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

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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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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Characterization of Pit, a Streptococcus pneumoniae Iron Uptake ABC Transporter

Infection and Immunity ◽

10.1128/iai.70.8.4389-4398.2002 ◽

2002 ◽

Vol 70 (8) ◽

pp. 4389-4398 ◽

Cited By ~ 86

Author(s):

Jeremy S. Brown ◽

Sarah M. Gilliland ◽

Javier Ruiz-Albert ◽

David W. Holden

Keyword(s):

Streptococcus Pneumoniae ◽

Abc Transporter ◽

Iron Uptake ◽

Systemic Infection ◽

Iron Chelator ◽

Iron Deficient ◽

Deficient Medium ◽

Mutant Strains

ABSTRACT Bacteria frequently have multiple mechanisms for acquiring iron, an essential micronutrient, from the environment. We have identified a four-gene Streptococcus pneumoniae operon, named pit, encoding proteins with similarity to components of a putative Brachyspira hyodysenteriae iron uptake ABC transporter, Bit. An S. pneumoniae strain containing a defined mutation in pit has impaired growth in medium containing the iron chelator ethylenediamine di-o-hydroxyphenylacetic acid, reduced sensitivity to the iron-dependent antibiotic streptonigrin, and impaired virulence in a mouse model of S. pneumoniae systemic infection. Furthermore, addition of a mutation in pit to a strain containing mutations in the two previously described S. pneumoniae iron uptake ABC transporters, piu and pia, resulted in a strain with impaired growth in two types of iron-deficient medium, a high degree of resistance to streptonigrin, and a reduced rate of iron uptake. Comparison of the susceptibilities to streptonigrin of the individual pit, piu, and pia mutant strains and comparison of the growth in iron-deficient medium and virulence of single and double mutant strains suggest that pia is the dominant iron transporter during in vitro and in vivo growth.

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Conjugation of Hydroxyethyl Starch to Desferrioxamine (DFO) Modulates the Dual Role of DFO in Yersinia enterocolitica Infection

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.7.3.457-462.2000 ◽

2000 ◽

Vol 7 (3) ◽

pp. 457-462 ◽

Cited By ~ 5

Author(s):

Sören Schubert ◽

Ingo B. Autenrieth

Keyword(s):

Yersinia Enterocolitica ◽

Hydroxyethyl Starch ◽

Growth Promotion ◽

Iron Chelator ◽

Dual Role ◽

Host Cells ◽

Immunosuppressive Action

ABSTRACT The iron chelator desferrioxamine (DFO) B is widely used in the therapy of patients with iron overload. As a side effect, DFO may favor the occurrence of fulminant Yersinia infections. Previous work from our laboratory showed that this might be due to a dual role of DFO: growth promotion of the pathogen and immunosuppression of the host. In this study, we sought to determine whether conjugation of DFO to hydroxyethyl starch (HES-DFO) may prevent exacerbation ofYersinia infection in mice. We found HES-DFO to promote neither growth of Yersinia enterocolitica nor mitogen-induced T-cell proliferation and gamma interferon production by T cells in vitro. Nevertheless, in vivo HES-DFO promoted growth ofY. enterocolitica possibly due to cleavage of HES and release of DFO. The pretreatment of mice with DFO resulted in death of all mice 2 to 5 days after application of a normally sublethal inoculum of Y. enterocolitica, while none of the mice pretreated with HES-DFO died within the first 7 days postinfection. However, some of the HES-DFO-treated mice died 8 to 14 days postinfection. Thus, due to the delayed in vivo effect HES-DFO failed to triggerYersinia-induced septic shock, which accounts for early mortality in DFO-associated septicemia. Moreover, our data suggest that DFO needs to be taken up by host cells in order to exert its immunosuppressive action. These results strongly suggest that HES-DFO might be a favorable drug with fewer side effects than DFO in terms of DFO-promoted fulminant infections.

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Minocycline-Induced Attenuation of Iron Overload and Brain Injury After Experimental Intracerebral Hemorrhage

Stroke ◽

10.1161/strokeaha.111.623926 ◽

2011 ◽

Vol 42 (12) ◽

pp. 3587-3593 ◽

Cited By ~ 74

Author(s):

Fan Zhao ◽

Ya Hua ◽

Yangdong He ◽

Richard F. Keep ◽

Guohua Xi

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Iron Overload ◽

Brain Edema ◽

Neuronal Death ◽

Iron Chelator ◽

Total Iron ◽

Brain Iron

Background and Purpose— Brain iron overload plays a detrimental role in brain injury after intracerebral hemorrhage (ICH). A recent study found that minocycline acts as an iron chelator and reduces iron-induced neuronal death in vitro. The present study investigated if minocycline reduces iron overload after ICH and iron-induced brain injury in vivo. Methods— This study was divided into 4 parts: (1) rats with different sizes of ICH were euthanized 3 days later for serum total iron and brain edema determination; (2) rats had an ICH treated with minocycline or vehicle. Serum iron, brain iron, and brain iron handling proteins were measured; (3) rats had an intracaudate injection of saline, iron, iron+minocycline, or iron+macrophage/microglia inhibitory factor and were used for brain edema and neuronal death measurements; and (4) rats had an intracaudate injection of iron and were treated with minocycline. The brains were used for edema measurement. Results— After ICH, serum total iron and brain nonheme iron increased and these changes were reduced by minocycline treatment. Minocycline also reduced ICH-induced upregulation of brain iron handling proteins and neuronal death. Intracaudate injection of iron caused brain edema, blood–brain barrier leakage, and brain cell death, all of which were significantly reduced by coinjection with minocycline. Conclusions— The current study found that minocycline reduces iron overload after ICH and iron-induced brain injury. It is also well known minocycline is an inhibitor of microglial activation. Minocycline may be very useful for patients with ICH because both iron accumulation and microglia activation contribute to brain damage after ICH.

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Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo

BMC Cancer ◽

10.1186/s12885-016-2744-9 ◽

2016 ◽

Vol 16 (1) ◽

Cited By ~ 21

Author(s):

Hirofumi Harima ◽

Seiji Kaino ◽

Taro Takami ◽

Shuhei Shinoda ◽

Toshihiko Matsumoto ◽

...

Keyword(s):

Pancreatic Cancer ◽

Antiproliferative Activity ◽

Iron Chelator ◽

Oral Iron ◽

Oral Iron Chelator

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Polyphosphate Functions In Vivo as Iron Chelator and Fenton Inhibitor

10.1101/2020.04.14.040345 ◽

2020 ◽

Author(s):

Francois Beaufay ◽

Ellen Quarles ◽

Allison Franz ◽

Olivia Katamanin ◽

Wei-Yun Wholey ◽

...

Keyword(s):

Fenton Reaction ◽

Oxidative Dna Damage ◽

Iron Homeostasis ◽

Iron Chelator ◽

Iron Stress ◽

Fenton Chemistry ◽

Cellular Iron ◽

Covalently Linked

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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The Iron Chelator L1 Potentiates Oxidative DNA Damage in Iron-Loaded Liver Cells

Blood ◽

10.1182/blood.v92.2.632 ◽

1998 ◽

Vol 92 (2) ◽

pp. 632-638 ◽

Cited By ~ 38

Author(s):

Louise Cragg ◽

Robert P. Hebbel ◽

Wesley Miller ◽

Alex Solovey ◽

Scott Selby ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Dna Damage ◽

Iron Overload ◽

Oxidative Dna Damage ◽

Iron Chelator ◽

Liver Cells ◽

Iron Chelators

Abstract Iron-mediated carcinogenesis is thought to occur through the generation of oxygen radicals. Iron chelators are used in attempts to prevent the long term consequences of iron overload. In particular, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), has shown promise as an effective chelator. Using an established hepatocellular model of iron overload, we studied the generation of iron-catalyzed oxidative DNA damage and the influence of iron chelators, including L1, on such damage. Iron loading of HepG2 cells was found to greatly exacerbate hydrogen peroxide–mediated DNA damage. Desferrithiocin was protective against iron/hydrogen peroxide–induced DNA damage; deferoxamine had no effect. In contrast, L1 exposure markedly potentiated hydrogen peroxide–mediated oxidative DNA damage in iron-loaded liver cells. However, when exposure to L1 was maintained during incubation with hydrogen peroxide, L1 exerted a protective effect. We interpret this as indicating that L1's potential toxicity is highly dependent on the L1:iron ratio. In vitro studies examining iron-mediated ascorbate oxidation in the presence of L1 showed that an L1:iron ratio must be at least 3 to 1 for L1 to inhibit the generation of free radicals; at lower concentrations of L1 increased oxygen radical generation occurs. In the clinical setting, such potentiation of iron-catalyzed oxidative DNA damage at low L1:iron ratios may lead to long-term toxicities that might preclude administration of L1 as an iron chelator. Whether this implication in fact extends to the in vivo situation will have to be verified in animal studies.

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