and with reversal of cardiac dysfunction. It is unclear whether this combined therapy could be associated with a reduction in iron load or decline in the severity of iron-induced endocrinopathies. Starting in January 2001, 42 patients with beta-thalassaemia major, previously maintained on subcutaneous DFO only, were switched to combined treatment with DFO and deferiprone. The primary endpoint was to investigate the effects of this therapy on the glucose metabolism characteristics of this population. Combination therapy markedly decreased ferritin levels (638 +/- 1345 vs. 2991 +/- 2093 microg/l, P < 0.001). Glucose responses were improved at all times during an oral glucose tolerance test, particularly in patients in early stages of glucose intolerance. Glucose quantitative secretion also decreased significantly with combined therapy, while no significant change occurred in insulin levels in any group. Insulin secretion, according to the homeostasis assessment model, markedly increased in all groups, while overall reduction in insulin sensitivity did not reach statistical significance. This study showed that the combination of DFO and deferiprone was associated with an improvement in liver iron deposition and glucose intolerance.

  7. 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

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

    PubMed

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

    2016-09-01

    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.

  9. Chelating agents related to ethylenediamine bis(2-hydroxyphenyl)acetic acid (EDDHA): synthesis, characterization, and equilibrium studies of the free ligands and their Mg2+, Ca2+, Cu2+, and Fe3+ chelates.

    PubMed

    Yunta, Felipe; García-Marco, Sonia; Lucena, Juan J; Gómez-Gallego, Mar; Alcázar, Roberto; Sierra, Miguel A

    2003-08-25

    Iron chelates such as ethylenediamine-N,N'-bis(2-hydroxyphenyl)acetic acid (EDDHA) and their analogues are the most efficient soil fertilizers to treat iron chlorosis in plants growing in calcareous soils. EDDHA, EDDH4MA (ethylenediamine-N,N'-bis(2-hydroxy-4-methylphenyl)acetic acid), and EDDCHA (ethylenediamine-N,N'-bis(2-hydroxy-5-carboxyphenyl)acetic acid) are allowed by the European directive, but also EDDHSA (ethylenediamine-N,N'-bis(2-hydroxy-5-sulfonylphenyl)acetic acid) and EDDH5MA (ethylenediamine-N,N'-bis(2-hydroxy-5-methylphenyl)acetic acid) are present in several commercial iron chelates. In this study, these chelating agents as well as p,p-EDDHA (ethylenediamine-N,N'-bis(4-hydroxyphenyl)acetic acid) and EDDMtxA (ethylenediamine-N,N'-bis(2-metoxyphenyl)acetic acid) have been obtained following a new synthetic pathway. Their chemical behavior has been studied to predict the effect of the substituents in the benzene ring on their efficacy as iron fertilizers for soils above pH 7. The purity of the chelating agents has been determined using a novel methodology through spectrophotometric titration at 480 nm with Fe(3+) as titrant to evaluate the inorganic impurities. The protonation constants were determined by both spectrophotometric and potentiometric methods, and Ca(2+) and Mg(2+) stability constants were determined from potentiometric titrations. To establish the Fe(3+) and Cu(2+) stability constants, a new spectrophotometric method has been developed, and the results were compared with those reported in the literature for EDDHA and EDDHMA and their meso- and rac-isomers. pM values have been also determined to provide a comparable basis to establish the relative chelating ability of these ligands. The purity obtained for the ligands is higher than 87% in all cases and is comparable with that obtained by (1)H NMR. No significant differences have been found among ligands when their protonation and stability constants were compared. As expected, no Fe(3

  10. [Remediation of Cu-Pb-contaminated loess soil by leaching with chelating agent and biosurfactant].

    PubMed

    Liu, Xia; Wang, Jian-Tao; Zhang, Meng; Wang, Li; Yang, Ya-Ti

    2013-04-01

    Because of its strong chelation, solubilization characteristics, the chelating agents and biosurfactant are widely used in remediation of heavy metals and organic contaminated soils. Ethylenediamine tetraacetic acid (EDTA), citric acid (CIT) and dirhamnolipid (RL2) were selected as the eluent. Batch experiments and column experiments were conducted to investigate the leaching effect of the three kinds of eluent, as well as the mixture of biosurfactant and chelating agent for Cu, Pb contaminated loess soil. The results showed that the leaching efficiencies of different eluent on Cu, Pb contaminated loess soil followed the sequence of EDTA > CIT > RL2. At an eluent concentration of 0.02 mol x L(-1), the Cu leaching efficiency was 62.74% (EDTA), 52.28% (CIT) and 15.35% (RL2), respectively; the Pb leaching efficiency was 96.10% (EDTA), 23.08% (CIT) and 14.42% (RL2), respectively. When the concentration of RL2 was 100 CMC, it had synergistic effects on the other two kinds of chelating agent in Cu leaching, and when the concentration of RL2 was 200 CMC, it had antagonism effects. The effect of RL2 on EDTA in Pb leaching was similar to that in Cu leaching. Pb leaching by CIT was inhibited in the presence of RL2. EDTA and CIT could effectively remove Cu and Pb in exchangeable states, adsorption states, carbonate salts and organic bound forms; RL2 could effectively remove Cu and Pb in exchangeable and adsorbed states.

  11. 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.

  12. [Enhanced phytoextraction of heavy metal contaminated soil by chelating agents and auxin indole-3-acetic acid].

    PubMed

    Zhou, Jian-min; Dang, Zhi; Chen, Neng-chang; Xu, Sheng-guang; Xie, Zhi-yi

    2007-09-01

    The environmental risk of chelating agents such as EDTA application to the heavy metals polluted soils and the stress on plant roots due to the abrupt increase metals concentration limit the wide commercial use of chelate-induced phytoextraction. Chelating agent ethylenediaminetetraacetic acid (EDTA) and nitrilotriacetic acid (NTA) and auxin indole-3-acetic acid (IAA) were used for enhancing heavy metals uptake from soils by Zea mays L. (corn) in pot experiments. The metals content in plant tissues was quantified using an inductively coupled plasma mass spectrometer (ICP-MS). The results showed that the combination of IAA and EDTA increased the biomass by about 40.0% and the contents of Cu, Zn, Cd and Pb in corn shoots by 27.0%, 26.8%, 27.5% and 32.8% respectively, as compared to those in EDTA treatment. While NTA&IAA treatment increased the biomass by about 29.9% and the contents of Cu, Zn, Cd and Pb in corn shoots by 31.8%, 27.6%, 17.0% and 26.9% respectively, as compared to those in NTA treatment. These results indicated that corn growth was promoted, and the biomass and the accumulation of heavy metals in plant shoots were increased significantly with the addition of IAA, which probably helps to change the cell membrane properties and the biomass distribution, resulting in the alleviation of the phytotoxicity of metals and the chelating agents.

  13. Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice

    SciTech Connect

    Porter, J.B.; Morgan, J.; Hoyes, K.P.; Burke, L.C.; Huehns, E.R.; Hider, R.C. )

    1990-12-01

    The relationship between the oral efficacy and the acute toxicity of hydroxypyridin-4-one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing 59Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.3 in the iron-free form with a trend of increasing oral efficacy with increasing Kpart values (r = .6). However, this is achieved at a cost of increasing acute toxicity, as shown by a linear correlation between 59Fe excretion increase per unit dose and 1/LD50 (r = .83). A sharp increase in the LD50 values is observed for compounds with Kpart values above 1.0, suggesting that such compounds are unlikely to possess a sufficient therapeutic safety margin. Below a Kpart of 1.0, acute toxicity is relatively independent of lipid solubility. All the compounds are less toxic by the oral route than by the intraperitoneal route, although iron excretion is not significantly different by these two routes. At least five compounds (CP51, CP94, CP93, CP96, and CP21) are more effective orally than the same dose of intraperitoneal desferrioxamine (DFO) (P less than or equal to .02) or orally administered L1(CP20) (P less than or equal to .02).

  14. Benzylidene acylhydrazides inhibit chlamydial growth in a type III secretion- and iron chelation-independent manner.

    PubMed

    Bao, Xiaofeng; Gylfe, Asa; Sturdevant, Gail L; Gong, Zheng; Xu, Shuang; Caldwell, Harlan D; Elofsson, Mikael; Fan, Huizhou

    2014-08-15

    Chlamydiae are widespread Gram-negative pathogens of humans and animals. Salicylidene acylhydrazides, developed as inhibitors of type III secretion system (T3SS) in Yersinia spp., have an inhibitory effect on chlamydial infection. However, these inhibitors also have the capacity to chelate iron, and it is possible that their antichlamydial effects are caused by iron starvation. Therefore, we have explored the modification of salicylidene acylhydrazides with the goal to uncouple the antichlamydial effect from iron starvation. We discovered that benzylidene acylhydrazides, which cannot chelate iron, inhibit chlamydial growth. Biochemical and genetic analyses suggest that the derivative compounds inhibit chlamydiae through a T3SS-independent mechanism. Four single nucleotide polymorphisms were identified in a Chlamydia muridarum variant resistant to benzylidene acylhydrazides, but it may be necessary to segregate the mutations to differentiate their roles in the resistance phenotype. Benzylidene acylhydrazides are well tolerated by host cells and probiotic vaginal Lactobacillus species and are therefore of potential therapeutic value. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  15. Molecular characterization of whey protein hydrolysate fractions with ferrous chelating and enhanced iron solubility capabilities.

    PubMed

    O'Loughlin, Ian B; Kelly, Phil M; Murray, Brian A; FitzGerald, Richard J; Brodkorb, Andre

    2015-03-18

    The ferrous (Fe2+) chelating capabilities of WPI hydrolysate fractions produced via cascade membrane filtration were investigated, specifically 1 kDa permeate (P) and 30 kDa retentate (R) fractions. The 1 kDa-P possessed a Fe2+ chelating capability at 1 g L(-1) equivalent to 84.4 μM EDTA (for 30 kDa-R the value was 8.7 μM EDTA). Fourier transformed infrared (FTIR) spectroscopy was utilized to investigate the structural characteristics of hydrolysates and molecular interactions with Fe2+. Solid-phase extraction was employed to enrich for chelating activity; the most potent chelating fraction was enriched in histidine and lysine. The solubility of ferrous sulfate solutions (10 mM) over a range of pH values was significantly (P<0.05) improved in dispersions of hydrolysate fraction solutions (10 g protein L(-1)). Total iron solubility was improved by 72% in the presence of the 1 kDa-P fraction following simulated gastrointestinal digestion (SGID) compared to control FeSO4·7H2O solutions.

  16. Release of organic chelating agents from solidified decontamination wastes

    SciTech Connect

    Piciulo, P.L.; Adams, J.W.; Milian, L.W.

    1986-01-01

    In order to provide technical information needed by the US Nuclear Regulatory Commission to evaluate the adequacy of near-surface disposal of decontamination wastes, Brookhaven National Laboratory has measured the release of organic complexing agents from simulated decontamination resin wastes solidified in cement and vinyl ester-styrene. The simulated waste consisted of either mixed bed ion-exchange resins or anion exchange resins equilibrated with EDTA, oxalic acid, citric acid, picolinic acid, formic acid, simulated LOMI reagent or the LND-101A decontamination reagent. The standard procedure ANS 16.1 appeared to be adequate for determining a leachability index for organic acids for comparing the leach resistance of decontamination waste forms. Leachability indexes appeared to be specific for each organic acid. Further, the apparent diffusivities were generally less than those observed for Cs releases from cement wastes forms. The finder material and the composition of the simulated wastes affected the release of the reagents.

  17. Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications.

    PubMed

    Farmaki, Kallistheni; Tzoumari, Ioanna; Pappa, Christina

    2011-06-15

    Combined chelation treatment may be a better approach for transfusion-dependent thalassemia major patients with iron overload complications because of increased efficacy. Combination therapy with desferrioxamine and deferiprone has already been reported to improve survival dramatically by reversing cardiac dysfunction and other endocrine complications. Some patients have intolerance or inconvenience to parenteral desferrioxamine. The hypothesis of this study was that combining two oral chelators, deferiprone and deferasirox, might lead to similar results. Following approval by the hospital ethical committee and a written informed consent from each patient, 16 patients who fulfilled the criteria participated in a study protocol for a period of up to 2 years. Efficacy measures analysis demonstrated a statistically significant decrease of total body iron load as estimated by serum ferritin, LIC and MRI T2* indices. Regarding the safety assessment, the incidence of adverse events was minor compared to the associated toxicity of monotherapy of each drug. No new onset of iron overload-related complications was demonstrated. A reversal of cardiac dysfunction was observed in 2/4 patients, while the mean LVEF increased significantly. Regarding endocrine assessment, in 2/8 patients with impaired glucose tolerance, we noted a significant decrease in the mean 2h glucose in OGTT. Additionally an improvement in gonadal function was observed and one male and one female gave birth to two healthy children without hormonal stimulation. Combined oral chelation in thalassemia offers the promise of easier administration, better compliance and may lead to an improvement of patient quality of life by preventing or even reversing iron overload complications.

  18. 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.

  19. Copper chelation and interleukin-6 proinflammatory cytokine effects on expression of different proteins involved in iron metabolism in HepG2 cell line.

    PubMed

    Di Bella, Luca Marco; Alampi, Roberto; Biundo, Flavia; Toscano, Giovanni; Felice, Maria Rosa

    2017-01-24

    In vertebrates, there is an intimate relationship between copper and iron homeostasis. Copper deficiency, which leads to a defect in ceruloplasmin enzymatic activity, has a strong effect on iron homeostasis resulting in cellular iron retention. Much is known about the mechanisms underlying cellular iron retention under "normal" conditions, however, less is known about the effect of copper deficiency during inflammation. We show that copper deficiency and the inflammatory cytokine interleukin-6 have different effects on the expression of proteins involved in iron and copper metabolism such as the soluble and glycosylphosphtidylinositol anchored forms of ceruloplasmin, hepcidin, ferroportin1, transferrin receptor1, divalent metal transporter1 and H-ferritin subunit. We demonstrate, using the human HepG2 cell line, that in addition to ceruloplasmin isoforms, copper deficiency affects other proteins, some posttranslationally and some at the transcriptional level. The addition of interleukin-6, moreover, has different effects on expression of ferroportin1 and ceruloplasmin, in which ferroportin1 is decreased while ceruloplasmin is increased. These effects are stronger when a copper chelating agent and IL-6 are used simultaneously. These results suggest that copper chelation has effects not only on ceruloplasmin but also on other proteins involved in iron metabolism, sometimes at the mRNA level and, in inflammatory conditions, the functions of ferroportin and ceruloplasmin may be independent.

  20. Deferasirox-TAT(47-57) peptide conjugate as a water soluble, bifunctional iron chelator with potential use in neuromedicine.

    PubMed

    Goswami, Dibakar; Vitorino, Hector A; Alta, Roxana Y P; Silvestre, Daniel M; Nomura, Cassiana S; Machini, M Teresa; Espósito, Breno P

    2015-10-01

    Deferasirox (DFX), an orally active and clinically approved iron chelator, is being used extensively for the treatment of iron overload. However, its water insolubility makes it cumbersome for practical use. In addition to this, the low efficacy of DFX to remove brain iron prompted us to synthesize and evaluate a DFX-TAT(47-57) peptide conjugate for its iron chelation properties and permeability across RBE4 cell line, an in vitro model of the blood-brain barrier. The water-soluble conjugate was able to remove labile iron from buffered solution as well as from iron overloaded sera, and the permeability of DFX-TAT(47-57) conjugate into RBE4 cells was not affected compared to parent deferasirox. The iron bound conjugate was also able to translocate through the cell membrane.

  1. Pharmacokinetic disposition of the oral iron chelator deferiprone in the domestic pigeon (Columba livia).

    PubMed

    Whiteside, Douglas P; Barker, Ian K; Conlon, Peter D; Tesoro, Angelo; Thiessen, Jake J; Mehren, Kay G; Jacobs, Robert M; Spino, Michael

    2007-06-01

    Deferiprone is a bidentate oral iron chelator used for the treatment of iron overload in people. The purpose of this study was to determine the pharmacokinetic disposition of deferiprone in the domestic pigeon (Columba livia) and to compare the results with a previous study in the white leghorn chicken. Deferiprone (DFP) was administered orally as a suspension at a single dose of 50 mg/kg to 10 iron-loaded (IL-DFP) pigeons and 10 non--iron-loaded controls (NIL-DFP). Six NIL-DFP birds were also administered deferiprone intravenously to determine the bioavailability of the drug after a 30-day washout period. To evaluate if deferiprone induces its own metabolism, the pharmacokinetic disposition of the drug was also studied in the IL-DFP group after oral therapy with deferiprone at a dosage of 50 mg/kg q12h for 30 days. For each phase, collected blood was analyzed for deferiprone by high-performance liquid chromatography to develop a plasma concentration versus time curve. Deferiprone was rapidly absorbed from the gastrointestinal tract, with plasma concentrations effective for iron chelation maintained for at least 8 hours after administration in iron-loaded birds. The half-life (mean +/- SD) for deferiprone given orally to the IL-DFP and NIL-DFP groups was 2.98 +/- 0.85 hours and 3.26 +/- 1.25 hours, respectively, and when intravenously administered was 3.79 +/- 1.23 hours. The half-life after 30 days of treatment was 3.42 +/- 1.18 hours. Oral bioavailability was 44%. This study demonstrated that oral absorption of deferiprone is acceptable, it does not induce its own metabolism, and the drug was widely distributed in the pigeon, as it was in the chicken, with a longer half-life than that reported in mammals. Minor interspecies variations in the pharmacokinetics of deferiprone exist between chickens and pigeons.

  2. 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.

  3. Iron regulated outer membrane proteins of Escherichia coli: variations in expression due to the chelator used to restrict the availability of iron.

    PubMed

    Chart, H; Buck, M; Stevenson, P; Griffiths, E

    1986-05-01

    Iron restriction was induced in Escherichia coli O 111, E. coli O 164 and E. coli C by growing the organisms in trypticase soy broth containing ovotransferrin, desferal, EDDA (ethylenediamine-dihydroxyphenylacetic acid) or alpha,alpha'-dipyridyl. There were marked qualitative and quantitative differences in the iron regulated outer membrane proteins expressed in the presence of the various iron chelators. Differences in the kinetics of growth were also noted. E. coli C was devoid of a ferric enterobactin iron uptake system.

  4. [Iron chelation therapy and its influence on the alleviation of EPO resistance in MDS patients].

    PubMed

    Zhang, Yao; Xiao, Chao; Gu, Shu-Cheng; Chang, Chun-Kang

    2014-08-01

    This study was aimed to investigate the changes of erythropoietin (EPO), hemoglobin(Hb) and recombinant EPO (rEPO) levels in MDS patients receiving iron chelation therapy, and to explore the relationship between EPO and serum ferritin(SF). A total of 172 MDS patients and 30 healthy controls were studied. The levels of SF, EPO, serum iron (SI), total iron binding capacity (TIBC), C-reaction protein (CRP) and Hb were measured respectively, the level of SF was adjusted according to the changes of CRP. Among them, there were 34 cases of low-risk (SF>1 000 mg/L) receiving deferoxamine therapy, whose changes of SF, EPO, SI, TIBC, Hb levels were detected and compared before and after treatment. Besides, the difference in the incidence of EPO resistance in iron overload group and non-iron overload group was assessed before and after therapy, and 58 cases of low-risk and EPO<1 000 U/L MDS patients were given rEPO therapy. The results showed that the level of EPO in non-iron overload group was higher than that in the normal control group (997.44 ± 473.48 vs 467.27 ± 238.49, P < 0.05). Obviously, the level of EPO in iron overload group was higher than that in non-iron overload group and control group (3257.59 ± 697.19 vs 997.44 ± 473.48, P = 0.012, 3257.59 ± 697.19 vs 467.27 ± 238.49, P = 0.002). Otherwise, the incidence of EPO resistance in iron overload group was higher than that in non-iron overload group (18/35 vs 2/23, P = 0.001), and the level of EPO and SF was positively related to each other in iron overload group (r = 0.310,P = 0.036). After receiving iron chelation therapy, the levels of SF, SI, TIBC and EPO in iron overload group were significantly lower than that before therapy (3942.38 ± 641.82 vs 2266.35 ± 367.31, P = 0.028;48.61 ± 10.65 vs 28.52 ± 12.61, P = 0.034;59.84 ± 12.62 vs 33.76 ± 15.43, P = 0.045;3808.01 ± 750.22 vs 1954.78 ± 473.18, P = 0.042). Moreover, the level of Hb increased (35 ± 18 vs 57 ± 21, P = 0.046) and the EPO resistance

  5. 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

  6. 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.

  7. Effects of temperature and chelating agents on cadmium uptake in the American oyster

    SciTech Connect

    Hung, Y.W.

    1982-05-01

    The effect of temperature on cadmium accumulations was evaluated in the tissue of the American oyster, Crassostrea virginica, under controlled laboratory conditions. Oysters have been reported to accumulate cadmium from seawater containing added cadmium chloride. However, the chemical form of cadmium in seawater has not been defined. This may profoundly influence the mechanism of uptake. Therefore, the report is also concerned with the effect of chelating agents on the uptake of cadmium. Chelating agents used were nitrilotriacetic acid, ethylene diaminetetraacetic acid and humic acid. At the end of a 40-day exposure to cadmium, 15 oysters were randomly selected from each tank of synthetic seawater, and each was dissected into 5 fractions, namely gills, mantle, adductor muscle, hepatopancreas and the remainder. The cadmium content of each fraction was analyzed by atomic absorption spectrophotometry with a flameless graphite furnace. (JMT)

  8. Degradation of chelating agents in aqueous solution using advanced oxidation process (AOP).

    PubMed

    Sillanpää, Mika E T; Kurniawan, Tonni Agustiono; Lo, Wai-hung

    2011-06-01

    This article presents an overview with critical analysis of technical applicability of advanced oxidation process (AOP) in removing chelating agents from aqueous solution. Apart from the effect of metals for chelating agents as a major influencing factor, selected information such as pH, oxidant's dose, concentrations of pollutants and treatment performance is presented. The performance of individual AOP is compared. It is evident from our literature survey that photocatalysis with UV irradiation alone or coupled with TiO(2), ozonation and Fenton's oxidation are frequently applied to mineralize target pollutants. Overall, the selection of the most suitable AOP depends on the characteristics of effluents, technical applicability, discharge standard, regulatory requirements and environmental impacts.

  9. The chelation of colonic luminal iron by a unique sodium alginate for the improvement of gastrointestinal health.

    PubMed

    Horniblow, Richard D; Latunde-Dada, Gladys O; Harding, Stephen E; Schneider, Melanie; Almutairi, Fahad M; Sahni, Manroy; Bhatti, Ahsan; Ludwig, Christian; Norton, Ian T; Iqbal, Tariq H; Tselepis, Chris

    2016-09-01

    Iron is an essential nutrient. However, in animal models, excess unabsorbed dietary iron residing within the colonic lumen has been shown to exacerbate inflammatory bowel disease and intestinal cancer. Therefore, the aims of this study were to screen a panel of alginates to identify a therapeutic that can chelate this pool of iron and thus be beneficial for intestinal health. Using several in vitro intestinal models, it is evident that only one alginate (Manucol LD) of the panel tested was able to inhibit intracellular iron accumulation as assessed by iron-mediated ferritin induction, transferrin receptor expression, intracellular (59) Fe concentrations, and iron flux across a Caco-2 monolayer. Additionally, Manucol LD suppressed iron absorption in mice, which was associated with increased fecal iron levels indicating iron chelation within the gastrointestinal tract. Furthermore, the bioactivity of Manucol LD was found to be highly dependent on both its molecular weight and its unique compositional sequence. Manucol LD could be useful for the chelation of this detrimental pool of unabsorbed iron and it could be fortified in foods to enhance intestinal health. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Enhanced uptake of As, Zn, and Cu by Vetiveria zizanioides and Zea mays using chelating agents.

    PubMed

    Chiu, K K; Ye, Z H; Wong, M H

    2005-09-01

    Vetiveria zizaniodes (vetiver) is commonly known for its effectiveness in soil and sediment erosion control. It can tolerate to extreme soil conditions and produce a high biomass even growing in contaminated areas. Zea mays (maize) can also produce a very high biomass with a fast growth rate and possesses some degree of metal tolerance. A greenhouse study was conducted to investigate the feasibility of using vetiver and maize for remediation of arsenic (As)-, zinc (Zn-), and copper (Cu)-amended soils and evaluate the effects of chelating agents on metal uptake by these plants. Vetiver had a better growth (dry weight yield of root and shoot) than maize under different treatment conditions. The effects of different chelating agents on As, Zn, and Cu extraction from soil to soil solution were studied. Among the nine chelating agents used, it was noted that 20 mmol NTA could maximize As and Zn bioavailability, while 20 mmol HEIDA could maximize Cu bioavailability in the soil solution. The surge time in maximizing metal uptake ranged from 16 to 20 days which indicated that timing on plant harvest was an important factor in enhanced metal accumulation. In general, vetiver was a more suitable plant species than maize in terms of phytoextraction of metals from metal-contaminated soil. Application of NTA in As-amended soil and HEIDA in Cu-amended soil at the rate of 20 mmol kg(-1) increased 3-4-fold of As and Cu in shoot of both plants, whereas application of NTA (20 mmol kg(-1)) increased 37- and 1.5-fold of Zn accumulation in shoot of vetiver and maize, respectively. The potential environmental risk of metal mobility caused by chelating agents used for phytoextraction should not be overlooked.

  11. 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.

  12. Safety Profile of Oral Iron Chelator Deferiprone in Chinese Children with Transfusion-Dependent Thalassaemia.

    PubMed

    Botzenhardt, Sebastian; Sing, Chor W; Wong, Ian C K; Chan, Godfrey Chi-Fung; Wong, Lisa Y L; Felisi, Mariagrazia; Rascher, Wolfgang; Ceci, Adriana; Neubert, Antje

    2016-01-01

    There is a lack of knowledge regarding the incidence of serious adverse drug reactions (ADR) to the oral iron chelator deferiprone in Chinese children with transfusion-dependent thalassaemia. In this retrospective population-based cohort study, paediatric thalassaemia patients in Hong Kong were screened for serious and medically important adverse events related to deferiprone therapy using diagnosis codes, laboratory data and hospital admissions. Potential ADRs were assessed by reviewing concomitant medications, diagnoses and laboratory data and evaluated using standardised causality assessment. Eighty-seven patients contributing 169.8 person-years were included. Thirty ADRs were identified in 21 patients. Most ADRs (56.0%) occurred in the first three months of therapy. Neutropenia occurred in 11 patients (12.6%; incidence rate 6.5 per 100 patient-years) and severe neutropenia (agranulocytosis) was observed in 5 patients (5.7%, incidence rate 2.9 per 100 patient-years). Other identified ADRs involve severe arthropathy, elevated liver enzymes and mild thrombocytopenia. In conclusion, the safety profile of DFP therapy in Chinese children suffering from transfusion-dependent thalassaemia is in line with previous studies of non-Chinese children. However, unlike previous studies, we observed a relatively high incidence of agranulocytosis and neutropenia in patients with simultaneous combined therapy. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy. Further prospective clinical and pharmacogenetic studies are required to better evaluate this important safety signal. • Half of the identified ADRs related to deferiprone therapy occurred during the first three months of treatment. • A relatively high incidence of agranulocytosis and neutropenia. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy.

  13. A subpopulation of Candida albicans and Candida tropicalis biofilm cells are highly tolerant to chelating agents.

    PubMed

    Harrison, Joe J; Turner, Raymond J; Ceri, Howard

    2007-07-01

    Many Candida spp. produce surface-adherent biofilm populations that are resistant to antifungal compounds and other environmental stresses. Recently, certain chelating agents have been recognized as having strong antimicrobial activity against biofilms of Candida species. This study investigated and characterized the concentration- and time-dependent killing of Candida biofilms by the chelators tetrasodium EDTA and sodium diethyldithiocarbamate. Here, Candida albicans and Candida tropicalis biofilms were cultivated in the Calgary Biofilm Device and then exposed to gradient arrays of these agents. Population survival was evaluated by viable cell counting and by confocal laser scanning microscopy (CLSM) in conjunction with fluorescent viability staining. At concentrations of > or =2 mM, both EDTA and diethyldithiocarbamate killed c. 90-99.5% of the biofilm cell populations. Notably, a small fraction (c. 0.5-10%) of biofilm cells were able to withstand the highest concentrations of these antifungals that were tested (16 and 32 mM for EDTA and diethyldithiocarbamate, respectively). Interestingly, CLSM revealed that these surviving cells were irregularly distributed throughout the biofilm community. These data suggest that the use of chelating agents against biofilms of Candida spp. may be limited by the refractory nature of a variant cell subpopulation in the surface-adherent community.

  14. Comparative Efficacy and Safety of Oral Iron Chelators and their Novel Combination in Children with Thalassemia.

    PubMed

    Gomber, Sunil; Jain, Prachi; Sharma, Satender; Narang, Manish

    2016-03-01

    To compare the efficacy and safety of oral iron chelators (Deferiprone and Deferasirox) when used singly and in combination in multi-transfused children with thalassemia. Prospective comparative study. Thalassemia Center of a medical college affiliated hospital. 49 multi-transfused children with thalassemia with a mean (SD) age 11.6 (6.21) y received daily chelation therapy with either deferiprone alone (75 mg/kg/day in 3 divided doses), deferasirox alone (30 mg/kg/day single dose) or their daily combination (same dose as monotherapy) for 12 months. Serum ferritin levels at the start of study, after 6 months and after 12 months. MRI T2* of liver and heart initially and after 6 months of follow up. 24-hour urinary iron excretion values at the outset and after 12 months of chelation therapy. At every visit for blood transfusion, all patients were clinically assessed for any adverse effects; liver and renal functions were monitored 6-monthly. After 12 months of respective chelation therapy, serum ferritin values decreased from a mean of 3140.5 ng/mL to 2910.0 ng/mL in deferiprone alone group, 3859.2 ng/mL to 3417.4 ng/mL in deferasirox alone group and from 3696.5 ng/mL to 2572.1 ng/mL in the combination group. The combination therapy was more efficacious in causing fall in serum ferritin levels compared to deferiprone and deferasirox monotherapy (P= 0.035 and 0.040, respectively). Results of MRI T2 were equivocal. Combined drug usage produced maximum negative iron balance in the body by maximally increasing the iron excretion in urine from 61.1 umol/day to 343.3 umol/day (P = 0.002). No significant adverse reactions were noticed in either the monotherapy or the combination group. Oral combination therapy of deferiprone and deferasirox appears to be an efficacious and safe modality to reduce serum ferritin in multi-transfused children with thalassemia.

  15. Mechanism of action of diabetogenic zinc-chelating agents. Model system studies.

    PubMed

    Epand, R M; Stafford, A R; Tyers, M; Nieboer, E

    1985-03-01

    Using model systems, we have studied the properties of a number of zinc-chelating agents which are known to cause diabetes in laboratory animals. The abilities to permeate membranes and to complex zinc inside liposomes with the release of protons are suggested as chemical properties that can enhance diabetogenicity. When such complexing agents are added to lipid vesicles at pH 6 containing entrapped zinc ions, they acidify the contents of these vesicles. We have demonstrated this effect by measuring intravesicular pH both with a fluorine-containing F NMR probe as well as with the fluorescent probe, quinine. For example, using quinine, we observed that 0.1 mM 8-hydroxyquinoline reduced the intravesicular pH of sonicated phospholipid vesicles containing entrapped Zn2+ (as sulfate) from pH 6.0 to 2.8. These diabetogenic chelating agents also solubilized zinc-insulin precipitates from unbuffered suspensions at pH 6.0. The solubilization results from the acidification of these suspensions. Dithizone and 8-hydroxyquinoline at 4 mM solubilized 97 and 42%, respectively, of the suspended insulin. We suggest that if such proton release occurs within the zinc-containing insulin storage granules of pancreatic beta-cells, solubilization of insulin would be induced. Such an event would lead to osmotic stress and eventually to rupture of the granule. The effects of diethyldithiocarbamate (DDC), an agent that has been found to protect rabbits against the induction of diabetes by some other zinc-chelating agents, were also studied. DDC caused a decrease of 3.5 units in the intravesicular pH of zinc-containing vesicles by a mechanism not involving the release of protons upon chelation of zinc. We have demonstrated several properties of DDC which may contribute to its ability to protect against the induction of diabetes. These include its ability to store zinc as a hydrophobic complex in membranes, its consumption of protons upon spontaneous decomposition, and the ability of one of

  16. [Effectiveness of iron amino acid chelate versus ferrous sulfate as part of a food complement in preschool children with iron deficiency, Medellín, 2011].

    PubMed

    Rojas, Maylen Liseth; Sánchez, Juliana; Villada, Óscar; Montoya, Liliana; Díaz, Alejandro; Vargas, Cristian; Chica, Javier; Herrera, Ana Milena

    2013-01-01

    Iron depleted deposits are the first link in the chain of events leading to iron deficiency which is the most prevalent nutritional shortage and main cause of anemia worldwide. This situation can be prevented through food fortification. To compare the efficacy of amino acid chelate iron with ferrous sulfate as fortifier of a dietary complement in preschoolers with iron deficiency. This study was a blinded clinical trial with randomized groups. We analyzed 56 preschoolers with iron deficiency (ferritin < 24 ng/ml) that received 13 g of milk with 12.5 mg of iron, either amino acid chelate or in the ferrous sulfate form. After two months, hemoglobin, hematocrit and serum ferritin concentrations were measured. In the ferrous sulfate group, ferritin concentration increased from 18.8 ng/ml to 24.1 ng/ml, while the variation was of 18.4 ng/ml to 29.7 ng/ml in the amino acid chelate group, with statistically differences in both cases. Serum ferritin was different between groups, being higher in iron amino acid chelate group (p=0.022). Hemoglobin and hematocrit levels did not change after the intervention. Adverse reactions in the ferrous sulfate group were 35.7%, compared with 42.9% in the iron amino acid chelate group; 5 children had respiratory tract infection, without statistical differences. Both compounds increased serum ferritin concentration, with a higher increase in those who were given milk with iron amino acid chelate. There were no differences in the adverse reactions and infections incidences between the groups.

  17. [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.

  18. Aluminum and other metals in Alzheimer's disease: a review of potential therapy with chelating agents.

    PubMed

    Domingo, Jose L

    2006-11-01

    Alzheimer's disease (AD) is characterized by the presence of neuritic plaques and neurofibrillary tangles in the brain. Although the causes of AD remain still unknown, it seems that certain environmental factors may be involved in the etiology and pathogenesis of the disease. While AD is associated with the abnormal aggregation of beta-amyloid protein in the brain, evidence shows that certain metals play a role in the precipitation and cytotoxicity of this protein. Among these metals, the potential role of aluminum as a possible ethiopathogenic factor in AD has been especially controversial. This review is mainly focused on the role of aluminum and metals such as copper and zinc in AD, as well as on metal chelator therapy as a potential treatment for AD. The effects of desferrioxamine and other Al chelating agents have been reviewed. The role of the metal chelator clioquinol in AD, which has been reported to reduce beta-amyloid plaques, presumably by chelation associated with copper and zinc, is also revised. Finally, the potential role of silicon in AD is also discussed.

  19. Iron chelation by cranberry juice and its impact on Escherichia coli growth.

    PubMed

    Lin, Baochuan; Johnson, Brandy J; Rubin, Robert A; Malanoski, Anthony P; Ligler, Frances S

    2011-01-01

    The various health benefits of Vaccinium macrocarpon (cranberry) are well documented and have been attributed mainly to its antioxidant capacity and anti-adhesive activity. Several different mechanisms have been proposed to explain the possible role of cranberries, cranberry juice, and cranberry extracts in inhibiting bacterial growth. These mechanisms of action (i.e., inhibition of the microbial growth) have not been thoroughly studied. Here, we took advantage of current advances in microarray technology and used GeneChip® Escherichia coli genome 2.0 arrays to gain insight into the molecular mechanisms involved in the impact of cranberry juice on the properties of E. coli growth. The inclusion of cranberry juice in bacterial growth media was found to significantly impact the doubling time of E. coli. The gene expression results revealed altered expression of genes associated with iron transport and essential metabolic enzymes as well as with adenosine triphosphate (ATP) synthesis and fumarate hydratase in these cultures. The altered expression of genes associated with iron transport was consistent with the strong iron chelating capability of proanthocyanidins, a major constituent of cranberry juice. The iron depletion effect was confirmed by adding exogenous iron to the growth media. This addition partially reversed the inhibitory effect on bacterial growth observed in the presence of cranberry juice/extracts.

  20. The iron-chelating potential of silybin in patients with hereditary haemochromatosis.

    PubMed

    Hutchinson, C; Bomford, A; Geissler, C A

    2010-10-01

    Milk thistle contains silybin, which is a potential iron chelator. We aimed to determine whether silybin reduced iron absorption in patients with hereditary haemochromatosis. In this crossover study, on three separate occasions, 10 patients who were homozygous for the C282Y mutation in the HFE gene (and fully treated) consumed a vegetarian meal containing 13.9 mg iron with: 200 ml water; 200 ml water and 140 mg silybin (Legalon Forte); or 200 ml tea. Blood was drawn once before, then 0.5, 1, 2, 3 and 4 h after the meal. Consumption of silybin with a meal resulted in a reduction in the postprandial increase in serum iron (AUC±s.e.) compared with water (silybin 1726.6±346.8 versus water 2988.8±167; P<0.05) and tea (silybin 1726.6±346.8 versus tea 2099.3±223.3; P<0.05). In conclusion, silybin has the potential to reduce iron absorption, and this deserves further investigation, as silybin could be an adjunct in the treatment of haemochromatosis.

  1. Decorporating efficacy of catecholaminocarboxylate chelating agents for thorium-234 and protective effects on associated radiation injury.

    PubMed

    Chen, Hh; Luo, Mc; Sun, Mz; Hu, Yx; Wang, Yh; Jin, My; Cheng, Wy

    2005-04-01

    The aim was to identify the decorporation and anti-oxidation efficacy of prompt and delayed consecutive administration of the catecholicpolyaminopolycarboxylate ligands 9501 and 7601 for radiothorium in vivo. The chelating agents 9501 or 7601 were administered intramuscularly to ICR mice 3 min or 3 days after intraperitoneal injection of 30 MBq kg(-1) (234)Th-citrate for 3 consecutive days. The animals were killed 4 or 5 days after administration of the chelating agents, respectively. The (234)Th radioactivity in the whole-body and its retention in liver and skeleton were determined. Malondialdehyde (MDA) production, as an index of (234)Th-induced lipid peroxidation in bone marrow and liver, was assayed and the number of bone marrow nucleated cells (NBMNC) were counted. The pathological changes of bone marrow and liver tissue were observed. CaNa(3)-diethylenetriaminepentaacetate (DTPA) and vitamin E were used as controls. The competitive ability of 9501 and 7601 to mobilize thorium with bovine serum albumin (BSA) was studied. Their inhibitory effect on superoxide anion radicals was measured by electron spin resonance. When promptly injected, 9501 or 7601 were superior to CaNa(3)-DTPA for reducing (234)Th retention in mouse. Their different bioactivity for decorporation of (234)Th was consistent with their competitive ability to mobilize thorium with BSA. Although the removal effectiveness of 9501 and 7601, given by delayed injection, was lower than that of the prompt administration, they could inhibit (234)Th-induced lipid peroxidation. This caused significant reductions of MDA content in bone marrow and liver and markedly ameliorated histological changes to bone marrow and liver tissue in (234)Th-treated mice. Their protective effects were better than CaNa(3)-DTPA and vitamin E. 9501 and 7601 could directly scavenge O(.-)(2). Their effects as O(.-)(2) scavengers were very significant. The chelating agents 9501 and 7601 are able to remove thorium as effectively as

  2. Treatment with the iron chelator, deferoxamine mesylate, alters serum markers of oxidative stress in stroke patients.

    PubMed

    Selim, Magdy

    2010-03-01

    The iron chelator, deferoxamine mesylate (DFO), has shown neuroprotective effects, mediated via suppression of iron-induced hydroxyl radical formation, in various animal models of ischemic and hemorrhagic stroke. Therefore, the objective of this study was to investigate whether DFO can exert similar actions in stroke patients, by examining the effects of treatment with DFO on biological markers of oxidative stress, namely serum total hydroperoxides and lipoperoxides and total radical trapping antioxidant capacity (TRAP), in stroke patients. We found that serum levels of peroxides were reduced, and TRAP levels increased after a 3-day treatment with DFO (500 mg). These findings provide a preliminary proof of concept that DFO can exert potential antioxidant neuroprotective effects in stroke patients. Future, larger-scale, randomized, and controlled studies to further evaluate the safety and efficacy of DFO in patients with stroke are warranted.

  3. Hydroxypyridinone Chelators: From Iron Scavenging to Radiopharmaceuticals for PET Imaging with Gallium-68

    PubMed Central

    Cusnir, Ruslan; Imberti, Cinzia; Hider, Robert C.; Blower, Philip J.; Ma, Michelle T.

    2017-01-01

    Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe3+ sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of iron overload disease. Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe3+ at very low iron concentrations, and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the positron emitting radiometal, 68Ga3+, which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex 68Ga3+ at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of 68Ga PET radiopharmaceuticals. 68Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images. PMID:28075350

  4. Hydroxypyridinone Chelators: From Iron Scavenging to Radiopharmaceuticals for PET Imaging with Gallium-68.

    PubMed

    Cusnir, Ruslan; Imberti, Cinzia; Hider, Robert C; Blower, Philip J; Ma, Michelle T

    2017-01-08

    Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe(3+) sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of iron overload disease. Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe(3+) at very low iron concentrations, and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the positron emitting radiometal, (68)Ga(3+), which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex (68)Ga(3+) at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of (68)Ga PET radiopharmaceuticals. (68)Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images.

  5. 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.

  6. 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

  7. 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.

  8. Aroylhydrazone iron chelators: Tuning antioxidant and antiproliferative properties by hydrazide modifications.

    PubMed

    Hrušková, Kateřina; Potůčková, Eliška; Hergeselová, Tereza; Liptáková, Lucie; Hašková, Pavlína; Mingas, Panagiotis; Kovaříková, Petra; Šimůnek, Tomáš; Vávrová, Kateřina

    2016-09-14

    Aroylhydrazones such as salicylaldehyde isonicotinoyl hydrazone (SIH) are tridentate iron chelators that may possess antioxidant and/or antineoplastic activities. Their main drawback, their low stability in plasma, has recently been partially overcome by exchanging the aldimine hydrogen for an unbranched alkyl group. In this study, ten analogs of methyl- and ethyl-substituted SIH derivatives with modified hydrazide scaffolds were synthesized to further explore their structure-activity relationships. Their iron-chelation efficiencies, anti- or pro-oxidant potentials, abilities to induce protection against model oxidative injury on the H9c2 cell line derived from rat embryonic cardiac tissue, cytotoxicities on the same H9c2 cells and antiproliferative activities on MCF-7 human breast adenocarcinoma and HL-60 human promyelotic leukemia cell lines were evaluated. Compounds derived from lipophilic naphthyl and biphenyl hydrazides displayed highly selective antiproliferative activities against both MCF-7 and HL-60 cell lines, and they showed markedly improved stabilities in plasma compared to SIH. Of particular interest is a hydrazone prepared from 2-hydroxypropiophenone and pyridazin-4-carbohydrazide that showed a considerable antiproliferative effect and protected cardiomyoblasts against oxidative stress with a five-fold higher selectivity compared to the parent compound SIH. Thus, this work highlighted new structure-activity relationships among antiproliferative and antioxidant aroylhydrazones and identified new lead compounds for further development. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. The effect of weak chelating agents on the removal of heavy metals by precipitation processes

    SciTech Connect

    Ku, Y.; Peters, W.

    1986-01-01

    Particle size distributions and heavy metal removals are presented for hydroxide precipitation and sulfide precipitation of zinc and cadmium in the presence of several weak complexing agents, namely citrate, tartrate, and ammonia. The pH was held constant at pH 10.0 in these experiments. The presence of these weak complexing agents had little effect on the chemical equilibrium for both the hydroxide and sulfide systems due to their weak complexing ability with metal ions. The presence of the complexing agents does affect the particle size distribution, generally forming smaller particles. Particle size distributions are presented for the Zn(OH)/sub 2/, ZnS, Cd(OH)/sub 2/, and CdS systems (at pH 10.0) in the presence of the chelating agents citrate, tartrate, and ammonia. Sulfide precipitation exhibits a better particle size distribution and settling characteristics than the corresponding metal hydroxide precipitation for both zinc and cadmium.

  10. 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

  11. 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.

  12. Comparison of different chelating agents to enhance reductive Cr(VI) removal by pyrite treatment procedure.

    PubMed

    Kantar, Cetin; Ari, Cihan; Keskin, Selda

    2015-06-01

    New technologies involving in-situ chemical hexavalent chromium [Cr(VI)] reduction to trivalent chromium [Cr(III)] with natural Fe(II)-containing minerals can offer viable solutions to the treatment of wastewater and subsurface systems contaminated with Cr(VI). Here, the effects of five different chelating agents including citrate, EDTA, oxalate, tartrate and salicylate on reductive Cr(VI) removal from aqueous systems by pyrite were investigated in batch reactors. The Cr(VI) removal was highly dependent on the type of ligand used and chemical conditions (e.g., ligand concentration). While salicylate and EDTA had no or little effect on Cr(VI) removal, the ligands including citrate, tartrate and oxalate significantly enhanced Cr(VI) removal at pH < 7 relative to non-ligand systems. In general, the efficiency of organic ligands on Cr(VI) removal decreased in the order: citrate ≥ oxalate ≈ tartrate > EDTA > salicylate ≈ non-ligand system. Organic ligands enhanced Cr(VI) removal by 1) removing surface oxide layer via the formation of soluble Fe-Cr-ligand complexes, and 2) enhancing the reductive iron redox cycling for the regeneration of new surface sites. While citrate, oxalate and tartrate eliminated the formation of surface Cr (III)-Fe(III)-oxides, the surface phase Cr (III) species was observed in the presence of EDTA and salicylate indicating that Cr(III) complexed with EDTA and salicylate sorbed or precipitated onto pyrite surface, thereby blocking the access of CrO4(2-) to pyrite surface. The binding of Fe(III) with the disulfide reactive sites (≡Fe-S-S-Fe(III)) was essential for the regeneration of new surface sites through pyrite oxidation. Although Fe(III)-S species was detected at the pyrite surface in the presence of citrate, oxalate and tartrate, Fe(III) complexed with EDTA and salicylate did not strongly interact with the disulfide reactive sites due to the formation of non-sorbing Fe(III)-ligand complexes. The absence of surface Fe

  13. Overexpression of the FRO2 ferric chelate reductase confers tolerance to growth on low iron and uncovers posttranscriptional control.

    PubMed

    Connolly, Erin L; Campbell, Nathan H; Grotz, Natasha; Prichard, Charis L; Guerinot, Mary Lou

    2003-11-01

    The Arabidopsis FRO2 gene encodes the low-iron-inducible ferric chelate reductase responsible for reduction of iron at the root surface. Here, we report that FRO2 and IRT1, the major transporter responsible for high-affinity iron uptake from the soil, are coordinately regulated at both the transcriptional and posttranscriptional levels. FRO2 and IRT1 are induced together following the imposition of iron starvation and are coordinately repressed following iron resupply. Steady-state mRNA levels of FRO2 and IRT1 are also coordinately regulated by zinc and cadmium. Like IRT1, FRO2 mRNA is detected in the epidermal cells of roots, consistent with its proposed role in iron uptake from the soil. FRO2 mRNA is detected at high levels in the roots and shoots of 35S-FRO2 transgenic plants. However, ferric chelate reductase activity is only elevated in the 35S-FRO2 plants under conditions of iron deficiency, indicating that FRO2 is subject to posttranscriptional regulation, as shown previously for IRT1. Finally, the 35S-FRO2 plants grow better on low iron as compared with wild-type plants, supporting the idea that reduction of ferric iron to ferrous iron is the rate-limiting step in iron uptake.

  14. Antioxidant and iron-chelating properties of taxifolin and its condensation product with glyoxylic acid.

    PubMed

    Shubina, Victoria S; Shatalin, Yuri V

    2017-05-01

    The condensation of taxifolin with glyoxylic acid was examined, and the properties of the resulting product were compared with those of taxifolin. The structure of the product was determined by NMR spectroscopy. The ability of the polyphenols to scavenge reactive oxygen species (ROS) was estimated by luminol-dependent chemiluminescence. The iron-chelating and iron-reducing activities were studied using absorption spectrophotometry. It was shown that the condensation leads to the formation of a dimer consisting of two taxifolin units linked through a carboxymethine bridge at the C-6 and C-8 positions of the A ring. The dimer exhibited a somewhat higher ROS scavenging activity than taxifolin. The iron-binding capacity of the compounds was proportional to the number of polyphenol units. The iron-reducing ability of the dimer was lower than that of taxifolin. Thus, the dimer possessed a higher antioxidant activity than the parent flavonoid. The data obtained may be useful for a better understanding of processes occurring in foods and beverages and in a search for new active compounds.

  15. 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.

  16. 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.

  17. The proceedings of the 17th International Conference on Chelation: application of effective chelation therapies in iron loading and non iron loading conditions, and the gap in the prevention and treatment policies on thalassemia between developed and developing countries.

    PubMed

    Kontoghiorghes, George J

    2009-01-01

    Substantial progress in the use of chelating drugs for the treatment of iron overload and of non iron loading conditions has been presented during the 17th International Conference on Chelation (ICOC) held in November 2007 at Shenzhen, China. Major challenges lie ahead for the prevention and treatment of thalassemia in China, India, Thailand, Indonesia and many other developing countries where millions of heterozygote thalassemia carriers live and thousands of homozygote thalassemia patients are born annually. The progressive improvement of the economic climate in developing countries will increase the demand and resources for more prenatal and antenatal diagnoses, transfusions and chelation therapy in forthcoming years. Despite the major advances in diagnosis and treatment in developed countries, the vast majority of thalassemia patients in developing countries die untreated because they cannot afford the cost of transfusions and chelation therapy. New approaches and infrastructures and more efforts are needed to overcome the difficulties of supplying new techniques and treatments to patients in developing countries. International and local organizations need to be persuaded to act collectively and effectively to improve chelation and related treatments for thalassemia and other conditions, especially at this time that universally effective and inexpensive chelation therapies can be applied.

  18. 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.

  19. 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

  20. The Urinary Antibiotic 5-Nitro-8-Hydroxyquinoline (Nitroxoline) Reduces the Formation and Induces the Dispersal of Pseudomonas aeruginosa Biofilms by Chelation of Iron and Zinc

    PubMed Central

    Klinger, M.; Hermann, B.; Sachse, S.; Nietzsche, S.; Makarewicz, O.; Keller, P. M.; Pfister, W.; Straube, E.

    2012-01-01

    Since cations have been reported as essential regulators of biofilm, we investigated the potential of the broad-spectrum antimicrobial and cation-chelator nitroxoline as an antibiofilm agent. Biofilm mass synthesis was reduced by up to 80% at sub-MIC nitroxoline concentrations in Pseudomonas aeruginosa, and structures formed were reticulate rather than compact. In preformed biofilms, viable cell counts were reduced by 4 logs at therapeutic concentrations. Complexation of iron and zinc was demonstrated to underlie nitroxoline's potent antibiofilm activity. PMID:22926564

  1. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major.

    PubMed

    Farmaki, Kallistheni; Tzoumari, Ioanna; Pappa, Christina; Chouliaras, Giorgos; Berdoukas, Vasilios

    2010-02-01

    Cardiac and endocrine disorders are common sequelae of iron overload in transfused thalassaemia patients. Combined chelation with desferrioxamine (DFO) and deferiprone (DFP) is well tolerated and produces an additive/synergistic effect superior to either drug alone. 52 thalassaemia major patients were transitioned from DFO to combined chelation with DFO and DFP. Serum ferritin, cardiac and hepatic iron levels were monitored regularly for up to 7 years, as were cardiac and endocrine function. Patients' iron load normalized, as judged by ferritin and cardiac and hepatic magnetic resonance imaging findings. In all 12 patients receiving treatment for cardiac dysfunction, symptoms reversed following combined chelation, enabling nine patients to discontinue heart medications. In the 39 patients with abnormal glucose metabolism, 44% normalized. In 18 requiring thyroxine supplementation for hypothyroidism, 10 were able to discontinue, and four reduced their thyroxine dose. In 14 hypogonadal males on testosterone therapy, seven stopped treatment. Of the 19 females, who were hypogonadal on DFO monotherapy, six were able to conceive. Moreover, no patients developed de novo cardiac or endocrine complications. These results suggest that intensive combined chelation normalized patients' iron load and thereby prevented and reversed cardiac and multiple endocrine complications associated with transfusion iron overload.

  2. Preventive Therapy of Experimental Colitis with Selected iron Chelators and Anti-oxidants

    PubMed Central

    Minaiyan, Mohsen; Mostaghel, Elahe; Mahzouni, Parvin

    2012-01-01

    Objectives: Iron chelators, such as maltol and kojic acid, have antioxidant and anti-inflammatory properties. They may have beneficial effects on inflammatory bowel disease (IBD) because iron can develop and aggravate inflammation in IBD. In the present study, the effect of selected iron chelators and anti-oxidants were evaluated on a model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Methods: Colitis was induced with instillation of 75 mg/kg TNBS in 0.25 ml ethanol 50% via the anus in fasted male Wistar rats. The animals were assigned randomly to 12 groups (n = 6) and treated once daily, started 2 hours before colitis induction, with normal saline (5 ml/kg), maltol (70, 140, 280 mg/kg), kojic acid (75, 150, 300 mg/kg), vitamin E (400 mg/kg), deferiprone (L1) (150 mg/kg) and prednisolone (4 mg/kg) orally and deferoxamine (50 mg/kg) intraperitoneally for 5 days. In the sixth day, rats were scarified and colon tissues were assessed macroscopically and pathologically. Results: Maltol (280 mg/kg) was able to reduce colon weight / length ratio, ulcer index and total colitis index similar to prednisolone, deferoxamine and deferiprone as positive controls. However, kojic acid and vitamin E could not significantly alleviate macroscopic and/or pathologic features of inflammation in comparison to normal saline. Conclusions: Maltol with the highest test dose was capable to protect against experimentally induced colitis. Kojic acid and vitamin E were not effective in this animal model of colon inflammation. More detailed studies are warranted to explore the mechanisms involved in anti-colitic property of maltol and to explain ineffectiveness of kojic acid and vitamin E. PMID:22826760

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

    PubMed Central

    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.

    2015-01-01

    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 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 may be a

  4. Chemical evaluation of HBED/Fe(3+) and the novel HJB/Fe(3+) chelates as fertilizers to alleviate iron chlorosis.

    PubMed

    López-Rayo, Sandra; Hernández, Diana; Lucena, Juan J

    2009-09-23

    Iron chelates such as ethylenediamine-N,N'-bis(2-hydroxyphenylacetic) acid (o,o-EDDHA) and their analogues are the most efficient soil fertilizers to treat iron chlorosis in plants growing in calcareous soil. A new chelating agent, HJB (N,N'-bis(2-hydroxy-5-methylphenyl)ethylendiamine-N,N'-diacetic acid) may be an alternative to o,o-EDDHA since its synthesis yields a purer product, but its chemical behavior and efficiency as chlorosis corrector should be evaluated. In this research, a known analogous HBED (N,N'-bis(2-hydroxyphenyl)ethylendiamine-N,N'-diacetic acid) has also been considered. First, an ion-pair high performance liquid chromatography (HPLC) method has been tested for the HJB/Fe(3+) and HBED/Fe(3+) determination. The ability of HJB and HBED to maintain Fe in solution has been compared with respect to o,o-EDDHA. Theoretical modelization for HBED and HJB in agronomic conditions has been done after the determination of the protonation and Ca(II), Mg(II), Fe(III), and Cu(II) stability constants for HJB. Also, batch interaction experiments with soils and soil materials have been conducted. According to our results, HJB/Fe(3+) and HBED/Fe(3+) present high stability, even when competing cations (Cu(2+), Ca(2+)) are present, and have low reactivity with soils and soil components. The chelating agent HJB dissolves a higher amount of Fe than o,o-EDDHA, and it seems as effective as o,o-EDDHA in keeping Fe in solution. These results indicate that these chelates may be very efficient products to correct Fe chlorosis, and additional plant experiments should demonstrate plants' ability to assimilate Fe from HJB/Fe(3+) and HBED/Fe(3+).

  5. 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

  6. Approaching low liver iron burden in chelated patients with non-transfusion-dependent thalassemia: the safety profile of deferasirox

    PubMed Central

    Taher, Ali T; Porter, John B; Viprakasit, Vip; Kattamis, Antonis; Chuncharunee, Suporn; Sutcharitchan, Pranee; Siritanaratkul, Noppadol; Origa, Raffaella; Karakas, Zeynep; Habr, Dany; Zhu, Zewen; Cappellini, M Domenica

    2014-01-01

    Objective Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload and related complications, and may require iron chelation. However, the risk of over-chelation emerges as patients reach low, near-normal body iron levels and dose adjustments may be needed. In the THALASSA study, the threshold for chelation interruption was LIC <3 mg Fe/g dw (LIC<3); 24 patients receiving deferasirox for up to 2 yr reached this target. A post hoc analysis was performed to characterize the safety profile of deferasirox as these patients approached LIC<3. Methods THALASSA was a randomized, double-blind, placebo-controlled study of two deferasirox regimens (5 and 10 mg/kg/d) versus placebo in patients with NTDT. Patients randomized to deferasirox or placebo in the core could enter a 1-yr extension, with all patients receiving deferasirox (extension starting doses based on LIC at end-of-core and prior chelation response). The deferasirox safety profile was assessed between baseline and 6 months before reaching LIC<3 (Period 1), and the 6 months immediately before achieving LIC<3 (Period 2). Results Mean ± SD deferasirox treatment duration up to reaching LIC<3 was 476 ± 207 d, and deferasirox dose was 9.7 ± 3.0 mg/kg/d. The exposure-adjusted AE incidence regardless of causality was similar in periods 1 (1.026) and 2 (1.012). There were no clinically relevant differences in renal and hepatic laboratory parameters measured close to the time of LIC<3 compared with measurements near the previous LIC assessment. Conclusions The deferasirox safety profile remained consistent as patients approached the chelation interruption target, indicating that, with appropriate monitoring and dose adjustments in relation to iron load, low iron burdens may be reached with deferasirox with minimal risk of over-chelation. PMID:24460655

  7. Iron burden and liver fibrosis decrease during a long-term phlebotomy program and iron chelating treatment after bone marrow transplantation.

    PubMed

    Meo, Anna; Ruggeri, Annalisa; La Rosa, Maria A; Zanghì, Laura; Morabito, Nancy; Duca, Lorena

    2006-01-01

    In this retrospective study, we report the results of the association of a combined phlebotomy program and chelation in hereditary sideroblastic anemia (HSA) to reduce iron overload after bone marrow transplantation (BMT). A male HSA patient, not responding to pyridoxine treatment, was submitted to successful allogeneic BMT. As there was a persistence of a tissue iron overload, a regular phlebotomy program was started followed by chelation. A significant decrease of iron burden was obtained using a combined treatment with deferoxamine (DFO) and deferiprone (L1) in addition to the phlebotomy program. A 10-year follow-up shows a marked decrease in the concentration of serum ferritin, non-transferrin-bound iron (NTBI), liver iron and normal hemoglobin (Hb), which allows the patient to reach and maintain a good quality of life.

  8. 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.

  9. Solubility and accumulation of metals in Chinese brake fern, vetiver and rostrate sesbania using chelating agents.

    PubMed

    Lou, L Q; Ye, Z H; Wong, M H

    2007-01-01

    Greenhouse experiments were conducted to study the effects of chelating agents on the growth and metal accumulation of Chinese brake fern (Pteris vittata L.), vetiver (Vetiveria zizanioides L.), and rostrate sesbania (Sesbania rostrata L.) in soil contaminated with arsenic (As), Cu, Pb, and Zn. Among the five chelating agents used [ethylenediaminetriacetic acid (EDTA), hydroxyethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), oxalic acid (OA), and phytic acid (PA)], OA was the best to mobilize As, EDTA to mobilize Cu and Pb, and HEDTA to mobilize Zn from soil, respectively. The biomass of vetiver was the highest, followed by rostrate sesbania. All chelating agents inhibited the growth of Chinese brake fern and rostrate sesbania, but HEDTA significantly increased the aboveground biomass of vetiver. Dry weights of both Chinese brake fern and rostrate sesbania decreased with increasing EDTA concentrations amended in the soil, especially in treatments with high EDTA concentrations. EDTA and HEDTA enhanced Cu, Zn, and Pb, but lowered As accumulation in all three plant species, except for As in vetiver, while OA significantly enhanced As accumulation in the aboveground part of vetiver. Concentrations of Cu, Zn, and Pb in the aboveground parts of plants increased significantly with the increase of EDTA concentrations and treatment time. In addition to As, Chinese brake fern also accumulated the highest Cu, Pb, and Zn in its aboveground parts among the three plant species grown in metal-contaminated soil with EDTA/HEDTA treatments. This species, therefore, can be used to simultaneously clean up As, Cu, Pb, and Zn from contaminated soils with the aid of EDTA or HEDTA.

  10. MANOTA: a promising bifunctional chelating agent for copper-64 immunoPET.

    PubMed

    Moreau, M; Poty, S; Vrigneaud, J-M; Walker, P; Guillemin, M; Raguin, O; Oudot, A; Bernhard, C; Goze, C; Boschetti, F; Collin, B; Brunotte, F; Denat, F

    2017-09-01

    Improved bifunctional chelating agents (BFC) are required for copper-64 radiolabelling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific imaging agents. Four different bifunctional chelating agents (BFC) were evaluated for Fab (Fragment antigen binding) conjugation and radiolabelling with copper-64. Two DOTA- (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and two NOTA- (1,4,7-triazacyclononane-1,4,7-triacetic acid) derivatives bearing a p-benzyl-isothiocyanate group were conjugated to Fab-trastuzumab - which targets the HER2/neu receptor - and the average number of chelators attached ranged from 2.4 to 4.3 macrocycles per Fab. Labelling of the immunoconjugate with copper-64 was achieved in high radiochemical yields after 45 min at 37 °C, and the radiochemical purity of each (64)Cu-BFC-Fab-trastuzumab reached 97% after purification. The affinity of each (64)Cu-BFC-Fab-trastuzumab ranged between 10 and 50 nM as evaluated by in vitro saturation assays using the HCC1954 breast cancer cell line. PET-MR imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumours were clearly visualized on PET images at 4 and 24 hours post-injection. The tumour uptake of (64)Cu-BFC-Fab-trastuzumab reached 8.9 to 12.8% ID g(-1) 24 hours post-injection and significant differences in non-specific liver uptake were observed depending on the BFC conjugated, the lowest being observed with MANOTA. These results show that MANOTA is a valuable tool for copper-64 radiolabelling.

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

    PubMed

    Magro, A M; Brai, M

    1983-05-01

    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.

  12. 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

  13. Preparation and protein conjugation of a divinyl sulphone derivatized bifunctional chelating agent.

    PubMed

    Somayaji, V V; Naicker, S S; Sykes, T R; Guay, V; Noujaim, A A

    1996-12-01

    A new bifunctional chelating agent with a novel linking arm, 2-[p-¿N-benzyl-N-(2-vinylsulfoethyl)¿- (aminobenzyl)¿-1,3-propane-diamine-N,N,N',N'-tetraacetic acid (VS-PDTA) was synthesized and was conjugated to protein for the purpose of attaching radiometals to monoclonal antibodies (MAbs). The effect of various parameters such as ligand concentration, protein concentration, pH, temperature and reaction period on the conjugation have been examined using chromatographic (SE and TLC) analysis after labeling with 111In. The parameters and chemical variables studied have significant effects on the efficiency and rate of protein conjugation.

  14. Design, synthesis, and evaluation of indanone derivatives as acetylcholinesterase inhibitors and metal-chelating agents.

    PubMed

    Meng, Fan-Chao; Mao, Fei; Shan, Wen-Jun; Qin, Fangfei; Huang, Ling; Li, Xing-Shu

    2012-07-01

    A series of novel indanone derivatives was designed, synthesised and evaluated as potential agents for Alzheimer's disease. Among them, compound 6a, with a piperidine group linked to indone by a two-carbon spacer, exhibited the most potent inhibitor activity, with an IC(50) of 0.0018 μM for AChE; the inhibitory activity of this compound was 14-fold more potent than that of donepezil. Furthermore, these compounds also exhibited good metal-chelating ability. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Siderochelin, a new ferrous-ion chelating agent produced by Nocardia.

    PubMed

    Liu, W C; Fisher, S M; Wells, J S; Ricca, C S; Principe, P A; Trejo, W H; Bonner, D P; Gougoutos, J Z; Toeplitz, B K; Sykes, R B

    1981-07-01

    A new ferrous-ion chelating agent, siderochelin, was isolated from fermentation broths of Nocardia sp. SC 11,340. Siderochelin was produced by conventional submerged culture and purified by solvent extraction and recrystallization. The antibiotic was crystallized from acetonitrile as a mixture of diastereoisomers. The molecular formula of siderochelin was determined as C11H13N3O3 on the basis of elemental analysis and mass spectrometry, and the structure was elucidated by X-ray crystallography. The compound shows a broad spectrum of antimicrobial activity, being active against bacteria, fungi and protozoa.

  16. Removing nitric oxide from flue gas using iron(II) citrate chelate absorption with microbial regeneration.

    PubMed

    Xu, Xinhua; Chang, Shih Ger

    2007-04-01

    The addition of metal chelates such as Fe(II)EDTA or Fe(II)Cit to wet flue gas desulfurization systems has been shown to increase the amount of NO(x) absorption from gas streams containing SO(2). This paper attempts to demonstrate the advantage of not only using Fe(II)Cit chelate to absorb nitrogen oxides from flue gas but also the advantage gained from adding microorganisms to the system. Two distinct classes of microorganisms are needed: denitrifying and iron-reducing bacteria. The presence of oxygen in flue gas will affect the absorption efficiency of NO by Fe(II)Cit chelate. The oxidation of Fe(II) can be slowed with the help of bacteria in two ways: bacteria can serve to directly reduce Fe(III) to Fe(II) or they can serve to keep levels of dissolved oxygen in the solution low. As a result, after NO absorption, Fe(II)(Cit)NO will be reduced by denitrifying bacteria to Fe(II)Cit while Fe(III) is reduced by anaerobic bacteria back to Fe(II). Our experiments have shown that the implementation of our protocol allowed for an NO reduction rate constant increase from standard levels of 0.0222-0.100 m Mh(-1) with inlet NO changed from 250 to 1000 ppm. We have also found that total Fe concentration tends to decrease after prolonged periods of operation due to the loss of some Fe to the formation of Fe(OH)(3) that settles together with the sludge at the bottom of bioreactor tank.

  17. 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

  18. 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.

  19. The iron chelator deferasirox induces apoptosis by targeting oncogenic Pyk2/β-catenin signaling in human multiple myeloma

    PubMed Central

    Sato, Tsutomu; Kawano, Yutaka; Murase, Kazuyuki; Arihara, Yohei; Kikuchi, Shohei; Hayasaka, Naotaka; Usami, Makoto; Iyama, Satoshi; Miyanishi, Koji; Sato, Yasushi; Kobune, Masayoshi; Kato, Junji

    2016-01-01

    Deregulated iron metabolism underlies the pathogenesis of many human cancers. Recently, low expression of ferroportin, which is the only identified non-heme iron exporter, has been associated with significantly reduced overall survival in multiple myeloma (MM); however, the altered iron metabolism in MM biology remains unclear. In this study we demonstrated, by live cell imaging, that MM cells have increased intracellular iron levels as compared with normal cells. In experiments to test the effect of iron chelation on the growth of MM cells, we found that deferasirox (DFX), an oral iron chelator used to treat iron overload in clinical practice, inhibits MM cell growth both in vivo and in vitro. Mechanistically, DFX was found to induce apoptosis of MM cells via the inhibition of proline-rich tyrosine kinase 2 (Pyk2), which is known to promote tumor growth in MM. Inhibition of Pyk2 is caused by the suppression of reactive oxygen species, and leads to downregulation of the Wnt/β-catenin signaling pathway. Taken together, our findings indicate that high levels of intracellular iron, which might be due to low ferroportin expression, play a role in MM pathophysiology. Therefore, DFX may provide a therapeutic option for MM that is driven by deregulated iron homeostasis and/or Pyk2/Wnt signaling. PMID:27602957

  20. Posttransplant oral iron-chelating therapy in patients with beta-thalassemia major.

    PubMed

    Yesilipek, M Akif; Karasu, Gulsun; Kazik, Mediha; Uygun, Vedat; Ozturk, Zeynep

    2010-08-01

    Allogeneic hematopoetic stem cell transplantation (HSCT) is the only radical cure of beta-thalassemia. However, iron overload remains a cause of morbidity and mortality in posttransplant period. The authors present 7 patients as a preliminary report who underwent bone marrow transplant (BMT) and received oral chelating therapy (deferasirox) because of poor compliance to phlebotomy and desferrioxamine. The patients investigated mainly for possible side effects of deferasirox. No negative effect was seen in aspartate aminotransferase (AST), alanine aminotransferase (ALT), hemoglobin (Hb), and donor chimerism of the patients while serum ferritin levels significantly reduced (P = .018). Although serum creatinin significantly increased (P = .034), it was in normal limits in all patients. The authors believe that this report shows promising findings to plan further studies to clarify clinical safety and efficacy of deferasirox in posttransplant period.

  1. Qualitative modification and development of patient- and caregiver-reported outcome measures for iron chelation therapy.

    PubMed

    Horodniceanu, Erica G; Bal, Vasudha; Dhatt, Harman; Carter, John A; Huang, Vicky; Lasch, Kathryn

    2017-06-23

    Compliance, palatability, gastrointestinal (GI) symptom, and treatment satisfaction patient- and observer-reported outcome (PRO, ObsRO) measures were developed/modified for patients with transfusion-dependent anemias or myelodysplastic syndrome (MDS) requiring iron chelation therapy (ICT). This qualitative cross-sectional observational study used grounded theory data collection and analysis methods and followed PRO/ObsRO development industry guidance. Patients and caregivers of patients with transfusion-dependent anemias or MDS were individually interviewed face-to-face to cognitively debrief the Compliance, Palatability, GI Symptom Diary, and Modified Satisfaction with Iron Chelation Therapy (SICT) instruments presented electronically. Interviews were conducted in sets. Interviews began open-endedly to spontaneously elicit ICT experiences. Item modifications were debriefed during the later interviews. Interviews were audio recorded, transcribed, and coded. Data was analyzed using ATLAS.ti qualitative research software. Twenty-one interviews were completed (Set 1: 5 patients, 6 caregivers; Set 2: 6 patients, 4 caregivers) in 6 US cities. Mean age was 43 years for patients and 9 years for children of caregivers. Conditions requiring ICT use across groups included transfusion-dependent anemias (85.7%) and MDS (14.3%). Concepts spontaneously reported were consistent with instruments debriefed. Interview analysis resulted in PRO and ObsRO versions of each instrument: Compliance (2 items), Palatability (4 items), GI Symptom Diary (6 items), and Modified SICT (PRO = 13, ObsRO = 17 items). Qualitative research data from cognitive interviews supports the content validity and relevance of the instruments developed/modified. Quantitative validation of these PRO and ObsRO measures is needed testing for validity, reliability, and responsiveness for future research use with new formulations of oral ICT.

  2. 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.

  3. 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.

  4. A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload

    PubMed Central

    Rienhoff, Hugh Young; Viprakasit, Vip; Tay, Lay; Harmatz, Paul; Vichinsky, Elliott; Chirnomas, Deborah; Kwiatkowski, Janet L.; Tapper, Amy; Kramer, William; Porter, John B.; Neufeld, Ellis J.

    2011-01-01

    Background There is still a clinical need for a well-tolerated and safe iron chelator for the treatment of transfusional iron overload. We describe the pharmacokinetic properties and safety data after 7 days of dosing of FBS0701, a novel oral, once-daily iron chelator. Design and Methods This phase 1b dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload, was conducted in 16 adult patients with iron overloaded consequent to transfusions. FBS0701 was given daily for 7 days at doses up to 32 mg/kg and was well tolerated at all dose levels. Results Pharmacokinetics showed dose-proportionality. The maxium plasma concentration (Cmax) was reached within 60–90 minutes of dosing and the drug was rapidly distributed at the predicted therapeutic doses. The plasma elimination half-life (t1/2) was approximately 19 hours. There were no serious adverse events associated with the drug. Conclusions On the basis of these safety and pharmacokinetic data, FBS0701 warrants further clinical evaluation in patients with transfusional iron overload. (Clinicaltrials.gov identifier: NCT01186419) PMID:21173101

  5. The hexadentate hydroxypyridinonate TREN-(Me-3,2-HOPO) is a more orally active iron chelator than its bidentate analogue.

    PubMed

    Yokel, R A; Fredenburg, A M; Durbin, P W; Xu, J; Rayens, M K; Raymond, K N

    2000-04-01

    Bidentate hydroxypyridinone chelators effectively complex and facilitate excretion of trivalent iron. To test the hypothesis that hexadentate chelators are more effective than bidentate chelators at low concentrations, urinary and biliary Fe excretions were determined in Fe-loaded rats before and after administration of a bidentate chelator, Pr-(Me-3,2-HOPO), or its hexadentate analogue, TREN-(Me-3,2-HOPO). The bidentate chelator slightly increased biliary Fe excretion in Fe-loaded rats after IV (90 micromol/kg) and PO (90 or 270 micromol/kg) administration, but chelation efficiency did not exceed 1%. The hexadentate chelator markedly increased biliary Fe excretion, achieving overall chelation efficiencies of 14% after IV administration of 30 micromol/kg and 8 or 3% after PO (30 or 90 micromol/kg) administration. The hexadentate chelator was significantly more effective than the bidentate chelator after IV injection and oral dosing. In chelator-treated Fe-loaded or saline-injected rats, >90% of the excreted Fe was in the bile. Oral TREN-(Me-3,2-HOPO), given to non-Fe-loaded rats, did not appreciably change Fe output, indicating that there was little Fe depletion in the absence of Fe overload. These results support the hypothesis that greater Fe chelation efficiency can be achieved with hexadentate than with bidentate chelators at lower, and presumably safer, concentrations. The results also demonstrate that TREN-(Me-3, 2-HOPO) is a promising, orally effective, Fe chelator.

  6. 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.

  7. Acute toxicity studies of aluminium compounds: antidotal efficacy of several chelating agents.

    PubMed

    Llobet, J M; Domingo, J L; Gómez, M; Tomás, J M; Corbella, J

    1987-04-01

    Four aluminum compounds--nitrate, chloride, sulphate and bromide--were administered orally and intraperitoneally to rats and mice. The LD50-values (14 days) were determined. The majority of deaths occurring during the first four days. The clinical and physical signs appearing after intoxication include among other lethargy, decreased locomotor activity, piloerection, weight loss and perorbital bleeding. After 14 days no alterations in liver and renal functions were detected in the animals which received intraperitoneally the LD50-values of aluminum nitrate as a single dose. Aluminum concentrations were highest in liver and spleen. No histopathological lesions could be observed. To compare the efficacies of nine chelating agents on the toxicity of aluminum in mice, the therapeutic index and the therapeutic effectiveness of each chelating agent have been calculated. Malic, succinic, oxalic and malonic acids showed the best results with malic and succinic acids being the most effective. Deferoxamine mesylate (DFOA), sodium salicylate, L-cysteine and citric acid were not so effective as antidotes for acute aluminum toxicity. Aurin tricarboxylic acid (ATCA) should not be used due to its high toxicity.

  8. Thermal Decomposition and Phase Formation of Cerate-Zirconate Ceramics Prepared with Different Chelating Agents

    NASA Astrophysics Data System (ADS)

    Osman, Nafisah; Abdullah, Nur Athirah; Hasan, Sharizal

    2013-07-01

    Chelating agents of citric acid, lactic acid, glycine and ethylenediaminetetra acetic acid (EDTA) were used to synthesize a ceramic compound of Ba(Ce0.6Zr0.4)0.9Y0.1O2.95 (BCZY10) by a sol-gel method. Thermal decomposition and phase formation of the samples were analyzed by thermogravimetric analysis (TGA), Fourier transform infra-red (FTIR) spectroscopy and X-ray diffractometer (XRD). At heating rate of 10 °C min-1, all the samples exhibited almost similar pattern of TG-DTG profiles. A complete thermal decomposition process of the samples took place by three stages. The powders prepared using EDTA exhibited the lowest temperature for thermal decomposition since there was no significant weight loss above than 770 °C. Even after calcined at 1100 °C, the carbonate residue still remains in the samples as proven by FTIR result. The presence of this intermediate phase was also detected in XRD spectra as a small peak at 2θ≈23.9 ° corresponds to BaCO3 appeared for S1, S2 S3 and S4 samples. It was found that the chelating agents used had a decisive influence on the thermal decomposition of samples but no significant effect in reducing calcination temperature to produce a pure perovskite-like phase.

  9. 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.

  10. 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.

  11. Chelating agents exert distinct effects on biofilm formation in Staphylococcus aureus depending on strain background: role for clumping factor B

    PubMed Central

    Abraham, Nabil M.; Lamlertthon, Supaporn; Fowler, Vance G.

    2012-01-01

    Staphylococcus aureus is a leading cause of catheter infections, and biofilm formation plays a key role in the pathogenesis. Metal ion chelators inhibit bacterial biofilm formation and viability, making them attractive candidates as components in catheter lock solutions. The goal of this study was to characterize further the effect of chelators on biofilm formation. The effect of the calcium chelators ethylene glycol tetraacetic acid (EGTA) and trisodium citrate (TSC) on biofilm formation by 30 S. aureus strains was tested. The response to subinhibitory doses of EGTA and TSC varied dramatically depending on strain variation. In some strains, the chelators prevented biofilm formation, in others they had no effect, and they actually enhanced biofilm formation in others. The molecular basis for this phenotypic variability was investigated using two related strains: Newman, in which biofilm formation was inhibited by chelators, and 10833, which formed strong biofilms in the presence of chelators. It was found that deletion of the gene encoding the surface adhesin clumping factor B (clfB) completely eliminated chelator-induced biofilm formation in strain 10833. The role of ClfB in biofilm formation activity in chelators was confirmed in additional strains. It was concluded that biofilm-forming ability varies strikingly depending on strain background, and that ClfB is involved in biofilm formation in the presence EGTA and citrate. These results suggest that subinhibitory doses of chelating agents in catheter lock solutions may actually augment biofilm formation in certain strains of S. aureus, and emphasize the importance of using these agents appropriately so that inhibitory doses are achieved consistently. PMID:22516131

  12. Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

    PubMed Central

    Kumari, Namita; Iordanskiy, Sergey; Kovalskyy, Dmytro; Breuer, Denitra; Niu, Xiaomei; Lin, Xionghao; Xu, Min; Gavrilenko, Konstantin; Kashanchi, Fatah; Dhawan, Subhash

    2014-01-01

    HIV-1 transcription is activated by the Tat protein, which recruits CDK9/cyclin T1 to the HIV-1 promoter. CDK9 is phosphorylated by CDK2, which facilitates formation of the high-molecular-weight positive transcription elongation factor b (P-TEFb) complex. We previously showed that chelation of intracellular iron inhibits CDK2 and CDK9 activities and suppresses HIV-1 transcription, but the mechanism of the inhibition was not understood. In the present study, we tested a set of novel iron chelators for the ability to inhibit HIV-1 transcription and elucidated their mechanism of action. Novel phenyl-1-pyridin-2yl-ethanone (PPY)-based iron chelators were synthesized and examined for their effects on cellular iron, HIV-1 inhibition, and cytotoxicity. Activities of CDK2 and CDK9, expression of CDK9-dependent and CDK2-inhibitory mRNAs, NF-κB expression, and HIV-1- and NF-κB-dependent transcription were determined. PPY-based iron chelators significantly inhibited HIV-1, with minimal cytotoxicity, in cultured and primary cells chronically or acutely infected with HIV-1 subtype B, but they had less of an effect on HIV-1 subtype C. Iron chelators upregulated the expression of IκB-α, with increased accumulation of cytoplasmic NF-κB. The iron chelators inhibited CDK2 activity and reduced the amount of CDK9/cyclin T1 in the large P-TEFb complex. Iron chelators reduced HIV-1 Gag and Env mRNA synthesis but had no effect on HIV-1 reverse transcription. In addition, iron chelators moderately inhibited basal HIV-1 transcription, equally affecting HIV-1 and Sp1- or NF-κB-driven transcription. By virtue of their involvement in targeting several key steps in HIV-1 transcription, these novel iron chelators have the potential for the development of new therapeutics for the treatment of HIV-1 infection. PMID:25155598

  13. Rates of nickel(II) capture from complexes with NTA, EDDA, and related tetradentate chelating agents by the hexadentate chelating agents EDTA and CDTA: Evidence of a "semijunctive" ligand exchange pathway

    NASA Astrophysics Data System (ADS)

    Boland, Nathan E.; Stone, Alan T.

    2017-09-01

    Many siderophores and metallophores produced by soil organisms, as well as anthropogenic chelating agent soil amendments, rely upon amine and carboxylate Lewis base groups for metal ion binding. UV-visible spectra of metal ion-chelating agent complexes are often similar and, as a consequence, whole-sample absorbance measurements are an unreliable means of monitoring the progress of exchange reactions. In the present work, we employ capillary electrophoresis to physically separate Ni(II)-tetradentate chelating agent complexes (NiL) from Ni(II)-hexadentate chelating agent complexes (NiY) prior to UV detection, such that progress of the reaction NiL + Y → NiY + L can be conveniently monitored. Rates of ligand exchange for Ni(II) are lower than for other +II transition metal ions. Ni(II) speciation in environmental media is often under kinetic rather than equilibrium control. Nitrilotriacetic acid (NTA), with three carboxylate groups all tethered to a central amine Lewis base group, ethylenediamine-N,N‧-diacetic acid (EDDA), with carboxylate-amine-amine-carboxylate groups arranged linearly, plus four structurally related compounds, are used as tetradentate chelating agents. Ethylenediaminetetraacetic acid (EDTA) and the structurally more rigid analog trans-cyclohexaneethylenediaminetetraacetic acid (CDTA) are used as hexadentate chelating agents. Effects of pH and reactant concentration are explored. Ni(II) capture by EDTA was consistently more than an order of magnitude faster than capture by CDTA, and too fast to quantify using our capillary electrophoresis-based technique. Using NiNTA as a reactant, Ni(II) capture by CDTA is independent of CDTA concentration and greatly enhanced by a proton-catalyzed pathway at low pH. Using NiEDDA as reactant, Ni(II) capture by CDTA is first order with respect to CDTA concentration, and the contribution from the proton-catalyzed pathway diminished by CDTA protonation. While the convention is to assign either a disjunctive

  14. The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial

    PubMed Central

    van Eijk, Lucas T.; Heemskerk, Suzanne; van der Pluijm, Rob W.; van Wijk, Susanne M.; Peters, Wilbert H.M.; van der Hoeven, Johannes G.; Kox, Matthijs; Swinkels, Dorine W; Pickkers, Peter

    2014-01-01

    In this double-blind randomized placebo-controlled trial involving 30 healthy male volunteers we investigated the acute effects of iron loading (single dose of 1.25 mg/kg iron sucrose) and iron chelation therapy (single dose of 30 mg/kg deferasirox) on iron parameters, oxidative stress, the innate immune response, and subclinical organ injury during experimental human endotoxemia. The administration of iron sucrose induced a profound increase in plasma malondialdehyde 1 h after administration (433±37% of baseline; P<0.0001), but did not potentiate the endotoxemia-induced increase in malondialdehyde, as was seen 3 h after endotoxin administration in the placebo group (P=0.34) and the iron chelation group (P=0.008). Endotoxemia resulted in an initial increase in serum iron levels and transferrin saturation that was accompanied by an increase in labile plasma iron, especially when transferrin saturation reached levels above 90%. Thereafter, serum iron decreased to 51.6±9.7% of baseline at T=8 h in the placebo group versus 84±15% and 60.4±8.9% of baseline at 24 h in the groups treated with iron sucrose and deferasirox, respectively. No significant differences in the endotoxemia-induced cytokine response (TNF-α, IL-6, IL-10 and IL-1RA), subclinical vascular injury and kidney injury were observed between groups. However, vascular reactivity to noradrenalin was impaired in the 6 subjects in whom labile plasma iron was elevated during endotoxemia as opposed to those in whom no labile plasma iron was detected (P=0.029). In conclusion, a single dose of iron sucrose does not affect the innate immune response in a model of experimental human endotoxemia, but may impair vascular reactivity when labile plasma iron is formed. (Clinicaltrials.gov identifier:01349699) PMID:24241495

  15. Structure-activity relationships of novel salicylaldehyde isonicotinoyl hydrazone (SIH) analogs: iron chelation, anti-oxidant and cytotoxic properties.

    PubMed

    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.

  16. Effect of age and caloric restriction on bleomycin-chelatable and nonheme iron in different tissues of C57BL/6 mice.

    PubMed

    Sohal, R S; Wennberg-Kirch, E; Jaiswal, K; Kwong, L K; Forster, M J

    1999-08-01

    The objective of this study was to test the hypothesis that the widely observed age-associated increase in the amounts of macromolecular oxidative damage is due to an elevation in the availability of redox-active iron, that is believed to catalyze the scission of H2O2 to generate the highly reactive hydroxyl radical. Concentrations of bleomycin-chelatable iron and nonheme iron were measured in various tissues and different regions of the brain of mice fed on ad libitum (AL) or a calorically restricted (to 60% of AL) diet at different ages. The concentrations of these two pools of iron varied markedly as a function of tissue, age, and caloric intake. There was no consistent ratio between the amounts of nonheme and the bleomycin-chelatable iron pools across these conditions. Nonheme iron concentration increased with age in the liver, kidney, heart, striatum, hippocampus, midbrain and cerebellum of AL animals, whereas bleomycin-chelatable iron increased significantly with age only in the liver. Amounts of both nonheme and bleomycin-chelatable iron remained unaltered during aging in the cerebral cortex and hindbrain of AL mice. Caloric restriction had no effect on iron concentration in the brain or heart, but caused a marked increase in the concentration of both bleomycin-chelatable and nonheme iron in the liver and the kidney. The results do not support the hypothesis that accumulation of oxidative damage with age, or its attenuation by CR, are associated with corresponding variations in redox-active iron.

  17. Nanoencapsulation of DMSA monoester for better therapeutic efficacy of the chelating agent against arsenic toxicity.

    PubMed

    Yadav, Abhishek; Mathur, Rashi; Samim, Mohammed; Lomash, Vinay; Kushwaha, Pramod; Pathak, Uma; Babbar, Anil Kumar; Flora, Swaran Jeet Singh; Mishra, Anil Kumar; Kaushik, Mahabir Parshad

    2014-04-01

    Exposure to toxic metals remains a widespread occupational and environmental problem in world. Chelation therapy is a mainstream treatment used to treat heavy metal poisoning. This paper describes the synthesis, characterization and therapeutic evaluation of monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA)-encapsulated polymeric nanoparticles as a detoxifying agent for arsenic poisoning. Polymeric nanoparticles entrapping the DMSA monoester, which can evade the reticulo-endothelial system and have a long circulation time in the blood, were prepared. Particle characterization was carried out by transmission electron microscopy and dynamic light scattering. An in vivo study was conducted to investigate the therapeutic efficacy of MiADMSA-encapsulated polymeric nanoparticles (nano- MiADMSA; 50 mg/kg orally for 5 days) and comparison drawn with bulk MiADMSA. Swiss albino mice exposed to sodium arsenite for 4 weeks were treated for 5 days to evaluate alterations in blood, brain, kidney and liver oxidative stress variables. The study also evaluated the histopathological changes in tissues and the chelating potential of the nanoformulation. Our results show that nano-MiADMSA have a narrow size distribution in the 50-nm range. We observed an enhanced chelating potential of nano-MiADMSA compared with bulk MiADMSA as evident in the reversal of biochemical changes indicative of oxidative stress and efficient removal of arsenic from the blood and tissues. Histopathological changes and urinary 8-OHdG levels also prove better therapeutic efficacy of the novel formulation for arsenic toxicity. The results from our study show better therapeutic efficacy of nano-MiADMSA in removing arsenic burden from the brain and liver.

  18. The effect of peroral administration of amino acid-chelated iron to pregnant sows in preventing sow and piglet anaemia.

    PubMed

    Egeli, A K; Framstad, T; Grønningen, D

    1998-01-01

    Two trials were performed in 2 different pig herds. In Trial 1, 9 pregnant Norwegian landrace sows were given a supplement in the feed of about 300 mg iron daily as amino acid-chelated iron (Bio-plex) during the last 3 weeks of gestation. Ten sows were included as controls. In Trial 2, 10 sows were fed a supplement of about 650 mg iron daily as glutamic acid-chelated iron (Super Fe-MAX) during the same period of pregnancy as in Trial 1. Twenty-two sows were included as controls. Blood samples were taken from the sows at the start of the experiment and on the day after parturition. The sows in Trial 1 were also bled at weaning 5 weeks after parturition. The piglets were weighted and blood samples collected 24 +/- 12 h after birth. Livers were taken from 65 piglets, which were either still-born or which died or were euthanised as one-day olds, and examined for iron content. The erythrocyte count (RBC), haemoglobin concentration (HGB), mean cell volume (MCV), erythrocyte distribution width (RDW), and haemoglobin distribution width (HDW) in blood were measured. Haematocrit (HCT), mean cell haemoglobin (MCH), and mean cell haemoglobin concentration (MCHC) were also estimated. Blood serum was analysed for total proteins, albumin, serum Fe, and total iron-binding capacity (TIBC). A slight increase in HGB and RBC in the piglets from the iron-treated sows compared with the controls was found in Trial 1, but this was considered to be of no practical importance. None of the other measured parameters were influenced by treating the pregnant sows with amino acid-chelated iron.

  19. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. 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

  1. A Young Adult with Unintended Acute Intravenous Iron Intoxication Treated with Oral Chelation: The Use of Liver Ferriscan for Diagnosing and Monitoring Tissue Iron Load

    PubMed Central

    Yassin, Mohamed; Soliman, Ashraf T; De Sanctis, Vincenzo; Moustafa, Abbas; Samaan, Sandra Abou; Nashwan, Abdulqadir

    2017-01-01

    Acute iron intoxication (FeI) in humans has not been adequately studied. The manifestation of FeI, defined as a serum iron concentration >300 μg/dL (55 μmol/L) within 12 hours of ingestion, include various symptoms appearing in progressive stages. Systemic toxicity is expected with an intake of 60 mg/kg. A 27-year-old female nurse presented with unintended acute intravenous iron intoxication (FeI) a week after self-injecting herself with 20 ampoules of IV iron (4,000 mg elemental iron, 60 mg/kg). She had stable vital signs and mild hepatic tenderness. Hepatic MRI (Ferriscan®) showed a moderate/severe liver iron content (LIC: 9 mg/g dry tissue). Her hemogram, electrolytes, hepatic and renal functions were normal. Based on the high dose of iron received and her elevated LIC, chelation therapy was advised. She accepted only oral therapy and was started on deferasirox at a dose of 30 mg/kg daily. This oral chelation proved to be effective in clearing her hepatic iron overload after six months (LIC: 2 mg/g dry tissue), without side effects. This case also proved the value of Ferriscan® in diagnosing the degree of hepatic FeI and monitoring therapy to achieve a safe level of LIC. PMID:28101313

  2. The use of chelating agents in the remediation of metal-contaminated soils: a review.

    PubMed

    Lestan, Domen; Luo, Chun-ling; Li, Xiang-dong

    2008-05-01

    This paper reviews current remediation technologies that use chelating agents for the mobilization and removal of potentially toxic metals from contaminated soils. These processes can be done in situ as enhanced phytoextraction, chelant enhanced electrokinetic extraction and soil flushing, or ex situ as the extraction of soil slurry and soil heap/column leaching. Current proposals on how to treat and recycle waste washing solutions after soil is washed are discussed. The major controlling factors in phytoextraction and possible strategies for reducing the leaching of metals associated with the application of chelants are also reviewed. Finally, the possible impact of abiotic and biotic soil factors on the toxicity of metals left after the washing of soil and enhanced phytoextraction are briefly addressed.

  3. Well completion technology. Chelating agent solves scale problem to halt production slide in Prudhoe Bay

    SciTech Connect

    Not Available

    1983-12-12

    Problems associated with scale deposition and the chemistry affecting Sadlerochit reservoir brine in Prudhoe Bay wells were investigated. It was found that the Sadlerochit Formation cannot be exposed to calcium chloride (CaCl/sub 2/) brine, either as a completion fluid or as a spent acid. The scale precipitate builds up, even though hydrochloric acid may dissolve the scale temporarily, and eventually exacerbates the problem. The technique showing the most promise in combating the problem proved to be use of a chelating agent to hold the dissolved scale in solution. The organic form that demonstrated all requisite properties was disodium dihydrogen EDTA. The EDTA matrix acid treatment is used only in wells identified as having the special case condition of sensitivity to CaCl/sub 2/ brine.

  4. Effects of pH, glucose, and chelating agents on lethality of paraquat to Escherichia coli.

    PubMed Central

    Minakami, H; Kitzler, J W; Fridovich, I

    1990-01-01

    Retention of paraquat by Escherichia coli B was greatest after exposure at pH 9.0 and was progressively less after exposure at pH 7.0 and 5.0, respectively. This retained paraquat was capable of persistent growth inhibition. Uptake and retention of paraquat by E. coli B was dependent upon a carbon source, such as glucose. Under comparable conditions E. coli K-12 did not retain paraquat. The lethality of paraquat was seen in TSY medium but not in VB medium. The addition of Soytone, tryptone, or yeast extract, to the VB medium allowed the lethality of paraquat to be seen. A variety of chelating agents, including EDTA, 8-hydroxyquinoline, and o-phenanthroline, prevented the lethal effect of paraquat in TSY medium. Although EDTA protected against the lethality of paraquat, it did not protect against its bacteriostatic effect. PMID:2404952

  5. Evaluation of a PACAP Peptide Analogue Labeled with (68)Ga Using Two Different Chelating Agents.

    PubMed

    Kumar, Pardeep; Tripathi, Sushil Kumar; Chen, Chang-Po; Mehta, Neil; Paudyal, Bishnuhari; Wickstrom, Eric; Thakur, Mathew L

    2016-02-01

    The authors have conjugated chelating agents (DOTA and NODAGA) with a peptide (pituitary adenylate cyclase-activating peptide [PACAP] analogue) that has a high affinity for VPAC1 receptors expressed on cancer cells. To determine a suitable chelating agent for labeling with (68)Ga, they have compared the labeling kinetics and stability of these peptide conjugates. For labeling, (68)GaCl3 was eluted in 0.1 M HCl from a [(68)Ge-(68)Ga] generator. The influences of peptide concentration, pH, and temperature on the radiolabeling efficiency were studied. The stability was evaluated in saline, human serum, DTPA, transferrin, and metallic ions (FeCl3, CaCl2, and ZnCl2). Cell binding assay was performed using human breast cancer cells (T47D). Tissue biodistribution was studied in normal athymic nude mice. Optimal radiolabeling (>95.0%) of the DOTA-peptide conjugates required a higher (50°C-90°C) temperature and 10 minutes of incubation at pH 2-5. The NODAGA-peptide conjugate needed incubation only at 25°C for 10 minutes. Both radiocomplexes were stable in saline, serum, as well as against transchelation and transmetallation. Cell binding at 37°C for 15 minutes of incubation with (68)Ga-NODAGA-peptide was 34.0% compared to 24.5% for (68)Ga-DOTA-peptide. Tissue biodistribution at 1 hour postinjection of both (68)Ga-labeled peptide conjugates showed clearance through the kidneys. NODAGA-peptide showed more convenient radiolabeling features than that of DOTA-peptide.

  6. The novel multitarget iron chelating and propargylamine drug M30 affects APP regulation and processing activities in Alzheimer's disease models.

    PubMed

    Amit, Tamar; Bar-Am, Orit; Mechlovich, Danit; Kupershmidt, Lana; Youdim, Moussa B H; Weinreb, Orly

    2017-09-01

    In many of the neurodegenerative diseases, such as Alzheimer's disease (AD) and AD-related disorders, as well as in the regular ageing process, excessive generation of oxidative stress (OS) and accumulation of iron levels and deposition have been observed in specific affected-brain regions and thus, regarded as contributing factors to the pathogenesis of the diseases. In AD, iron promotes amyloid β (Aβ) neurotoxicity by producing free radical damage and OS in brain areas affected by neurodegeneration, presumably by facilitating the aggregation of Aβ. In addition, it was shown that iron modulates intracellular levels of the holo amyloid precursor protein (APP) by iron-responsive elements (IRE) RNA stem loops in the 5' untranslated region (5'UTR) of the APP transcript. As a consequence of these observations, iron chelation is one of the major new therapeutic strategies for the treatment of AD. This review describes the benefits and importance of the multimodal brain permeable chimeric iron-chelating/propargylamine drug M30, concerning its neuroprotective/neurorestorative inter-related activities relevant of the pathological features ascribed to AD, with a special focus on the effect of the drug on APP regulation and processing. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Oral iron chelating therapy. A single center interim report on deferiprone (L1) in thalassemia.

    PubMed

    Mazza, P; Amurri, B; Lazzari, G; Masi, C; Palazzo, G; Spartera, M A; Giua, R; Sebastio, A M; Suma, V; De Marco, S; Semeraro, F; Moscogiuri, R

    1998-06-01

    Deferiprone (L1) is a largely studied oral chelator in clinical setting, however, no definite conclusions concerning efficacy and toxicity still could be drawn. In an ongoing prospective trial with L1, we evaluated the efficacy and tolerance-toxicity in patients with thalassemia major previously treated by desferrioxamine (DFO); the specific aim of the study is to demonstrate that L1 could be an alternative to DFO in some patients with an acceptable toxicity. Sixty-nine patients over 13 years of age with poor compliance to DFO were considered for the study. The design included a liver biopsy before starting L1 in all patients in order to define liver siderosis either by histologic grading or by hepatic iron concentration (HIC); only patients with a minimum HIC of 4 mg/g dry weight entered the study. A repetition of the liver biopsy after one year of L1 was planned; further evaluations included serum ferritin, plasma iron, transferrin TIBC and iron urine excretion. L1 was given at 70 mg/kg/day in three divided doses. Toxicity was monitored either clinically or by controlling liver, kidney and marrow function by specific tests. Concerning clinical characteristics 52 patients showed hypogonadism (78%), 39 growth retardation (58%), 6 diabetes (9%), 4 cardiomyopathy (6%), 9 hypothyroidism (12%); 45 patients had chronic liver damage (65%). We focus this report on data collected in a group of 29 patients with a minimum follow-up of one year (14-33 months). The mean ferritin value was 3748 ng/mL (range: 200-10,000) and 2550 ng/mL (range: 80-14,500), before and while on L1 therapy, respectively (p = 0.001); the mean sideruria changed from 17.25 mg/dL (range: 5.4-50) to 20.98 mg/dL (range: 10-40), on DFO and L1, respectively (p = 0.078); the ratio between plasma iron (sideremia) and transferrin TIBC changed from 0.96 with DFO to 0.86 with L1 (0.014). A correlation with grade of liver siderosis and serum ferritin (p = 0.069) and iron urine excretion (p = 0.008) was recorded

  8. 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

  9. The Oral Iron Chelator, Deferasirox, Reverses the Age-Dependent Alterations in Iron and Amyloid-β Homeostasis in Rat Brain: Implications in the Therapy of Alzheimer's Disease.

    PubMed

    Banerjee, Priyanjalee; Sahoo, Arghyadip; Anand, Shruti; Bir, Aritri; Chakrabarti, Sasanka

    2016-01-01

    The altered metabolism of iron impacts the brain function in multiple deleterious ways during normal aging as well as in Alzheimer's disease. We have shown in this study that chelatable iron accumulates in the aged rat brain along with overexpression of transferrin receptor 1 (TfR1) and ferritin, accompanied by significant alterations in amyloid-β (Aβ) peptide homeostasis in the aging brain, such as an increased production of the amyloid-β protein precursor, a decreased level of neprilysin, and increased accumulation of Aβ42. When aged rats are given daily the iron chelator, deferasirox, over a period of more than 4 months starting from the 18th month, the age-related accumulation of iron and overexpression of TfR1 and ferritin in the brain are significantly prevented. More interestingly, the chelator treatment also considerably reverses the altered Aβ peptide metabolism in the aging brain implying a significant role of iron in the latter phenomenon. Further, other results indicate that iron accumulation results in oxidative stress and the activation of NF-κB in the aged rat brain, which are also reversed by the deferasirox treatment. The analysis of the results together suggests that iron accumulation and oxidative stress interact at multiple levels that include transcriptional and post-transcriptional mechanisms to bring about changes in the expression levels of TfR1 and ferritin and also alterations in Aβ peptide metabolism in the aging rat brain. The efficacy of deferasirox in preventing age-related changes in iron and Aβ peptide metabolism in the aging brain, as shown here, has obvious therapeutic implications for Alzheimer's disease.

  10. Relevant interactions of antimicrobial iron chelators and membrane models revealed by nuclear magnetic resonance and molecular dynamics simulations.

    PubMed

    Coimbra, João T S; Moniz, Tânia; Brás, Natércia F; Ivanova, Galya; Fernandes, Pedro A; Ramos, Maria J; Rangel, Maria

    2014-12-18

    The dynamics and interaction of 3-hydroxy-4-pyridinone fluorescent iron chelators, exhibiting antimicrobial properties, with biological membranes were evaluated through NMR and molecular dynamics simulations. Both NMR and MD simulation results support a strong interaction of the chelators with the lipid bilayers that seems to be strengthened for the rhodamine containing compounds, in particular for compounds that include ethyl groups and a thiourea link. For the latter type of compounds the interaction reaches the hydrophobic core of the lipid bilayer. The molecular docking and MD simulations performed for the potential interaction of the chelators with DC-SIGN receptors provide valuable information regarding the cellular uptake of these compounds since the results show that the fluorophore fragment of the molecular framework is essential for an efficient binding. Putting together our previous and present results, we put forward the hypothesis that all the studied fluorescent chelators have access to the cell, their uptake occurs through different pathways and their permeation properties correlate with a better access to the cell and its compartments and, consequently, with the chelators antimicrobial properties.

  11. 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

  12. Comparison of food antioxidants and iron chelators in two cellular free radical assays: strong protection by luteolin.

    PubMed

    Hofer, Tim; Jørgensen, Trond Ø; Olsen, Ragnar L

    2014-08-20

    Liver (HepG2) cells were incubated with 21 edible flavonoids, carotenoids, polyunsaturated fatty acid (PUFA) chromones, and metal chelators for 1 h, washed in PBS, and challenged in the cellular antioxidant activity (CAA) and the cellular lipid peroxidation antioxidant activity (CLPAA) assays. These microplate format assays assess the compounds' ability to protect against cytosolic peroxyl radicals (CAA) and induced membrane lipid peroxidation (CLPAA), respectively. Incubation encompassing a broad compound concentration range determined half-maximal inhibitory concentrations (IC(50)) by using sigmoidal curve fits. Overall, considering both assays, luteolin offered the greatest protection. The carotenoid astaxanthin offered only modest protection, whereas β-carotene was ineffective. Subtle structural differences between flavonoids were found to have amplified effects on protective abilities, and mechanisms of flavonoid antioxidant action are discussed. Membrane-permeable iron chelators (deferasirox and SIH) offered strong protective effects in CLPAA, but not in CAA, suggesting that CLPAA is dependent on membrane-associated free iron ions.

  13. 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

  14. Effects of liming on potential oxalate secretion and iron chelation of beech ectomycorrhizal root tips.

    PubMed

    Rineau, François; Garbaye, Jean

    2010-08-01

    Liming is used to counteract forest decline induced by soil acidification. It consists of Ca and Mg input to forest soil and not only restores tree mineral nutrition but also modifies the availability of nutrients in soil. Ectomycorrhizal (ECM) fungi are involved in mineral nutrient uptake by trees and can recover them through dissolution of mineral surface. Oxalate and siderophore secretion are considered as the main agents of mineral weathering by ECMs. Here, we studied the effects of liming on the potential oxalate secretion and iron complexation by individual beech ECM root tips. Results show that freshly excised Lactarius subdulcis root tips from limed plots presented a high potential oxalate exudation of 177 μM tip(-1) h(-1). As this ECM species distribution is very dense, it is likely that, in the field, oxalate concentrations in the vicinity of its clusters could be very high. This points out that not only extraradical mycelium but also ECM root tips of certain species can contribute significantly to mineral weathering. Nonmetric multidimensional scaling (NMDS) separated potential oxalate production by ECM root tips in limed and untreated plots, and this activity was mainly driven by L. subdulcis ECMs, but NMDS on potential activity of iron mobilization by ECM root tips did not show a difference between limed and untreated plots. As the mean oxalate secretion did not significantly correlated with the mean iron mobilization by ECM morphotype, we conclude that iron complexation was due to either other organic acids or to siderophores.

  15. Transient Proteotoxicity of Bacterial Virulence Factor Pyocyanin in Renal Tubular Epithelial Cells Induces ER-Related Vacuolation and Can Be Efficiently Modulated by Iron Chelators

    PubMed Central

    Mossine, Valeri V.; Waters, James K.; Chance, Deborah L.; Mawhinney, Thomas P.

    2016-01-01

    Persistent infections of biofilm forming bacteria, such as Pseudomonas aeruginosa, are common among human populations, due to the bacterial resistance to antibiotics and other adaptation strategies, including release of cytotoxic virulent factors such as pigment pyocyanin (PCN). Urinary tract infections harbor P. aeruginosa strains characterized by the highest PCN-producing capacity, yet no information is available on PCN cytotoxicity mechanism in kidney. We report here that renal tubular epithelial cell (RTEC) line NRK-52E responds to PCN treatments with paraptosis-like activity features. Specifically, PCN-treated cells experienced dilation of endoplasmic reticulum (ER) and an extensive development of ER-derived vacuoles after about 8 h. This process was accompanied with hyper-activation of proteotoxic stress-inducible transcription factors Nrf2, ATF6, and HSF-1. The cells could be rescued by withdrawal of PCN from the culture media before the vacuoles burst and cells die of non-programmed necrosis after about 24–30 h. The paraptosis-like activity was abrogated by co-treatment of the cells with metal-chelating antioxidants. A microscopic examination of cells co-treated with PCN and agents aiming at a variety of the cellular stress mediators and pathways have identified iron as a single most significant co-factor of the PCN cytotoxicity in the RTECs. Among biologically relevant metal ions, low micromolar Fe2+ specifically mediated anaerobic oxidation of glutathione by PCN, but catechol derivatives and other strong iron complexing agents could inhibit the reaction. Our data suggest that iron chelation could be considered as a supplementary treatment in the PCN-positive infections. PMID:27613716

  16. 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)

  17. 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)

  18. 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).

  19. 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.

  20. 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

  1. Competitive binding of Pu and Am with bone mineral and novel chelating agents.

    PubMed

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

    2003-01-01

    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 CaNa3DTPA or ZnNa3DTPA. This study, using an established in vitro system, compared removal of Pu and Am bound to bone mineral by ZnNa3DTPA 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 microM 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 ZnNa3DTPA removed only 0.086%. The most effective ligands for Am removal (100 microM, 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 ZnNa3DTPA 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.

  2. 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.

  3. 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.

  4. Favorable pendant-amino metal chelation in VX nerve agent model systems.

    PubMed

    Bandyopadhyay, Indrajit; Kim, Min Jeong; Lee, Yoon Sup; Churchill, David G

    2006-03-16

    We have performed DFT computational studies [B3LYP, 6-31+G] to obtain metal ion coordination isomers of VX-Me [MeP(O)(OMe)(SCH2CH2NMe2)], a model of two of the most lethal nerve agents: VX [MeP(O)(OEt)(SCH2CH2N(iPr)2)] and Russian-VX [MeP(O)(OCH2CHMe2)(SCH2CH2N(Et)2)]. Our calculations involved geometry optimizations of the neutral VX-Me model as well as complexes with H+, Li+, Na+, K+, Be2+, Mg2+, and Ca2+ that yielded 2-8 different stable chelation modes for each ion that involved mainly mono- and bidentate binding. Importantly, our studies revealed that the [O(P),N] bidentate binding mode, long thought to be the active mode in differentiating the hydrolytic path of VX from other nerve agents, was the most stable for all ions studied here. Binding energy depended mainly on ionic size as well as charge, with binding energies ranging from 364 kcal mol(-1) for Be2+ to 33 kcal mol(-1) for K+. Furthermore, calculated NMR shifts for VX-Me correlate to experimental values of VX.

  5. 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.

  6. Hydroxyiminodisuccinic acid (HIDS): A novel biodegradable chelating ligand for the increase of iron bioavailability and arsenic phytoextraction.

    PubMed

    Rahman, M Azizur; Hasegawa, H; Kadohashi, K; Maki, T; Ueda, K

    2009-09-01

    The influence of biodegradable chelating ligands on arsenic and iron uptake by hydroponically grown rice seedlings (Oryza sativa L.) was investigated. Even though the growth solution contained sufficient Fe, the growth of rice seedlings gradually decreased up to 76% with the increase of pH of the solution from 7 to 11. Iron forms insoluble ferric hydroxide complexes at neutral or alkaline pH in oxic condition. Chelating ligands produce soluble 'Fe-ligand complex' which assist Fe uptake in plants. The biodegradable chelating ligand hydroxyiminodisuccinic acid (HIDS) was more efficient then those of ethylenediaminetetraacetic acid (EDTA), ethylenediaminedisuccinic acid (EDDS), and iminodisuccinic acid (IDS) in the increase of Fe uptake and growth of rice seedling. A total of 79+/-20, 87+/-6, 116+/-15, and 63+/-18mg dry biomass of rice seedlings were produced with the addition of 0.5mM of EDDS, EDTA, HIDS, and IDS in the nutrient solution, respectively. The Fe concentrations in rice tissues were 117+/-15, 82+/-8, 167+/-25, and 118+/-22micromolg(-1) dry weights when 0.25mM of EDDS, EDTA, HIDS, and IDS were added to the nutrient solution, respectively. Most of the Fe accumulated in rice tissues was stored in roots after the addition of chelating ligands in the solution. The results indicate that the HIDS would be a potential alternative to environmentally persistent EDTA for the increase of Fe uptake and plant growth. The HIDS also increased As uptake in rice root though its translocation from root to shoot was not augmented. This study reports HIDS for the first time as a promising chelating ligand for the enhancement of Fe bioavailability and As phytoextraction.

  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.

  8. 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

  9. Determination of a new oral iron chelator, ICL670, and its iron complex in plasma by high-performance liquid chromatography and ultraviolet detection.

    PubMed

    Rouan, M C; Marfil, F; Mangoni, P; Séchaud, R; Humbert, H; Maurer, G

    2001-05-05

    ICL670 is a representative of a new class of orally active tridentate selective iron chelators. Two molecules of ICL670 are required to form a complete hexacoordinate chelate Fe-[ICL670]2 with one ferric iron. A simple and rapid HPLC-UV method for the separate determination of ICL670 and Fe-[ICL670]2 in the plasma of iron-overloaded patients is described. Plasma samples were prepared as rapidly as possible, the tubes being kept at 4 degrees C. Plasma proteins were precipitated with methanol. The supernatant was diluted with water and placed on the refrigerated sample rack of an autosampler before injection. The chromatographic separations were achieved on an Alltima C18 column using 0.05 M Na2HPO4 and 0.01 M tetrabutylammonium hydrogen sulfate-acetonitrile-methanol (41:9:50, v/v/v) as mobile phase. The analytes were detected at 295 nm. Calibration and quality control samples were prepared in normal human plasma. The mean accuracy (n=6) over the entire investigated concentration range 0.25-20 microg/ml ranged from 91 to 109% with a coefficient of variation (C.V.) from 4 to 8% for ICL670, and from 95 to 105% with a C.V. from 2 to 20% for the iron complex. The dissociation of the complex during analysis was shown to be marginal. The iron removal from plasma of iron-overloaded patients by free ICL670 during analysis was low. The in vitro iron transfer from the iron pools of iron-overloaded plasma onto ICL670 was shown to be a slow process.

  10. [Influence of ionizing radiation, application of iron ions and their chelate complexes on the oxidative status of blood serum of rats].

    PubMed

    Riabchenko, N I; Ivannik, B P; Riabchenko, V I; Dzikovskaia, L A

    2011-01-01

    Influence of ionizing radiation, ions of iron and their chelate complexes on the oxidative status of blood serum of rats has been investigated. Animals were irradiated by gamma-rays 60Co at a dose of 4 Gy. Ions of iron and iron chelates with nitrilotriacetic acid and citric acid were introduced into animals intra-abdominally at a doze of 10 mg of iron on 1 kg of body weight. The oxidative status of blood serum was determined according to the estimated content of oxidizing peroxide equivalents which oxidize ferrous iron in ferric iron with the subsequent estimation of ferric iron by means of xylenol orange. We also estimated the total content of iron in blood serum using ferrozine as an indicator. The oxidative status was defined 24 and 96 hours after irradiation and 2 hours after introduction of iron ions and their chelates. The research conducted has shown that the concentration of oxidizing peroxide equivalents in serum and the total iron concentration increase 1.47 times and 1.63 times correspondingly 24 hours after irradiation. The increase in the content of oxidizing peroxide equivalents and iron owing to Fenton's reaction can lead to the appearance of OH* radical and raise the level of damage of nuclear and membrane structures in irradiated cells. 2 hours after introduction of iron ions and their chelates, the content of oxidizing peroxide equivalents increased in the blood serum of irradiated and non-irradiated rats, and the maximum effect was observed when introducing ferrous iron and its chelate with citric acid.

  11. Nitrosothiol Formation and Protection against Fenton Chemistry by Nitric Oxide-induced Dinitrosyliron Complex Formation from Anoxia-initiated Cellular Chelatable Iron Increase*

    PubMed Central

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

    2014-01-01

    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. PMID:24891512

  12. 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. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Lactoferrin inhibits or promotes Legionella pneumophila intracellular multiplication in nonactivated and interferon gamma-activated human monocytes depending upon its degree of iron saturation. Iron-lactoferrin and nonphysiologic iron chelates reverse monocyte activation against Legionella pneumophila.

    PubMed Central

    Byrd, T F; Horwitz, M A

    1991-01-01

    We have been exploring the role of iron in the pathogenesis of the intracellular bacterial pathogen Legionella pneumophila. In previous studies, we have demonstrated that L. pneumophila intracellular multiplication in human monocytes is iron dependent and that IFN gamma-activated monocytes inhibit L. pneumophila intracellular multiplication by limiting the availability of iron. In this study, we have investigated the effect on L. pneumophila intracellular multiplication of lactoferrin, an iron-binding protein which is internalized via specific receptors on monocytes, and of nonphysiologic iron chelates which enter monocytes by a receptor-independent route. Apolactoferrin completely inhibited L. pneumophila multiplication in nonactivated monocytes, and enhanced the capacity of IFN gamma-activated monocytes to inhibit L. pneumophila intracellular multiplication. In contrast, iron-saturated lactoferrin had no effect on the already rapid rate of L. pneumophila multiplication in nonactivated monocytes. Moreover, it reversed the capacity of activated monocytes to inhibit L. pneumophila intracellular multiplication, demonstrating that L. pneumophila can utilize iron from the lactoferrin-lactoferrin receptor pathway. The capacity of iron-lactoferrin to reverse monocyte activation was dependent upon its percent iron saturation and not just its total iron content. Similarly, the nonphysiologic iron chelates ferric nitrilotriacetate and ferric ammonium citrate completely reverse and ferric pyrophosphate partially reversed the capacity of IFN gamma-activated monocytes to inhibit L. pneumophila intracellular multiplication, demonstrating that L. pneumophila can utilize iron derived from nonphysiologic iron chelates internalized by monocytes independently of the transferrin and lactoferrin endocytic pathways. This study suggests that at sites of inflammation, lactoferrin may inhibit or promote L. pneumophila intracellular multiplication in mononuclear phagocytes depending upon

  14. Factors influencing the DNA nuclease activity of iron, cobalt, nickel, and copper chelates.

    PubMed

    Joyner, Jeff C; Reichfield, Jared; Cowan, J A

    2011-10-05

    A library of complexes that included iron, cobalt, nickel, and copper chelates of cyclam, cyclen, DOTA, DTPA, EDTA, tripeptide GGH, tetrapeptide KGHK, NTA, and TACN was evaluated for DNA nuclease activity, ascorbate consumption, superoxide and hydroxyl radical generation, and reduction potential under physiologically relevant conditions. Plasmid DNA cleavage rates demonstrated by combinations of each complex and biological co-reactants were quantified by gel electrophoresis, yielding second-order rate constants for DNA(supercoiled) to DNA(nicked) conversion up to 2.5 × 10(6) M(-1) min(-1), and for DNA(nicked) to DNA(linear) up to 7 × 10(5) M(-1) min(-1). Relative rates of radical generation and characterization of radical species were determined by reaction with the fluorescent radical probes TEMPO-9-AC and rhodamine B. Ascorbate turnover rate constants ranging from 3 × 10(-4) to 0.13 min(-1) were determined, although many complexes demonstrated no measurable activity. Inhibition and Freifelder-Trumbo analysis of DNA cleavage supported concerted cleavage of dsDNA by a metal-associated reactive oxygen species (ROS) in the case of Cu(2+)(aq), Cu-KGHK, Co-KGHK, and Cu-NTA and stepwise cleavage for Fe(2+)(aq), Cu-cyclam, Cu-cyclen, Co-cyclen, Cu-EDTA, Ni-EDTA, Co-EDTA, Cu-GGH, and Co-NTA. Reduction potentials varied over the range from -362 to +1111 mV versus NHE, and complexes demonstrated optimal catalytic activity in the range of the physiological redox co-reactants ascorbate and peroxide (-66 to +380 mV).

  15. Factors Influencing the DNA Nuclease Activity of Iron, Cobalt, Nickel, and Copper Chelates

    PubMed Central

    Joyner, Jeff C.; Reichfield, Jared; Cowan, J. A.

    2012-01-01

    A library of complexes that included iron, cobalt, nickel, and copper chelates of cyclam, cyclen, DOTA, DTPA, EDTA, tripeptide GGH, tetrapeptide KGHK, NTA, and TACN was evaluated for DNA nuclease activity, ascorbate consumption, superoxide and hydroxyl radical generation, and reduction potential under physiologically relevant conditions. Plasmid DNA cleavage rates demonstrated by combinations of each complex and biological coreactants were quantified by gel electrophoresis, yielding second-order rate constants for DNAsupercoiled to DNAnicked conversion up to 2.5 ×106 M-1min-1, and for DNAnicked to DNAlinear up to 7 ×105 M-1min-1. Relative rates of radical generation and characterization of radical species were determined by reaction with the fluorescent radical probe TEMPO-9-AC and rhodamine B. Ascorbate turnover rate constants ranging from 9.1×10-3 to 8.2 min-1 were determined, although many complexes demonstrated no measureable activity. Inhibition and Freifelder-Trumbo analysis of DNA cleavage supported concerted cleavage of dsDNA by a metal associated ROS in the case of Cu2+(aq), Cu-KGHK, Co-KGHK, and Cu-NTA and stepwise cleavage for Fe2+(aq), Cu-cyclam, Cu-cyclen, Co-cyclen, Cu-EDTA, Ni-EDTA, Co-EDTA, Cu-GGH, and Co-NTA. Reduction potentials varied over the range from -362 mV to +1111 mV versus NHE, and complexes demonstrated optimal catalytic activity in the range of the physiological redox coreactants ascorbate and peroxide (-66 to +380 mV). PMID:21815680

  16. Immunological evaluation of β-thalassemia major patients receiving oral iron chelator deferasirox.

    PubMed

    Aleem, Aamer; Shakoor, Zahid; Alsaleh, Khalid; Algahtani, Farjah; Iqbal, Zafar; Al-Momen, Abdulkareem

    2014-07-01

    To determine the immune abnormalities and occurrence of infections in transfusion-dependent β-thalassemia major patients receiving oral iron chelator deferasirox (DFX). An observational study. Hematology Clinics, King Khalid University Hospital, Riyadh, Saudi Arabia, from July to December 2010. Seventeen patients with β-thalassemia major (12 females, median age 26 years) receiving deferasirox (DFX) for a median duration of 27 months were observed for any infections and had their immune status determined. Immune parameters studied included serum immunoglobulins and IgG subclasses, serum complement (C3 and C4) and anti-nuclear antibody (ANA) level, total B and T-lymphocytes, CD4+ and CD8+ counts, CD4+/CD8+ ratio, and natural killer (NK) cells. Immunological parameters of the patients were compared with age, gender, serum ferritin level and splenectomy status. Lymphocyte subsets were also compared with age and gender matched normal controls. A considerable reduction in serum ferritin was achieved by DFX from a median level of 2528 to 1875 μmol/l. Serum IgG levels were increased in 7 patients. Low C4 levels were found in 9 patients. Total B and T-lymphocytes were increased in 14 patients each, while CD4+, CD8+ and NK cells were increased in 13, 12 and 11 patients respectively. Absolute counts for all lymphocyte subsets were significantly higher compared to the normal controls (p ² 0.05 for all parameters). Raised levels of IgG were associated with older age, female gender, splenectomized status and higher serum ferritin levels but this did not reach statistical significance except for the higher ferritin levels (p=0.044). Increased tendency to infections was not observed. Patients with β-thalassemia major receiving DFX exhibited significant immune abnormalities. Changes observed have been described previously, but could be related to DFX. The immune abnormalities were not associated with increased tendency to infections.

  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. 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.

  19. 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.

  20. From early prophylaxis to delayed treatment: Establishing the plutonium decorporation activity window of hydroxypyridinonate chelating agents.

    PubMed

    An, Dahlia D; Kullgren, Birgitta; Jarvis, Erin E; Abergel, Rebecca J

    2017-04-01

    The potential consequences of a major radiological event are not only large-scale external radiation exposure of the population, but also uncontrolled dissemination of, and internal contamination with, radionuclides. When planning an emergency response to radiological and nuclear incidents, one must consider the need for not only post-exposure treatment for contaminated individuals, but also prophylactic measures to protect the workforce facing contaminated areas and patients in the aftermath of such events. In addition to meeting the desired criteria for post-exposure treatments such as safety, ease of administration, and broad-spectrum efficacy against multiple radionuclides and levels of challenge, ideal prophylactic countermeasures must include rapid onset; induce minimal to no performance-decrementing side effects; be compatible with current military Chemical, Biological, Radiological, Nuclear, and Explosive countermeasures; and require minimal logistical burdens. Hydroxypyridinone-based actinide decorporation agents have shown the most promise as decorporation strategies for various radionuclides of concern, including the actinides plutonium and americium. The studies presented here probe the extent of plutonium decorporation efficacy for two chelating agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), from early pre-exposure time points to a delay of up to 7 days in parenteral or oral treatment administration, i.e., well beyond the initial hours of emergency response. Despite delayed treatment after a contamination event, both ligands clearly enhanced plutonium elimination through the investigated 7-day post-treatment period. In addition, a remarkable prophylactic efficacy was revealed for 3,4,3-LI(1,2-HOPO) with treatment as early as 48 h before the plutonium challenge. This work provides new perspectives in the indication and use of experimental actinide decorporation treatments.

  1. Radiochemical studies of 99mTc complexes of modified cysteine ligands and bifunctional chelating agents.

    PubMed

    Pillai, M R; Kothari, K; Banerjee, S; Samuel, G; Suresh, M; Sarma, H D; Jurisson, S

    1999-07-01

    The synthesis of four novel ligands using the amino-acid cysteine and its ethyl carboxylate derivative is described. The synthetic method involves a two-step procedure, wherein the intermediate Schiff base formed by the condensation of the amino group of the cysteine substrate and salicylaldehyde is reduced to give the target ligands. The intermediates and the final products were characterized by high resolution nuclear magnetic resonance spectroscopy. Complexation studies of the ligands with 99mTc were optimized using stannous tartrate as the reducing agent under varying reaction conditions. The complexes were characterized using standard quality control techniques such as thin layer chromatography, paper electrophoresis, and paper chromatography. Lipophilicities of the complexes were estimated by solvent extraction into chloroform. Substantial changes in net charge and lipophilicity of the 99mTc complexes were observed on substituting the carboxylic acid functionality in ligands I and II with the ethyl carboxylate groups (ligands II and IV). All the ligands formed 99mTc complexes in high yield. Whereas the complexes with ligands I and II were observed to be hydrophilic in nature and not extractable into CHCl3, ligands III and IV resulted in neutral and lipophilic 99mTc complexes. The 99mTc complex with ligand II was not stable and on storage formed a hydrophilic and nonextractable species. The biodistribution of the complexes of ligands I and II showed that they cleared predominantly through the kidneys, whereas the complexes with ligands III and IV were excreted primarily through the hepatobiliary system. No significant brain uptake was observed with the 99mTc complexes with ligands III and IV despite their favorable properties of neutrality, lipophilicity, and conversion into a hydrophilic species. These ligands offer potential for use as bifunctional chelating agents.

  2. 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.

  3. An Intracellular Iron Chelator Pleiotropically Suppresses Enzymatic and Growth Defects of Superoxide Dismutase-Deficient Escherichia coli

    PubMed Central

    Maringanti, Sujatha; Imlay, James A.

    1999-01-01

    Mutants of Escherichia coli that lack cytoplasmic superoxide dismutase (SOD) exhibit auxotrophies for sulfur-containing, branched-chain, and aromatic amino acids and cannot catabolize nonfermentable carbon sources. A secondary-site mutation substantially relieved all of these growth defects. The requirement for fermentable carbon and the branched-chain auxotrophy occur because superoxide (O2−) leaches iron from the [4Fe-4S] clusters of a family of dehydratases, thereby inactivating them; the suppression of these phenotypes was mediated by the restoration of activity to these dehydratases, evidently without changing the intracellular concentration of O2−. Cloning, complementation, and sequence analysis identified the suppressor mutation to be in dapD, which encodes tetrahydrodipicolinate succinylase, an enzyme involved in diaminopimelate and lysine biosynthesis. A block in dapB, which encodes dihydrodipicolinate reductase in the same pathway, conferred similar protection. Genetic analysis indicated that the protection stems from the intracellular accumulation of tetrahydro- or dihydrodipicolinate. Heterologous expression in the SOD mutants of the dipicolinate synthase of Bacillus subtilis generated dipicolinate and similarly protected them. Dipicolinates are excellent iron chelators, and their accumulation in the cell triggered derepression of the Fur regulon and a large increase in the intracellular pool of free iron, presumably as a dipicolinate chelate. A fur mutation only partially relieved the auxotrophies, indicating that Fur derepression assists but is not sufficient for suppression. It seems plausible that the abundant internal iron permits efficient reactivation of superoxide-damaged iron-sulfur clusters. This result provides circumstantial evidence that the sulfur and aromatic auxotrophies of SOD mutants are also directly or indirectly linked to iron metabolism. PMID:10368155

  4. Health-Related Quality of Life and Health Utility Values in Beta Thalassemia Major Patients Receiving Different Types of Iron Chelators in Iran.

    PubMed

    Seyedifar, Meysam; Dorkoosh, Farid Abedin; Hamidieh, Amir Ali; Naderi, Majid; Karami, Hossein; Karimi, Mehran; Fadaiyrayeny, Masoomeh; Musavi, Masoumeh; Safaei, Sanaz; Ahmadian-Attari, Mohammad Mahdi; Hadjibabaie, Molouk; Cheraghali, Abdol Majid; Akbari Sari, Ali

    2016-10-01

    Background: Thalassemia is a chronic, inherited blood disorder, which in its most severe form, causes life-threatening anemia. Thalassemia patients not only engage with difficulties of blood transfusion and iron chelating therapy but also have some social challenges and health threatening factors. There are some reports on quality of life in thalassemia patients around the world from southeast of Asia to Italy in Europe and United States. In this study, we tried to evaluate and compare Health Related Quality of life (HRQoL) and the health utility in beta thalassemia major patients receiving different types of iron chelators and living in different socio-economical situations. Subjects and Methods: EQ-5D-3L accompanied by a Visual Analogue Scale (VAS) questionnaire was used. The respondents were patients with beta thalassemia major that were at least 12 years old selected from 3 provinces of Sistan-Blouchestan, Fars and Mazandaran. Comorbidities including heart complication, Diabetes Mellitus and Hepatitis and also types of iron chelators (oral, injection, combination of both) were also asked. Cross tab and ANOVA analysis conducted to evaluate each dimension score and health utility differences between provinces, iron chelation methods, comorbidities, age group and gender. Results: 528 patients answered the questionnaires. The health utility of patients that received oral iron chelator were 0.87 ± .01 for oral iron chelators versus 0.81 ± .01 for injection dosage form (p<0.05). Increase in age was accompanied by decrease in health utility. Females faced more usual activity problems, anxiety and depression. Heart problems were more prevalent in males. Conclusion: This study suggests that the quality of life of beta thalassemia major patients is dependent on type of iron chelation treatment which they received, the gender they have, the comorbidities they suffer and socio-economical situations they live in.

  5. Health-Related Quality of Life and Health Utility Values in Beta Thalassemia Major Patients Receiving Different Types of Iron Chelators in Iran

    PubMed Central

    Seyedifar, Meysam; Dorkoosh, Farid Abedin; Hamidieh, Amir Ali; Naderi, Majid; Karami, Hossein; Karimi, Mehran; Fadaiyrayeny, Masoomeh; Musavi, Masoumeh; Safaei, Sanaz; Ahmadian-Attari, Mohammad Mahdi; Hadjibabaie, Molouk; Cheraghali, Abdol Majid; Akbari Sari, Ali

    2016-01-01

    Background: Thalassemia is a chronic, inherited blood disorder, which in its most severe form, causes life-threatening anemia. Thalassemia patients not only engage with difficulties of blood transfusion and iron chelating therapy but also have some social challenges and health threatening factors. There are some reports on quality of life in thalassemia patients around the world from southeast of Asia to Italy in Europe and United States. In this study, we tried to evaluate and compare Health Related Quality of life (HRQoL) and the health utility in beta thalassemia major patients receiving different types of iron chelators and living in different socio-economical situations. Subjects and Methods: EQ-5D-3L accompanied by a Visual Analogue Scale (VAS) questionnaire was used. The respondents were patients with beta thalassemia major that were at least 12 years old selected from 3 provinces of Sistan-Blouchestan, Fars and Mazandaran. Comorbidities including heart complication, Diabetes Mellitus and Hepatitis and also types of iron chelators (oral, injection, combination of both) were also asked. Cross tab and ANOVA analysis conducted to evaluate each dimension score and health utility differences between provinces, iron chelation methods, comorbidities, age group and gender. Results: 528 patients answered the questionnaires. The health utility of patients that received oral iron chelator were 0.87 ± .01 for oral iron chelators versus 0.81 ± .01 for injection dosage form (p<0.05). Increase in age was accompanied by decrease in health utility. Females faced more usual activity problems, anxiety and depression. Heart problems were more prevalent in males. Conclusion: This study suggests that the quality of life of beta thalassemia major patients is dependent on type of iron chelation treatment which they received, the gender they have, the comorbidities they suffer and socio-economical situations they live in. PMID:27928477

  6. 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.

  7. 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.

  8. The effect of chemical agents, beverages, and spinach on the in vitro solubilization of iron from cooked pinto beans.

    PubMed

    Kojima, N; Wallace, D; Bates, G W

    1981-07-01

    The solubilization of iron from cooked pinto beans was examined using an improved in vitro methodology. The iron content of the beans was found to exist in three populations: 1) that which is spontaneously soluble upon incubation; 2) that which can be mobilized by chelating or reducing agents; and 3) that which is more firmly bound to the insoluble bean residue. These fractions constitute approximately 25, 45, and 30%, respectively, of the bean iron content when using consecutive 30-min incubations at pH 2 and 6. Ascorbic acid is maximally effective in iron mobilization under acidic conditions and acts via iron reduction. Citric acid is maximally effective near pH 6. The combination of ascorbic acid and citric acid leads to the solubilization of 70% of the iron content of the beans. Orange juice also leads to maximal soluble iron, predominantly in the Fe2+ state. Tea severely decreases iron solubility in the system. Only 3% of the iron content of spinach is solubilized by 10 mM ascorbic acid. Whole spinach suspension and the insoluble spinach residue are able to remove iron from solution that was previously solubilized from beans.

  9. Monofunctionalization of Calix[4]arene Tetracarboxylic Acid at the Upper Rim with Isothiocyanate Group: First Bifunctional Chelating Agent for Alpha-Emitter Ac-225

    PubMed Central

    Chen, Xiaoyuan; Ji, Min; Fisher, Darrell R.

    2010-01-01

    A procedure is reported for synthesizing a novel, water-soluble bifunctional chelating agent derived from calix[4]arene. This chelate features tetracarboxylic acid groups at the lower rim as an actinium-225 ionophore, and an isothiocyanate functional group at the upper rim for labeling of the N-terminus of monoclonal antibodies through thiourea linkage. PMID:20651937

  10. Enteric-coated tablet of risedronate sodium in combination with phytic acid, a natural chelating agent, for improved oral bioavailability.

    PubMed

    Kim, Jeong S; Jang, Sun W; Son, Miwon; Kim, Byoung M; Kang, Myung J

    2016-01-20

    The oral bioavailability (BA) of risedronate sodium (RS), an antiresorptive agent, is less than 1% due to its low membrane permeability as well as the formation of non-absorbable complexes with multivalent cations such as calcium ion (Ca(2+)) in the gastrointestinal tract. In the present study, to increase oral BA of the bisphosphonate, a novel enteric-coated tablet (ECT) dosage form of RS in combination with phytic acid (IP6), a natural chelating agent recognized as safe, was formulated. The chelating behavior of IP6 against Ca(2+), including a stability constant for complex formulation was characterized using the continuous variation method. Subsequently, in vitro dissolution profile and in vivo pharmacokinetic profile of the novel ECT were evaluated comparatively with that of the marketed product (Altevia, Sanofi, US), an ECT containing ethylenediaminetetraacetic acid (EDTA) as a chelating agent, in beagle dogs. The logarithm of stability constant for Ca(2+)-IP6 complex, an equilibrium constant approximating the strength of the interaction between two chemicals to form complex, was 19.05, which was 3.9-fold (p<0.05) and 1.7-fold (p<0.05) higher than those of Ca(2+)-RS and Ca(2+)-EDTA complexes. The release profile of RS from both enteric-coated dosage forms was equivalent, regardless of the type of chelating agent. An in vivo absorption study in beagle dogs revealed that the maximum plasma concentration and area under the curve of RS after oral administration of IP6-containing ECT were approximately 7.9- (p<0.05) and 5.0-fold (p<0.05) higher than those of the marketed product at the same dose (35mg as RS). Therefore, our study demonstrates the potential usefulness of the ECT system in combination with IP6 for an oral therapy with the bisphosphonate for improved BA.

  11. Synthesis and Evaluation of Nanoglobular Macrocyclic Mn(II) Chelate Conjugates As Non-Gadolinium(III) MRI Contrast Agents

    PubMed Central

    Tan, Mingqian; Ye, Zhen; Jeong, Eun-Kee; Wu, Xueming; Parker, Dennis L.; Lu, Zheng-Rong

    2011-01-01

    Because of the recent observation of the toxic side effects of Gd(III) based MRI contrast agents in the patients with impaired renal functions, there is a strong interest on developing alternative contrast agents for MRI. In this study, lysine dendrimers with a silsesquioxane core acted as nanoglobular carriers that were conjugated to Mn(II)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate monoamide (Generation 2, 3, 4-DOTA-Mn) to synthesize non-Gd(III) based contrast agents for magnetic resonance imaging (MRI). A generation 3 nanoglobular conjugate of Mn(II)-1,4,7-triaazacyclononane-1,4,7-triacetate-GA amide (G3-NOTA-Mn) was also synthesized and evaluated. The per ion T1 and T2 relaxivities of G2, G3, G4 nanoglobular Mn(II)-DOTA monoamide conjugates decreased with increasing generation of the carriers. The T1 relaxivity of G2, G3, G4 nanoglobular Mn(II)-DOTA conjugates was 3.3, 2.8, 2.4 mM−1sec−1 per Mn(II) chelate at 3 T, respectively. The T1 relaxivity of G3-NOTA-Mn was 3.80 mM−1sec−1 per Mn(II) chelate at 3 T. The nanoglobular macrocyclic Mn(II) chelate conjugates showed good in vivo stability and were readily excreted via renal filtration. The conjugates resulted in much less non-specific liver enhancement than MnCl2 and were effective for contrast enhanced tumor imaging in nude mice bearing MDA-MB-231 breast tumor xenografts at a dose of 0.03 mmol Mn/kg. The nanoglobular macrocyclic Mn(II) chelate conjugates are promising non-gadolinium based MRI contrast agents. PMID:21473650

  12. Introducing saccharic acid as an efficient iron chelate to enhance photo-Fenton degradation of organic contaminants.

    PubMed

    Subramanian, Gokulakrishnan; Madras, Giridhar

    2016-11-01

    The identification of iron chelates that can enhance photo-Fenton degradation is of great interest in the field of advanced oxidation process. Saccharic acid (SA) is a polyhydroxy carboxylic acid and completely non-toxic. Importantly, it can effectively bind Fe(III) as well as induce photoreduction of Fe(III). Despite having these interesting properties, the effect of SA on photo-Fenton degradation has not been studied. Herein, we demonstrate the first assessment of SA as an iron chelate in photo-Fenton process using methylene blue (MB) as a model organic contaminant. Our results demonstrate that SA has the ability to (i) enhance the photo-Fenton degradation of MB by about 11 times at pH 4.5 (ii) intensify photochemical reduction of Fe(III) to Fe(II) by about 17 times and (iii) accelerate the rate of consumption of H2O2 in photo-Fenton process by about 5 times (iv) increase the TOC reduction by about 2 times and (v) improve the photo-Fenton degradation of MB in the presence of a variety of common inorganic ions and organic matter. The influential properties of SA on photo-Fenton degradation is attributed to the efficient photochemical reduction of Fe(III) via LMCT (ligand to metal charge transfer reaction) to Fe(II), which then activated H2O2 to generate OH and accelerated photo-Fenton degradation efficiency. Moreover, the effect of operational parameters such as oxidant: contaminant (H2O2: MB) ratio, catalyst: contaminant (Fe(III)SA: MB) ratio, Fe(III): SA stoichiometry and pH on the degradation of MB by photo-Fenton in the presence of SA is demonstrated. Importantly, SA assisted photo-Fenton caused effective degradation of MB and 4-Chlorophenol under natural sunlight irradiation in natural water matrix. The findings strongly support SA as a deserving iron chelate to enhance photo-Fenton degradation.

  13. 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).

  14. 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.

  15. The role of chelating agents on the structural and magnetic properties of α-Fe2O3 nanoparticles

    NASA Astrophysics Data System (ADS)

    Lima, R. J. S.; Jesus, J. R.; Moura, K. O.; Jesus, C. B. R.; Duque, J. G. S.; Meneses, C. T.

    2011-06-01

    In this work we have studied the role of the addition of chelating agents on the structural and magnetic properties of α-Fe2O3 nanoparticles obtained by the co-precipitation method. The precursors were prepared for the addition of different concentrations of the chelating agents: sucrose and glycerine. To obtain the nanoparticles, these precursors were heated in the temperature range between 200 and 400 °C. The samples have been characterized via x-ray diffraction (XRD), scanning electron microscopy (SEM), and magnetization measurements. The XRD data confirm that the crystalline phase is already formed at temperatures around 200 °C and there is a preferential growth to the (110) crystallographic plane to the sample at 0.01 mol/l of sucrose. Besides, a more careful analysis performed in the XRD, SEM, and zero field cooling and field cooling magnetization data clearly show the dependence of the size, shape, and size distribution of the samples as function of the chelating agent concentration.

  16. Regulation of gene expression in bovine blastocysts in response to oxygen and the iron chelator desferrioxamine.

    PubMed

    Harvey, A J; Kind, K L; Thompson, J G

    2007-07-01

    Low (2%) oxygen conditions during postcompaction culture of bovine blastocysts improve embryo quality and are associated with small increases in the expression of glucose transporter 1 (SLC2A1), anaphase promoting complex (ANAPC1), and myotrophin (MTPN), suggesting a role for oxygen in the regulation of embryo development, mediated through oxygen-sensitive gene expression. However, bovine embryos, to at least the blastocyst stage, lack detectable levels of the key regulator of oxygen-sensitive gene expression, hypoxia-inducible 1 alpha (HIF1A), while the less well-characterized HIF2 alpha protein is readily detectable. Here we report that other key HIF1 regulated genes are not significantly altered in their expression pattern in bovine blastocysts in response to reduced oxygen concentrations postcompaction-with the exception of lactate dehydrogenase A (LDHA), which was significantly increased following 2% oxygen culture. Antioxidant enzymes have been suggested as potential HIF2 target genes, but their expression was not altered following low-oxygen culture in the bovine blastocyst. The addition of desferrioxamine (an iron chelator and inducer of HIF-regulated gene expression) during postcompaction stages significantly increased SLC2A1, LDHA, inducible nitric oxide synthase (NOS2A), and MTPN gene expression in bovine blastocysts, although development to the blastocyst stage was not significantly affected. These results further suggest that expression of genes, known to be regulated by oxygen via HIF-1 in somatic cells, is not influenced by oxygen during preimplantation postcompaction bovine embryo development. Oxygen-regulated expression of LDHA and SLC2A1 in bovine blastocysts suggests that regulation of these genes may be mediated by HIF2. Furthermore, the effect of a reduced-oxygen environment on gene expression can be mimicked in vitro through the use of desferrioxamine. These results further support our data that the bovine blastocyst stage embryo is unique in

  17. 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.

  18. Environmentally relevant concentrations of aminopolycarboxylate chelating agents mobilize Cd from humic acid.

    PubMed

    North, Ashley E; Sarpong-Kumankomah, Sophia; Bellavie, Andrew R; White, Wade M; Gailer, Jürgen

    2017-07-01

    Although Cd is a pollutant of public health relevance, many dietary sources from which it can be absorbed into human tissues remain unknown. While it is well established that the biogeochemical cycle of Cd involves its complexation with environment-derived ligands (e.g., humic acids, HAs) and anthropogenic ones (e.g., chelating agents, CAs), the interaction of Cd with both of these ligands is less well understood. To gain insight, a HA-Cd complex was injected on a size-exclusion chromatography (SEC) column coupled on-line with a flame atomic absorption spectrometer (FAAS) using 10mmol/L Tris buffer (pH8.0) as the mobile phase. This approach allowed us to observe the intact HA-Cd complex and the retention behavior of Cd as a function of 2-20μmol/L concentrations of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) or methylglycinediacetic acid (MGDA) that were added to the mobile phase. An increase of the retention time of Cd was indicative of a partial or complete abstraction of Cd from HA. Our results revealed that all CAs abstracted Cd from the HA-Cd complex at concentrations of 5μmol/L, while MGDA and DTPA were effective at 2μmol/L. The bioavailability of some of the on-column formed CA-Cd complexes explains the previously reported increased accumulation of Cd in periphyton in the ecosystem downstream of wastewater treatment plants. In addition, our results imply that the use of effluents which contain CAs and Cd for the irrigation of food crops can introduce Cd into the food supply and compromise food safety. Copyright © 2017. Published by Elsevier B.V.

  19. 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.

  20. Investigation of a potential macromolecular MRI contrast agent prepared from PPI (G = 2, polypropyleneimine, generation 2) dendrimer bifunctional chelates

    NASA Astrophysics Data System (ADS)

    Wang, Jianxin Steven

    The long-term objective is to develop magnetic resonance (MR) contrast agents that actively and passively target tumors for diagnosis and therapy. Many diagnostic imaging techniques for cancer lack specificity. A dendrimer based magnetic resonance imaging contrast agent has been developed with large proton relaxation enhancements and high molecular relaxivities. A new type of linear dendrimer based MRI contrast agent that is built from the polypropyleneimine and polyamidoamine dendrimers in which free amines have been conjugated to the chelate DTPA, which further formed the complex with Gadolinium (Gd) was studied. The specific research goals were to test the hypothesis that a linear chelate with macromolecular agents can be used in vitro and in vivo. This work successfully examined the adequacy and viability of the application for this agent in vitro and in vivo. A small animal whole body counter was designed and constructed to allow us to monitor biodistribution and kinetic mechanisms using a radioisotope labeled complex. The procedures of metal labeling, separation and purification have been established from this work. A biodistribution study has been performed using radioisotope induced organ/tissue counting and gamma camera imaging. The ratio of percentage of injected dose per gram organ/tissue for kidney and liver is 3.71 from whole body counter and 3.77 from the gamma camera. The results suggested that retention of Gd (III) is too high and a more kinetically stable chelate should be developed. The pharmacokinetic was evaluated in the whole animal model with the whole body clearance, and a kinetics model was developed. The pharmacokinetic results showed a bi-exponential decay in the animal model with two component excretion constants 1.43e(-5) and 0.0038511, which give half-lives of 3 hours and 33.6 days, respectively. Magnetic resonance imaging of this complex resulted in a 52% contrast enhancement in the rat kidney following the agents' administration in

  1. 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.

  2. Regulation of AhFRO1, an Fe(III)-chelate reductase of peanut, during iron deficiency stress and intercropping with maize.

    PubMed

    Ding, Hong; Duan, Lihong; Wu, Huilan; Yang, Rongxin; Ling, Hongqing; Li, Wen-Xue; Zhang, Fusuo

    2009-07-01

    Iron deficiency-induced chlorosis in peanut during anthesis was alleviated when peanut was intercropped with maize in field and pot experiments. Iron acquisition of graminaceous plants is characterized by the synthesis and secretion of the iron-chelating phytosiderophores. Compared to the roots of monocropped maize, the roots of maize intercropped with peanut always secreted higher amounts of phytosiderophores during peanut anthesis. For non-graminaceous plants, reduction of ferric to ferrous iron on the root surface is the rate-limiting step for mobilizing iron from soil. The full-length cDNA, AhFRO1, which is encoding an Fe(III)-chelate reductase, was isolated from peanut. AhFRO1 expression in yeast conferred Fe(III)-chelate reductase activity to the cells. Consistent with its function in iron uptake, AhFRO1 was determined to be a membrane protein by transient expression analysis. AhFRO1 mRNA accumulated under iron deficiency conditions. During pre-anthesis, the Fe(III)-chelate reductase activity and the transcript levels of AhFRO1 were similar in monocropped and intercropped peanut. When the iron deficiency-induced chlorosis developed in the monocropped peanuts, both the Fe(III)-chelate reductase activity of peanut and the transcript levels of AhFRO1 were higher in intercropped than in monocropped peanuts, which is consistent with the secretion of phytosiderophores by maize roots. We conclude that AhFRO1 in peanut and phytosiderophores from maize co-operate to improve the iron nutrition of peanut when intercropped with maize.

  3. Reversed-phase high-performance liquid chromatography of non-transferrin-bound iron and some hydroxypyridone and hydroxypyrone chelators.

    PubMed

    el-Jammal, A; Templeton, D M

    1994-08-05

    The pursuit of orally available Fe(III) chelating agents has resulted in several clinical trials of 1,2-dimethyl-3-hydroxypyrid-4-one (CP20). Chromatography of this and related Fe chelators on silica-based columns has proven difficult due to unwanted interactions with the stationary phase, including with contaminating Fe bound to silanol groups. By addition of Fe3+ (50 microM ferric ammonium citrate) to an acidified aqueous mobile phase, we have successfully separated a series of hydroxypyridones-including CP20-and the related pyrones maltol and ethylmaltol by HPLC on microBondapak C18. Complexation occurs with these agents even at low pH, and they elute in an order consistent with the partition coefficients of their Fe(III) complexes. By the reverse strategy of adding ethylmaltol to the mobile phase, chelatable Fe was chromatographed and the peak response at 500 nm was linear down to a detection limit below 0.5 microM. This method was applied to pooled serum and to serum spiked with Fe after filtration at 10 kDa cut-off. The direct determination of non-transferrin-bound Fe at micromolar concentrations in serum is possible with this approach.

  4. The effect of chelating agent on the separation of Fe(III) and Ti(IV) from binary mixture solution by cation-exchange membrane.

    PubMed

    Kir, Esengül; Cengeloğlu, Yunus; Ersöz, Mustafa

    2005-12-15

    The competitive transport of Fe(III) and Ti(IV) ions and the effect of chelating agents on separation from binary mixture solutions through charged polysulfone cation-exchange membrane (SA3S) has been studied under Donnan dialysis conditions. The amount of chelating agent was taken as an equimolar of Fe(III) ion in the feed phase. In this process, the membrane separated two electrolyte solutions: the feed solution, initially containing metal salts (Fe, Ti), or metal salts solution, containing a chelating agent, and the other side (receiver solution) being HCl solution. An external potential field is not applied. It was observed that the chelating agents affect the metal transport; the transport of Fe(III) is decreased and the transport of Ti(IV) is increased.

  5. Role of vitamin C as an adjuvant therapy to different iron chelators in young β-thalassemia major patients: efficacy and safety in relation to tissue iron overload.

    PubMed

    Elalfy, Mohsen S; Saber, Maha M; Adly, Amira Abdel Moneam; Ismail, Eman A; Tarif, Mohamed; Ibrahim, Fatma; Elalfy, Omar M

    2016-03-01

    Vitamin C, as antioxidant, increases the efficacy of deferoxamine (DFO). To investigate the effects of vitamin C as an adjuvant therapy to the three used iron chelators in moderately iron-overloaded young vitamin C-deficient patients with β-thalassemia major (β-TM) in relation to tissue iron overload. This randomized prospective trial that included 180 β-TM vitamin C-deficient patients were equally divided into three groups (n = 60) and received DFO, deferiprone (DFP), and deferasirox (DFX). Patients in each group were further randomized either to receive vitamin C supplementation (100 mg daily) or not (n = 30). All patients received vitamin C (group A) or no vitamin C (group B) were followed up for 1 yr with assessment of transfusion index, hemoglobin, iron profile, liver iron concentration (LIC) and cardiac magnetic resonance imaging (MRI) T2*. Baseline vitamin C was negatively correlated with transfusion index, serum ferritin (SF), and LIC. After vitamin C therapy, transfusion index, serum iron, SF, transferrin saturation (Tsat), and LIC were significantly decreased in group A patients, while hemoglobin and cardiac MRI T2* were elevated compared with baseline levels or those in group B without vitamin C. The same improvement was found among DFO-treated patients post-vitamin C compared with baseline data. DFO-treated patients had the highest hemoglobin with the lowest iron, SF, and Tsat compared with DFP or DFX subgroups. Vitamin C as an adjuvant therapy possibly potentiates the efficacy of DFO more than DFP and DFX in reducing iron burden in the moderately iron-overloaded vitamin C-deficient patients with β-TM, with no adverse events. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. 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. Copyright 2001 Wiley-Liss, Inc.

  7. Iron acquisition by Cryptococcus neoformans.

    PubMed

    Vartivarian, S E; Cowart, R E; Anaissie, E J; Tashiro, T; Sprigg, H A

    1995-01-01

    Iron is an essential element for the growth and metabolism of microbial cells. Most pathogenic microbes elaborate powerful iron chelating agents (siderophores) to mobilize iron from ferric ligands. The pathogenic yeast, Cryptococcus neoformans has not been found to produce siderophores and its mechanism of iron acquisition is unknown. This investigation explored an alternative pathway for iron acquisition by examining the interactions of iron with the cell surface. Iron uptake experiments were conducted utilizing radiolabelled ferrous iron and ferric iron chelates, with evidence for the presence of iron(II) receptors and the generation of ferrous iron by surface reduction. Hyperbolic kinetics were found when 59FeII was presented to the organism and uptake was blocked with bathophenanthroline sulphonate, an Fe2+ chelator. The yeast also acquired iron as [59Fe3+]-citrate and [59Fe3+]-pyrophosphate while bathophenanthroline sulphonate reduced the acquisition of these ferric ligands by 48% and 52% respectively. Pre-incubation with either ferric ligand also reduced iron acquisition by 50%. KCN inhibited uptake of iron(II) by 90% and uptake of [59Fe3+]-pyrophosphate and [59Fe3+]-citrate by 46% and 56% respectively; dinitrophenol had no effect on these processes. The data suggest that C. neoformans can (i) generate ferrous iron at the cell surface via a reduction of ferric chelates, with the subsequent acquisition of the ferrous iron, and (ii) acquire iron through the interaction of ferric chelates with a surface component.

  8. Production of the natural iron chelator deferriferrichrysin from Aspergillus oryzae and evaluation as a novel food-grade antioxidant.

    PubMed

    Todokoro, Takehiko; Fukuda, Katsuharu; Matsumura, Kengo; Irie, Motoko; Hata, Yoji

    2016-07-01

    Deferriferrichrysin (Dfcy) is a siderophore found in foods fermented by Aspergillus oryzae and is a promising candidate for an antioxidant food additive because of its high binding constant toward iron. However, the Dfcy concentration is typically low in foods and cultures. We optimised culture conditions to improve Dfcy production to 2800 mg L(-1) from 22.5 mg L(-1) under typical conditions. Then, we evaluated the potential of Dfcy as a food additive by measuring its safety, stability, and antioxidant activity. Dfcy was sufficiently stable that over 90% remained after pasteurisation at 63 °C for 30 min at pH 3-11, or after sterilisation at 120 °C for 4 min at pH 4-6. Dfcy showed high antioxidant activity in an oil-in-water model, where inhibition of lipid oxidation was measured by peroxide value (PV) and thiobarbituric acid reactive substances (TBARS) assays. Dfcy decreased PV and TBARS by 83% and 75%, respectively. Antioxidant activity of Dfcy was equal to or higher than that of the synthetic chelator EDTA. Our study provides the first practical method for production of Dfcy. Dfcy can be a novel food-grade antioxidant and the first natural alternative to the synthesised iron chelator EDTA. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

  9. Enhancement of 5-aminolevulinic acid-based fluorescence detection of side population-defined glioma stem cells by iron chelation

    PubMed Central

    Wang, Wenqian; Tabu, Kouichi; Hagiya, Yuichiro; Sugiyama, Yuta; Kokubu, Yasuhiro; Murota, Yoshitaka; Ogura, Shun-ichiro; Taga, Tetsuya

    2017-01-01

    Cancer stem cells (CSCs) are dominantly responsible for tumor progression and chemo/radio-resistance, resulting in tumor recurrence. 5-aminolevulinic acid (ALA) is metabolized to fluorescent protoporphyrin IX (PpIX) specifically in tumor cells, and therefore clinically used as a reagent for photodynamic diagnosis (PDD) and therapy (PDT) of cancers including gliomas. However, it remains to be clarified whether this method could be effective for CSC detection. Here, using flow cytometry-based analysis, we show that side population (SP)-defined C6 glioma CSCs (GSCs) displayed much less 5-ALA-derived PpIX fluorescence than non-GSCs. Among the C6 GSCs, cells with ultralow PpIX fluorescence exhibited dramatically higher tumorigenicity when transplanted into the immune-deficient mouse brain. We further demonstrated that the low PpIX accumulation in the C6 GSCs was enhanced by deferoxamine (DFO)-mediated iron chelation, not by reserpine-mediated inhibition of PpIX-effluxing ABCG2. Finally, we found that the expression level of the gene for heme oxygenase-1 (HO-1), a heme degradation enzyme, was high in C6 GSCs, which was further up-regulated when treated with 5-ALA. Our results provide important new insights into 5-ALA-based PDD of gliomas, particularly photodetection of SP-defined GSCs by iron chelation based on their ALA-PpIX-Heme metabolism. PMID:28169355

  10. Neuroprotective effect of the natural iron chelator, phytic acid in a cell culture model of Parkinson's disease.

    PubMed

    Xu, Qi; Kanthasamy, Anumantha G; Reddy, Manju B

    2008-03-12

    Disrupted iron metabolism and excess iron accumulation has been reported in the brains of Parkinson's disease (PD) patients. Because excessive iron can induce oxidative stress subsequently causing degradation of nigral dopaminergic neurons in PD, we determined the protective effect of a naturally occurring iron chelator, phytic acid (IP6), on 1-methyl-4-phenylpyridinium (MPP(+))-induced cell death in immortalized rat mesencephalic/dopaminergic cells. Cell death was induced with MPP(+) in normal and iron-excess conditions and cytotoxicity was measured by thiazolyl blue tetrazolium bromide (MTT assay) and trypan blue staining. Apoptotic cell death was also measured with caspase-3 activity, DNA fragmentation, and Hoechst nuclear staining. Compared to MPP(+) treatment, IP6 (30 micromol/L) increased cell viability by 19% (P<0.05) and decreased cell death by 22% (P<0.05). A threefold increase in caspase-3 activity (P<0.001) and a twofold increase in DNA fragmentation (P<0.05) with MPP(+) treatment was decreased by 55% (P<0.01) and 52% (P<0.05), respectively with IP6. Cell survival was increased by 18% (P<0.05) and 42% (P<0.001) with 30 and 100 micromol/L of IP6, respectively in iron-excess conditions. A 40% and 52% (P<0.001) protection was observed in caspase-3 activity with 30 and 100 micromol/L IP6, respectively in iron-excess condition. Similarly, a 45% reduction (P<0.001) in DNA fragmentation was found with 100 micromol/L IP6. In addition, Hoechst nuclear staining results confirmed the protective effect of IP6 against apoptosis. Similar protection was also observed with the differentiated cells. Collectively, our results demonstrate a significant neuroprotective effect of phytate in a cell culture model of PD.

  11. 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.

  12. 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

  13. [A new concept of cardioplegic protection in cardiac surgery: iron chelation].

    PubMed

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

    1988-06-01

    Hydroxyl is one of the most cytotoxic of all oxygen-derived free radicals produced during the myocardial ischaemia-reperfusion sequence. The purpose of the present study was to determine the effects of various interventions aimed at diminishing the production of hydroxyl radicals by reducing either one of their precursors (hydrogen peroxide) or the metal (ferric iron) which catalyzes the reaction generating these radicals. Sixty isolated and perfused rat hearts with isovolaemic contraction were studied. Except for non-ischaemic controls, these hearts were subjected to a 3-hour cardioplegic arrest in hypothermia (15-18 degrees C) followed by a 45-min reperfusion. The following interventions were performed: pretreatment with peroxidase, a hydrogen peroxide scavenger; pretreatment with peroxidase combined with deferoxamine, an ironchelating agent; pretreatment with peroxidase followed by addition of deferoxamine to the cardioplegic solution; addition of deferoxamine to the cardioplegic solution without pretreatment with the enzyme. Judging from the post-ischaemic values of developed pressure (maximum systolic pressure--diastolic pressure), left ventricular dP/dt and diastolic pressure and coronary flow rate, it appeared that the best myocardial protection was provided by deferoxamine-enriched cardioplegia. This study confirms that hydroxyl radicals most probably play a role in the genesis of the myocardial lesions associated with global ischaemia followed by reperfusion. Moreover, our results highlight the potential value of deferoxamine added to cardioplegic protection in heart surgery performed under extracorporeal circulation.

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

    PubMed

    Duque, Ximena; Martinez, Homero; Vilchis-Gil, Jenny; Mendoza, Eugenia; Flores-Hernández, Sergio; Morán, Segundo; Navarro, Fabiola; Roque-Evangelista, Victoria; Serrano, Anayeli; Mera, Robertino M

    2014-07-15

    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. 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. 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 supplementation. Supplementing

  15. 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

  16. Combination therapy with a Tmprss6 RNAi-therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β-thalassemia intermedia.

    PubMed

    Schmidt, Paul J; Racie, Tim; Westerman, Mark; Fitzgerald, Kevin; Butler, James S; Fleming, Mark D

    2015-04-01

    β-thalassemias result from diminished β-globin synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To further interrogate the efficacy of an RNAi-therapeutic downregulating Tmprss6, β-thalassemic Hbb(th3/+) animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbb(th3/+) animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-thalassemia intermedia. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

  17. Lead(II) binding to the chelating agent d-penicillamine in aqueous solution

    DOE PAGES

    Sisombath, Natalie S.; Jalilehvand, Farideh; Schell, Adam C.; ...

    2014-11-11

    Here, 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 betweenmore » 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.« less

  18. 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

  19. Lead(II) binding to the chelating agent d-penicillamine in aqueous solution

    SciTech Connect

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

    2014-11-11

    Here, 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.

  20. Application of a macromolecular chelating agent in chemical mechanical polishing of copper film under the condition of low pressure and low abrasive concentration

    NASA Astrophysics Data System (ADS)

    Yan, Li; Yuling, Liu; Xinhuan, Niu; Xiaofeng, Bu; Hongbo, Li; Jiying, Tang; Shiyan, Fan

    2014-01-01

    The mechanism of the FA/O chelating agent in the process of chemical mechanical polishing (CMP) is introduced. CMP is carried on a Φ300 mm copper film. The higher polishing rate and lower surface roughness are acquired due to the action of an FA/O chelating agent with an extremely strong chelating ability under the condition of low pressure and low abrasive concentration during the CMP process. According to the results of several kinds of additive interaction curves when the pressure is 13.78 kPa, flow rate is 150 mL/min, and the rotating speed is 55/60 rpm, it can be demonstrated that the FA/O chelating agent plays important role during the CMP process.

  1. Oxidation and reduction of bis(imino)pyridine iron dinitrogen complexes: evidence for formation of a chelate trianion.

    PubMed

    Tondreau, Aaron M; Stieber, S Chantal E; Milsmann, Carsten; Lobkovsky, Emil; Weyhermüller, Thomas; Semproni, Scott P; Chirik, Paul J

    2013-01-18

    Oxidation and reduction of the bis(imino)pyridine iron dinitrogen compound, ((iPr)PDI)FeN(2) ((iPr)PDI = 2,6-(2,6-(i)Pr(2)-C(6)H(3)-N═CMe)(2)C(5)H(3)N) has been examined to determine whether the redox events are metal or ligand based. Treatment of ((iPr)PDI)FeN(2) with [Cp(2)Fe][BAr(F)(4)] (BAr(F)(4) = B(3,5-(CF(3))(2)-C(6)H(3))(4)) in diethyl ether solution resulted in N(2) loss and isolation of [((iPr)PDI)Fe(OEt(2))][BAr(F)(4)]. The electronic structure of the compound was studied by SQUID magnetometry, X-ray diffraction, EPR and zero-field (57)Fe Mössbauer spectroscopy. These data, supported by computational studies, established that the overall quartet ground state arises from a high spin iron(II) center (S(Fe) = 2) antiferromagnetically coupled to a bis(imino)pyridine radical anion (S(PDI) = 1/2). Thus, the oxidation event is principally ligand based. The one electron reduction product, [Na(15-crown-5)][((iPr)PDI)FeN(2)], was isolated following addition of sodium naphthalenide to ((iPr)PDI)FeN(2) in THF followed by treatment with the crown ether. Magnetic, spectroscopic, and computational studies established a doublet ground state with a principally iron-centered SOMO arising from an intermediate spin iron center and a rare example of trianionic bis(imino)pyridine chelate. Reduction of the iron dinitrogen complex where the imine methyl groups have been replaced by phenyl substituents, ((iPr)BPDI)Fe(N(2))(2) resulted in isolation of both the mono- and dianionic iron dinitrogen compounds, [((iPr)BPDI)FeN(2)](-) and [((iPr)BPDI)FeN(2)](2-), highlighting the ability of this class of chelate to serve as an effective electron reservoir to support neutral ligand complexes over four redox states.

  2. 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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Protection against hydrogen peroxide-mediated cytotoxicity in Friedreich's ataxia fibroblasts using novel iron chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone class.

    PubMed

    Lim, C K; Kalinowski, D S; Richardson, D R

    2008-07-01

    Iron-loading diseases remain an important problem because of the toxicity of iron-catalyzed redox reactions. Iron loading occurs in the mitochondria of Friedreich's ataxia (FA) patients and may play a role in its pathogenesis. This suggests that iron chelation therapy could be useful. We developed previously the lipophilic iron chelators known as the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) ligands and identified 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH) as the most promising analog. Hence, this study assessed the efficacy of PCTH and other PCIH analogs compared with various chelators, including deferiprone and desferrioxamine (DFO). Age- and sex-matched control and FA fibroblasts were preincubated with iron chelators and subsequently challenged with 50 microM H2O2 for up to 24 h. The current study demonstrates an interesting structure-activity relationship among the closely related PCIH series of ligands, with only PCTH being highly effective at preventing H2O2-induced cytotoxicity. PCTH increased FA fibroblast cell viability by up to 70%, whereas DFO rescued viability by 1 to 5% only. Hence, PCTH, which was well tolerated by cells was far more effective than DFO at preventing oxidative stress. It is noteworthy that kinetic studies demonstrated PCTH to rapidly penetrate cells to induce 59Fe efflux, whereas DFO, PCIH, 2-pyridylcarboxaldehyde benzoyl hydrazone, and 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone were far slower, indicating it is the rate of chelator permeation that is crucial for protection against H2O2. In addition, PCTH was found to be as effective as or more effective than conventional radical scavengers or the antioxidant idebenone (which has undergone clinical trials) at protecting cells against H2O2-mediated cytotoxicity. These findings further indicate the potential of PCTH for treatment of iron overload.

  4. Bipyridine, an iron chelator, does not lessen intracerebral iron-induced damage or improve outcome after intracerebral hemorrhagic stroke in rats.

    PubMed

    Caliaperumal, Jayalakshmi; Wowk, Shannon; Jones, Sarah; Ma, Yonglie; Colbourne, Frederick

    2013-12-01

    Iron chelators, such as the intracellular ferrous chelator 2,2'-bipyridine, are a potential means of ameliorating iron-induced injury after intracerebral hemorrhage (ICH). We evaluated bipyridine against the collagenase and whole-blood ICH models and a simplified model of iron-induced damage involving a striatal injection of FeCl2 in adult rats. First, we assessed whether bipyridine (25 mg/kg beginning 12 h post-ICH and every 12 h for 3 days) would attenuate non-heme iron levels in the brain and lessen behavioral impairments (neurological deficit scale, corner turn test, and horizontal ladder) 7 days after collagenase-induced ICH. Second, we evaluated bipyridine (20 mg/kg beginning 6 h post-ICH and then every 24 h) on edema 3 days after collagenase infusion. Body temperature was continually recorded in a subset of these rats beginning 24 h prior to ICH until euthanasia. Third, bipyridine was administered (as per experiment 2) after whole-blood infusion to examine tissue loss, neuronal degeneration, and behavioral impairments at 7 days post-stroke, as well as body temperature for 3 days post-stroke. Finally, we evaluated whether bipyridine (25 mg/kg given 2 h prior to surgery and then every 12 h for 3 days) lessens tissue loss, neuronal death, and behavioral deficits after striatal FeCl2 injection. Bipyridine caused a significant hypothermic effect (maximum drop to 34.6 °C for 2-5 h after each injection) in both ICH models; however, in all experiments bipyridine-treated rats were indistinguishable from vehicle controls on all other measures (e.g., tissue loss, behavioral impairments, etc.). These results do not support the use of bipyridine against ICH.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  6. Transfusional Iron Overload in a Cohort of Children with Sickle Cell Disease: Impact of Magnetic Resonance Imaging, Transfusion Method, and Chelation

    PubMed Central

    Stanley, Helen M.; Friedman, David F.; Webb, Jennifer

    2016-01-01

    Background Transfusions prevent a number of complications of sickle cell disease (SCD), but cause inevitable iron loading. With magnetic resonance imaging (MRI), liver iron can be monitored noninvasively. Erythrocytapheresis can limit iron loading and oral chelation provides a more tolerable alternative to subcutaneous administration. The impact of these factors on control of iron burden in SCD has not been well studied. Procedure Iron monitoring practices, chelation use, and transfusion methods were assessed in our cohort of pediatric patients with SCD receiving chronic transfusion. The impact of these factors on iron burden was assessed. Results Among 84 subjects, the proportion that underwent appropriate liver iron concentration (LIC) assessment rose from 21% before to 81% after implementation of R2‐MRI in 2006. Among subjects with at least two R2‐MRI examinations, median LIC improved (13.2–7.9 mg/g dw, P = 0.027) from initial to final study. Most (67.9%) subjects initially received simple transfusions and subsequently transitioned to erythrocytapheresis. After switching, LIC improved from 13.1 to 4.3 mg/g dw (P < 0.001) after a median of 2.7 years and ferritin improved (2,471–392 ng/ml, P < 0.001) after a median of 4.2 years. Final serum ferritin and LIC correlated negatively with the proportion of transfusions administered by erythrocytapheresis and chelation adherence. Conclusions Routine liver R2‐MRI should be performed in individuals with SCD who receive chronic red cell transfusions. Adherence with chelation should be assessed regularly and erythrocytapheresis utilized when feasible to minimize iron loading or reduce iron stores accumulated during periods of simple transfusion. PMID:27100139

  7. Spectral properties of pro-multimodal imaging agents derived from a NIR dye and a metal chelator.

    PubMed

    Zhang, Zongren; Achilefu, Samuel

    2005-01-01

    Monomolecular multimodal imaging agents (MOMIAs) are able to provide complementary diagnostic information of a target diseased tissue. We developed a convenient solid-phase approach to construct two pro-MOMIAs (before incorporating radiometal) derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and cypate, a near-infrared (NIR) fluorescent dye analogous to indocyanine green (ICG). The possible interaction between d orbitals of transition metal DOTA complexes or free metals and the p orbitals of cypate chromophore could quench the fluorescence of pro-MOMIAs. However, we did not observe significant changes in the spectral properties of cypate upon conjugation with DOTA and subsequent chelation with metals. The fluorescence intensity of the chelated and nonmetal-chelated PRO-MOMIAs remained fairly the same in dilute 20% aqueous dimethylsulfoxide (DMSO) solution (1 x 10(-6) M). Significant reduction in the fluorescence intensity of pro-MOMIAs occurred in the presence of a large excess of metal ions (>1 molar ratio for indium and 20-fold for a copper relative to pro-MOMIA). This study suggests the feasibility of using MOMIAs for combined optical and radioisotope imaging.

  8. 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.

  9. Reversible precipitation of bovine serum albumin by metal ions and synthesis, structure and reactivity of new tetrathiometallate chelating agents.

    PubMed

    Lee, Victoria E; Schulman, Joshua M; Stiefel, Edward I; Lee, Catherine Coyle

    2007-11-01

    Independent research is an important component of any undergraduate chemistry program. This article reports the findings of two of many undergraduate research projects directed by Ed Stiefel in the hopes that the results will be inspiring and useful to the scientific community. The neurological disorders associated with insufficient copper in Menkes disease and an excess of copper in Wilson's disease are well established; however, recent evidence suggests that copper may also be involved in other disorders, such as Alzheimer's, angiogenesis, and prion diseases. The exact role of copper, however, is uncertain. This study examines the role of copper and zinc in the formation of protein deposits and the chelation and removal of the metal ions to reverse the process. The bovine serum albumin (BSA) protein forms a precipitate after the addition of approximately 6 copper(II) atoms or 8 zinc(II) atoms. Other metal ions, such as Ca(II), Al(III), Ni(II), and Co(II), did not precipitate the BSA even when the metal ion to BSA ratios were in excess of 1000. The copper and zinc protein precipitates returned to solution after addition of the chelating agents, ethylenediaminetetraacetic acid (EDTA) or tetrathiometallates [(MS(4)(2-)), where M=Mo, W]. Two new choline and acetylcholine tetrathiomolybdate and tetrathiotungstate chelating agents have been synthesized and characterized. The infrared (IR) and X-ray crystal structures of the complexes revealed that the (MS(4)(2-)) cores had approximate T(d) symmetry in the choline (Ch) salts and C(2v) symmetry in the acetylcholine (AcCh) salts. The AcCh salts hydrolyzed more slowly than the ammonium or Ch salts and the tetrathiotungstate salts hydrolyzed approximately two orders of magnitude more slowly than the tetrathiomolybdate salts. The slower hydrolysis of tetrathiotungstate may make it more useful as an inorganic reagent and therapeutic agent.

  10. Novel immunosuppressive agent caerulomycin A exerts its effect by depleting cellular iron content

    PubMed Central

    Kaur, Suneet; Srivastava, Gautam; Sharma, Amar Nath; Jolly, Ravinder S

    2015-01-01

    Background and Purpose Recently, we have described the use of caerulomycin A (CaeA) as a potent novel immunosuppressive agent. Immunosuppressive drugs are crucial for long-term graft survival following organ transplantation and treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. The objective of this study was to identify cellular targets of CaeA and decipher its mechanism of action. Experimental Approach Jurkat cells were treated with CaeA and cellular iron content, iron uptake/release, DNA content and deoxyribonucleoside triphosphate pool determined. Activation of MAPKs; expression level of transferrin receptor 1, ferritin and cell cycle control molecules; reactive oxygen species (ROS) and cell viability were measured using Western blotting, qRT-PCR or flow cytometry. Key Results CaeA caused intracellular iron depletion by reducing its uptake and increasing its release by cells. CaeA caused cell cycle arrest by (i) inhibiting ribonucleotide reductase (RNR) enzyme, which catalyses the rate-limiting step in the synthesis of DNA; (ii) stimulating MAPKs signalling transduction pathways that play an important role in cell growth, proliferation and differentiation; and (iii) by targeting cell cycle control molecules such as cyclin D1, cyclin-dependent kinase 4 and p21CIP1/WAF1. The effect of CaeA on cell proliferation was reversible. Conclusions and Implications CaeA exerts its immunosuppressive effect by targeting iron. The effect is reversible, which makes CaeA an attractive candidate for development as a potent immunosuppressive drug, but also indicates that iron chelation can be used as a rationale approach to selectively suppress the immune system, because compared with normal cells, rapidly proliferating cells require a higher utilization of iron. PMID:25537422

  11. 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.

  12. Influence of chelating agents on biogenic uraninite reoxidation by Fe(III) (Hydr)oxides.

    PubMed

    Stewart, Brandy D; Girardot, Crystal; Spycher, Nicolas; Sani, Rajesh K; Peyton, Brent M

    2013-01-02

    Microbially mediated reduction of soluble U(VI) to U(IV) with subsequent precipitation of uraninite, UO(2(S)), has been proposed as a method for limiting uranium (U) migration. However, microbially reduced UO(2) may be susceptible to reoxidation by environmental factors, with Fe(III) (hydr)oxides playing a significant role. Little is known about the role that organic compounds such as Fe(III) chelators play in the stability of reduced U. Here, we investigate the impact of citrate, DFB, EDTA, and NTA on biogenic UO(2) reoxidation with ferrihydrite, goethite, and hematite. Experiments were conducted in anaerobic batch systems in PIPES buffer (10 mM, pH 7) with bicarbonate for approximately 80 days. Results showed EDTA accelerated UO(2) reoxidation the most at an initial rate of 9.5 μM day(-1) with ferrihydrite, 8.6 μM day(-1) with goethite, and 8.8 μM day(-1) with hematite. NTA accelerated UO(2) reoxidation with ferrihydrite at a rate of 4.8 μM day(-1); rates were less with goethite and hematite (0.66 and 0.71 μM day(-1), respectively). Citrate increased UO(2) reoxidation with ferrihydrite at a rate of 1.8 μM day(-1), but did not increase the extent of reaction with goethite or hematite, with no reoxidation in this case. In all cases, bicarbonate increased the rate and extent of UO(2) reoxidation with ferrihydrite in the presence and absence of chelators. The highest rate of UO(2) reoxidation occurred when the chelator promoted both UO(2) and Fe(III) (hydr)oxide dissolution as demonstrated with EDTA. When UO(2) dissolution did not occur, UO(2) reoxidation likely proceeded through an aqueous Fe(III) intermediate with lower reoxidation rates observed. Reaction modeling suggests that strong Fe(II) chelators promote reoxidation whereas strong Fe(III) chelators impede it. These results indicate that chelators found in U contaminated sites may play a significant role in mobilizing U, potentially affecting bioremediation efforts.

  13. Effect of metal chelators on the aggregation of beta-amyloid peptides in the presence of copper and iron.

    PubMed

    Tahmasebinia, Foozhan; Emadi, Saeed

    2017-04-01

    Amyloid β (Aβ) fibrils and amorphous aggregates are found in the brain of patients with Alzheimer's disease (AD), and are implicated in the etiology of AD. The metal imbalance is also among leading causes of AD, owing to the fact that Aβ aggregation takes place in the synaptic cleft where Aβ, Cu(II) and Fe(III) are found in abnormally high concentrations. Aβ40 and Aβ42 are the main components of plaques found in afflicted brains. Coordination of Cu(II) and Fe(III) ions to Aβ peptides have been linked to Aβ aggregation and production of reactive oxygen species, two key events in the development of AD pathology. Metal chelation was proposed as a therapy for AD on the basis that it might prevent Aβ aggregation. In this work, we first examined the formation of Aβ40 and Aβ42 aggregates in the presence of metal ions, i.e. Fe(III) and Cu(II), which were detected by fluorescence spectroscopy and atomic force microscopy. Second, we studied the ability of the two chelators, ethylenediaminetetraacetic acid and 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol), to investigate their effect on the availability of these metal ions to interact with Aβ and thereby their effect on Aβ accumulation. Our findings show that Fe(III), but not Cu(II), promote aggregation of both Aβ40 and Aβ42. We also found that only clioquinol decreased significantly iron ion-induced aggregation of Aβ42. The presence of ions and/or chelators also affected the morphology of Aβ aggregates.

  14. 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

  15. Acetylacetone as chelating reagent, extracting solvent, and electrolysis medium: Polarographic determination of uranium(VI) and iron(III).

    PubMed

    Fujinaga, T; Lee, H L

    1977-06-01

    The chelating reagent acetylacetone has been examined as a polarographic medium; a method for its purification has been developed and it is found that the specific conductance is 4.2 x 10(-8) mho/cm, the accessible potential ranges are from -0.16 to -2.26 V vs. Ag/0.1M AgClO(4) for the pure solvent and from -0.35 to -2.20 V in the solvent after extraction. In pure solvent ferric acetylacetonate exhibits one wave and the uranyl complex gives two waves. After extraction from aqueous solution at pH 6.8-7.0, both metal acetylacetonates are reduced more reversibly and at more positive potential than in the pure solvent. Calibration curves are linear in the range 10(-5) -10(-3)M metal ion in the extract. The direct polarographic determination of uranium and iron in acetylacetone after extraction of the chelate from aqueous solution has been developed.

  16. α(N)-Heterocyclic Thiosemicarbazones: Iron Chelators That Are Promising for Revival of Gallium in Cancer Chemotherapy.

    PubMed

    Cao, Shuhong; Chen, Xiahui; Chen, Ligen; Chen, Jingwen

    2016-03-10

    The metal-based drugs have gained increasing attention in the fight against cancer. Ga(III) in the form of inorganic salts has demonstrated efficacy in the treatment of a number of malignancies in experimental animals and humans, and has therefore attracted considerable pharmaceutical interest. However, the poor hydrolytic stability of Ga(III) in physiological medium owing to its property of hard Lewis acid prevents its widespread use in systemic cancer chemotherapy. Complexation of suitable chelators capable of stabilising Ga(III) against hydrolysis affords an opportunity for overcoming this drawback. Thiosemicarbazone (TSC) derivatives, a class of well-studied iron chelators featuring softer donor sulfur, also were evaluated to possess antineoplastic activities in an arrary of tumour cell lines. The structural modifications can affect the activities of TSCs, and related structure-activity relationships (SAR) have been studied over these years. Combination of Ga(III) and TSCs that are both pharmaceutically active has proved to exert synergistic effects of each component in one compound in most cases, and may produce more potent Ga(III) drugs. In this review, the SAR of α(N)-heterocyclic thiosemicarbazone (HCT) analogues, a family of TSCs, were scrupulously surveyed, and the effect of Ga(III) complexation on their anticancer activity sparsely reported in literature was comparatively examined, in order to stimulate further advances in the field of gallium-based anticancer drugs.

  17. Sulfur Nanoparticles Synthesis and Characterization from H2S Gas, Using Novel Biodegradable Iron Chelates in W/O Microemulsion

    NASA Astrophysics Data System (ADS)

    Deshpande, Aniruddha S.; Khomane, Ramdas B.; Vaidya, Bhalchandra K.; Joshi, Renuka M.; Harle, Arti S.; Kulkarni, Bhaskar D.

    2008-06-01

    Sulfur nanoparticles were synthesized from hazardous H2S gas using novel biodegradable iron chelates in w/o microemulsion system. Fe3+ malic acid chelate (0.05 M aqueous solution) was studied in w/o microemulsion containing cyclohexane, Triton X-100 and n-hexanol as oil phase, surfactant, co-surfactant, respectively, for catalytic oxidation of H2S gas at ambient conditions of temperature, pressure, and neutral pH. The structural features of sulfur nanoparticles have been characterized by X-ray diffraction (XRD), transmission electron microscope (TEM), energy dispersive spectroscopy (EDS), diffused reflectance infra-red Fourier transform technique, and BET surface area measurements. XRD analysis indicates the presence of α-sulfur. TEM analysis shows that the morphology of sulfur nanoparticles synthesized in w/o microemulsion system is nearly uniform in size (average particle size 10 nm) and narrow particle size distribution (in range of 5 15 nm) as compared to that in aqueous surfactant systems. The EDS analysis indicated high purity of sulfur (>99%). Moreover, sulfur nanoparticles synthesized in w/o microemulsion system exhibit higher antimicrobial activity (against bacteria, yeast, and fungi) than that of colloidal sulfur.

  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

    2011-12-02

    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. Succinate, iron chelation, and monovalent cations affect the transformation efficiency of Acinetobacter baylyi ATCC 33305 during growth in complex media.

    PubMed

    Leong, Colleen G; Boyd, Caroline M; Roush, Kaleb S; Tenente, Ricardo; Lang, Kristine M; Lostroh, C Phoebe

    2017-10-01

    Natural transformation is the acquisition of new genetic material via the uptake of exogenous DNA by competent bacteria. Acinetobacter baylyi is model for natural transformation. Here we focus on the natural transformation of A. baylyi ATCC 33305 grown in complex media and seek environmental conditions that appreciably affect transformation efficiency. We find that the transformation efficiency for A. baylyi is a resilient characteristic that remains high under most conditions tested. We do find several distinct conditions that alter natural transformation efficiency including addition of succinate, Fe(2+) (ferrous) iron chelation, and substitution of sodium ions with potassium ones. These distinct conditions could be useful to fine tune transformation efficiency for researchers using A. baylyi as a model organism to study natural transformation.

  20. 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 alkoxid