Faculty Opinions recommendation of Polyphosphate functions in vivo as an iron chelator and fenton reaction inhibitor.

AbstractMaintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion negatively affects the many metabolic pathways that depend on the activity of iron-containing enzymes, any excess of iron can cause the rapid formation of highly toxic reactive oxygen species (ROS) through Fenton chemistry. Although several cellular iron chelators have been identified, little is known about if and how organisms can prevent the Fenton reaction. By studying the effects of cisplatin, a commonly used anticancer drug and effective antimicrobial, we discovered that cisplatin elicits severe iron stress and oxidative DNA damage in bacteria. We found that both of these effects are successfully prevented by polyphosphate (polyP), an abundant polymer consisting solely of covalently linked inorganic phosphates. Subsequent in vitro and in vivo studies revealed that polyP provides a crucial iron reservoir under non-stress conditions, and effectively complexes free iron and blocks ROS formation during iron stress. These results demonstrate that polyP, a universally conserved biomolecule, plays a hitherto unrecognized role as an iron chelator and an inhibitor of the Fenton reaction.

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Polyphosphate Functions In Vivo as an Iron Chelator and Fenton Reaction Inhibitor

mBio ◽

10.1128/mbio.01017-20 ◽

2020 ◽

Vol 11 (4) ◽

Cited By ~ 2

Author(s):

François Beaufay ◽

Ellen Quarles ◽

Allison Franz ◽

Olivia Katamanin ◽

Wei-Yun Wholey ◽

...

Keyword(s):

Hydroxyl Radicals ◽

Fenton Reaction ◽

Iron Homeostasis ◽

Iron Chelator ◽

Iron Chelators ◽

Iron Stress ◽

Fenton Chemistry ◽

Free Iron ◽

Cellular Iron

ABSTRACT Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion negatively affects the many metabolic pathways that depend on the activity of iron-containing enzymes, any excess of iron can cause the rapid formation of highly toxic reactive oxygen species (ROS) through Fenton chemistry. Although several cellular iron chelators have been identified, little is known about if and how organisms can prevent the Fenton reaction. By studying the effects of cisplatin, a commonly used anticancer drug and effective antimicrobial, we discovered that cisplatin elicits severe iron stress and oxidative DNA damage in bacteria. We found that both of these effects are successfully prevented by polyphosphate (polyP), an abundant polymer consisting solely of covalently linked inorganic phosphates. Subsequent in vitro and in vivo studies revealed that polyP provides a crucial iron reservoir under nonstress conditions and effectively complexes free iron and blocks ROS formation during iron stress. These results demonstrate that polyP, a universally conserved biomolecule, plays a hitherto unrecognized role as an iron chelator and an inhibitor of the Fenton reaction. IMPORTANCE How do organisms deal with free iron? On the one hand, iron is an essential metal that plays crucial structural and functional roles in many organisms. On the other hand, free iron is extremely toxic, particularly under aerobic conditions, where iron rapidly undergoes the Fenton reaction and produces highly reactive hydroxyl radicals. Our study now demonstrates that we have discovered one of the first physiologically relevant nonproteinaceous iron chelators and Fenton inhibitors. We found that polyphosphate, a highly conserved and ubiquitous inorganic polyanion, chelates iron and, through its multivalency, prevents the interaction of iron with peroxide and therefore the formation of hydroxyl radicals. We show that polyP provides a crucial iron reservoir for metalloproteins under nonstress conditions and effectively chelates free iron during iron stress. Importantly, polyP is present in all cells and organisms and hence is likely to take on this crucial function in both prokaryotic and eukaryotic cells.

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Fe3O4@Pt nanoparticles to enable combinational electrodynamic/chemodynamic therapy

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00957-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Tong Chen ◽

Qiang Chu ◽

Mengyang Li ◽

Gaorong Han ◽

Xiang Li

Keyword(s):

Fenton Reaction ◽

Pt Nanoparticles ◽

Therapeutic Modality ◽

Ros Generation ◽

Tumor Treatment ◽

Superior Efficacy ◽

Platinum Nanocrystals ◽

First Time

AbstractElectrodynamic therapy (EDT) has recently emerged as a potential external field responsive approach for tumor treatment. While it presents a number of clear superiorities, EDT inherits the intrinsic challenges of current reactive oxygen species (ROS) based therapeutic treatments owing to the complex tumor microenvironment, including glutathione (GSH) overexpression, acidity and others. Herein for the first time, iron oxide nanoparticles are decorated using platinum nanocrystals (Fe3O4@Pt NPs) to integrate the current EDT with chemodynamic phenomenon and GSH depletion. Fe3O4@Pt NPs can effectively induce ROS generation based on the catalytic reaction on the surface of Pt nanoparticles triggered by electric field (E), and meanwhile it may catalyze intracellular H2O2 into ROS via Fenton reaction. In addition, Fe3+ ions released from Fe3O4@Pt NPs under the acidic condition in tumor cells consume GSH in a rapid fashion, inhibiting ROS clearance to enhance its antitumor efficacy. As a result, considerable in vitro and in vivo tumor inhibition phenomena are observed. This study has demonstrated an alternative concept of combinational therapeutic modality with superior efficacy.

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Deferasirox, an oral iron chelator, with gemcitabine synergistically inhibits pancreatic cancer cell growth in vitro and in vivo

Oncotarget ◽

10.18632/oncotarget.25421 ◽

2018 ◽

Vol 9 (47) ◽

pp. 28434-28444 ◽

Cited By ~ 11

Author(s):

Shuhei Shinoda ◽

Seiji Kaino ◽

Shogo Amano ◽

Hirofumi Harima ◽

Toshihiko Matsumoto ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Growth ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Iron Chelator ◽

Oral Iron ◽

Cancer Cell Growth ◽

Oral Iron Chelator

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Growth of Neisseria gonorrhoeae in the Female Mouse Genital Tract Does Not Require the Gonococcal Transferrin or Hemoglobin Receptors and May Be Enhanced by Commensal Lactobacilli

Infection and Immunity ◽

10.1128/iai.70.5.2549-2558.2002 ◽

2002 ◽

Vol 70 (5) ◽

pp. 2549-2558 ◽

Cited By ~ 39

Author(s):

Ann E. Jerse ◽

Emily T. Crow ◽

Amy N. Bordner ◽

Ishrat Rahman ◽

Cynthia Nau Cornelissen ◽

...

Keyword(s):

Neisseria Gonorrhoeae ◽

Genital Tract ◽

Female Genital Tract ◽

Iron Chelator ◽

Iron Store ◽

Human Transferrin ◽

Mucosal Surfaces ◽

Phase Variants

ABSTRACT Neisseria gonorrhoeae is capable of utilizing a variety of iron sources in vitro, including human transferrin, human lactoferrin, hemoglobin, hemoglobin-haptoglobin complexes, heme, and heterologous siderophores. Transferrin has been implicated as a critical iron store for N. gonorrhoeae in the human male urethra. The demonstration that gonococci can infect the lower genital tracts of estradiol-treated BALB/c mice in the absence of human transferrin, however, suggests that other usable iron sources are present in the murine genital tract. Here we demonstrate that gonococcal transferrin and hemoglobin receptor mutants are not attenuated in mice, thereby ruling out transferrin and hemoglobin as essential for murine infection. An increased frequency of phase variants with the hemoglobin receptor “on” (Hg+) occurred in ca. 50% of infected mice; this increase was temporally associated with an influx of neutrophils and detectable levels of hemoglobin in the vagina, suggesting that the presence of hemoglobin in inflammatory exudates selects for Hg+ phase variants during infection. We also demonstrate that commensal lactobacilli support the growth of N. gonorrhoeae in vitro unless an iron chelator is added to the medium. We hypothesize that commensal lactobacilli may enhance growth of gonococci in vivo by promoting the solubilization of iron on mucosal surfaces through the production of metabolic intermediates. Finally, transferrin-binding lipoprotein (TbpB) was detected on gonococci in vaginal smears, suggesting that although gonococci replicate within the genital tracts of mice, they may be sufficiently iron-stressed to express iron-repressible proteins. In summary, these studies support the potential role of nontransferrin, nonhemoglobin iron sources during gonococcal infection of the female genital tract.

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Hematin-derived anticoagulant. Generation in vitro and in vivo.

Journal of Experimental Medicine ◽

10.1084/jem.163.3.724 ◽

1986 ◽

Vol 163 (3) ◽

pp. 724-739 ◽

Cited By ~ 15

Author(s):

R L Jones

Keyword(s):

Aqueous Solutions ◽

Anticoagulant Activity ◽

Parent Compound ◽

Iron Chelator ◽

Ferric Citrate ◽

Anticoagulant Effect ◽

Single Peak

Prolongation of clotting times produced by hematin was investigated both in vitro and in vivo. Hematin-derived anticoagulant (HDA) was found to be due to a degradative product or derivative of hematin, and was generated in vitro in standing (aging) aqueous solutions of the parent compound. Generation of HDA in vitro was inhibited by antioxidants. The anticoagulant effect of HDA was inhibited by freshly prepared hematin, fresh Sn-protoporphyrin, imidazole, or the iron chelator desferrioxamine. Ferrioxamine did not inhibit HDA, and inhibition by imidazole was reversed with ferric citrate, suggesting a role for iron in the mechanism of HDA activity. HDA activity was dissociated from hematin in plasma by clotting with thrombin. HDA segregated into the clot fraction, whereas hematin remained largely in the serum fraction, suggesting that HDA may preferentially bind to fibrinogen. TLC and HPLC showed a single peak of HDA activity that was not associated with the parent compound. Evidence for HDA generation in vivo was found when rats were injected with fresh (no HDA) hematin. Prolongation of clotting times appeared after hematin appeared in the plasma, and anticoagulant activity persisted after a fall in plasma hematin concentration. Thus, there was a temporal dissociation between hematin and HDA, suggesting that a modification of hematin must occur in vivo before an anticoagulant effect is produced. Generation of HDA in vitro has implications for hematin preparation and administration. Generation of HDA in vivo suggests that similar modifications of endogenous heme or other porphyrins may occur to produce HDA under physiologic or pathophysiologic conditions.

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Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator

Blood ◽

10.1182/blood-2008-05-155952 ◽

2009 ◽

Vol 113 (2) ◽

pp. 462-469 ◽

Cited By ~ 140

Author(s):

Yan Jiao ◽

John Wilkinson ◽

Xiumin Di ◽

Wei Wang ◽

Heather Hatcher ◽

...

Keyword(s):

Iron Deficiency ◽

Cultured Cells ◽

Transferrin Saturation ◽

Iron Chelator ◽

Biologically Active ◽

Liver Iron ◽

Liver Iron Content ◽

Inflammatory Conditions ◽

Dose Dependent

Abstract Curcumin is a natural product currently in human clinical trials for a variety of neoplastic, preneoplastic, and inflammatory conditions. We previously observed that, in cultured cells, curcumin exhibits properties of an iron chelator. To test whether the chelator activity of curcumin is sufficient to induce iron deficiency in vivo, mice were placed on diets containing graded concentrations of both iron and curcumin for 26 weeks. Mice receiving the lowest level of dietary iron exhibited borderline iron deficiency, with reductions in spleen and liver iron, but little effect on hemoglobin, hematocrit, transferrin saturation, or plasma iron. Against this backdrop of subclinical iron deficiency, curcumin exerted profound 2 effects on systemic iron, inducing a dose-dependent decline in hematocrit, hemoglobin, serum iron, and transferrin saturation, the appearance of microcytic anisocytotic red blood cells, and decreases in spleen and liver iron content. Curcumin repressed synthesis of hepcidin, a peptide that plays a central role in regulation of systemic iron balance. These results demonstrate that curcumin has the potential to affect systemic iron metabolism, particularly in a setting of subclinical iron deficiency. This may affect the use of curcumin in patients with marginal iron stores or those exhibiting the anemia of cancer and chronic disease.

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Desferrithiocin is an effective iron chelator in vivo and in vitro but ferrithiocin is toxic

British Journal of Haematology ◽

10.1111/j.1365-2141.1992.tb08251.x ◽

1992 ◽

Vol 81 (3) ◽

pp. 424-431 ◽

Cited By ~ 27

Author(s):

E. Baker ◽

A. Wong ◽

H. Peter ◽

A. Jacobs

Keyword(s):

Iron Chelator

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Deferiprone Stimulates Aged Dermal Fibroblasts via HIF-1α Modulation

Aesthetic Surgery Journal ◽

10.1093/asj/sjaa142 ◽

2020 ◽

Cited By ~ 1

Author(s):

Andrea Pagani ◽

B Manuela Kirsch ◽

Ursula Hopfner ◽

Matthias M Aitzetmueller ◽

Elizabeth A Brett ◽

...

Keyword(s):

Lactate Dehydrogenase ◽

Cell Metabolism ◽

Hypoxia Inducible Factor ◽

Survival Rates ◽

Iron Chelation ◽

Iron Chelator ◽

Dermal Fibroblasts ◽

Topical Formulation

Abstract Background Hypoxia-inducible factor 1α (HIF-1α), a transcription factor responsible for tissue homeostasis and regeneration, presents reduced functionality in advanced age. In addition to absence of oxygen, sequestration of iron also stimulates HIF-1α. Therefore, we analyzed the efficacy of the iron-chelator deferiprone (DFP) at stimulating dermal fibroblasts. Objectives The main objective of this study was to quantify the DFP concentrations capable of stimulating dermal fibroblasts in vitro and to correlate the effective DFP concentrations with the ability of DFP to penetrate the epidermis, reach the dermis, and activate HIF-1α in vivo. Methods We measured cell proliferation, metabolic activity, HIF-1α expression, and lactate dehydrogenase levels of both young and aged fibroblasts after a 24-hour in vitro preconditioning with DFP. In addition, we evaluated cell survival rates and morphology with different cellular stainings. Finally, we performed a transdermal permeation study with a 1% DFP topical formulation to quantify the concentration required to reach the dermis. Results In vitro administration of iron-chelation therapy (156-312.5 µg/mL DFP ) on aged fibroblasts resulted in activation of various antiaging processes. The concentration required to reach the dermis within 24 hours was 1.5% (0.15 mg/mL), which corresponds well with the effective doses of our laboratory analyses. Conclusions The activation of HIF-1α by DFP enhances cell metabolism, proliferation, and survival of fibroblasts while reducing lactate dehydrogenase levels. Modulation of HIF-1α is linked to activation of key regeneration enzymes and proteins, and by proxy, antiaging. Therefore, the antiaging properties of DFP and its satisfactory dermal penetration make it a promising regenerative agent.

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A Novel Star Like Eight-Arm Polyethylene Glycol-Deferoxamine Conjugate for Iron Overload Therapy

Pharmaceutics ◽

10.3390/pharmaceutics12040329 ◽

2020 ◽

Vol 12 (4) ◽

pp. 329

Author(s):

Bohong Yu ◽

Yinxian Yang ◽

Qi Liu ◽

Aiyan Zhan ◽

Yang Yang ◽

...

Keyword(s):

Polyethylene Glycol ◽

Iron Overload ◽

Iron Chelator ◽

Iron Chelators ◽

Iron Binding ◽

Binding Ability ◽

Amide Bonds ◽

Plasma Half Life ◽

Iron Chelator Deferoxamine

The traditional iron chelator deferoxamine (DFO) has been widely used in the treatment of iron overload disease. However, DFO has congenital disadvantages, including a very short circular time and non-negligible toxicity. Herein, we designed a novel multi-arm conjugate for prolonging DFO duration in vivo and reducing cytotoxicity. The star-like 8-arm-polyethylene glycol (8-arm-PEG) was used as the macromolecular scaffold, and DFO molecules were bound to the terminals of the PEG branches via amide bonds. The conjugates displayed comparable iron binding ability to the free DFO. Furthermore, these macromolecule conjugates could significantly reduce the cytotoxicity of the free DFO, and showed satisfactory iron clearance capability in the iron overloaded macrophage RAW 246.7. The plasma half-life of the 8-arm-PEG-DFO conjugate was about 190 times than that of DFO when applied to an intravenously administered rat model. In conclusion, research indicated that these star-like PEG-based conjugates could be promising candidates as long circulating, less toxic iron chelators.

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