RESUMO
The redox reactivity of iron is a double-edged sword for cell functions, being either essential or harmful depending on metal concentration and location. Deregulation of iron homeostasis is associated with several clinical conditions, including viral infections. Clinical studies as well as in silico, in vitro and in vivo models show direct effects of several viruses on iron levels. There is support for the strategy of iron chelation as an alternative therapy to inhibit infection and/or viral replication, on the rationale that iron is required for the synthesis of some viral proteins and genes. In addition, abnormal iron levels can affect signaling immune response. However, other studies report different effects of viral infections on iron homeostasis, depending on the class and genotype of the virus, therefore making it difficult to predict whether iron chelation would have any benefit. This review brings general aspects of the relationship between iron homeostasis and the nonspecific immune response to viral infections, along with its relevance to the progress or inhibition of the inflammatory process, in order to elucidate situations in which the use of iron chelators could be efficient as antivirals.
Assuntos
Quelantes de Ferro , Viroses , Humanos , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Ferro/metabolismo , Viroses/tratamento farmacológicoRESUMO
Abstract Introduction Magnetic resonance imaging (MRI) T2* technique is used to assess iron overload in the heart, liver and pancreas of thalassaemic patients. Optimal iron chelation and expected tissue iron response rates remain under investigation. The objective of this study was to analyse serum ferritin and the iron concentration in the heart, liver and pancreas measured by MRI T2*/R2* during regular chelation therapy in a real-world cohort of patients with thalassemia. Methods We evaluated thalassaemic patients ≥ 7 years old undergoing chelation/transfusion therapy by MRI and assessed serum ferritin at baseline and follow-up from 2004-2011. Results We evaluated 136 patients, 92% major thalassaemic, with a median age of 18 years, and median baseline ferritin 2.033ng/ml (range: 59-14,123). Iron overload distribution was: liver (99%), pancreas (74%) and heart (36%). After a median of 1.2 years of follow-up, the iron overload in the myocardium reduced from 2,63 Fe mg/g to 2,05 (p 0.003). The optimal R2* pancreas cut-off was 148 Hertz, achieving 78% sensitivity and 73% specificity. However, when combining the R2* pancreas cut off ≤ 50 Hertz and a ferritin ≤ 1222 ng/ml, we could reach a negative predictive value (NPV) of 98% for cardiac siderosis. Only 28% were undergoing combined chelation at baseline assessment, which increased up to 50% on follow up evaluation. Conclusions Chelation therapy significantly reduced cardiac siderosis in thalassaemic patients. In patients with moderate/severe liver iron concentration undergoing chelation therapy, ferritin levels and myocardium iron improved earlier than the liver siderosis.
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Humanos , Criança , Talassemia , Sobrecarga de Ferro , Terapia por QuelaçãoRESUMO
INTRODUCTION: Magnetic resonance imaging (MRI) T2* technique is used to assess iron overload in the heart, liver and pancreas of thalassaemic patients. Optimal iron chelation and expected tissue iron response rates remain under investigation. The objective of this study was to analyse serum ferritin and the iron concentration in the heart, liver and pancreas measured by MRI T2*/R2* during regular chelation therapy in a real-world cohort of patients with thalassemia. METHODS: We evaluated thalassaemic patients ≥ 7 years old undergoing chelation/transfusion therapy by MRI and assessed serum ferritin at baseline and follow-up from 2004-2011. RESULTS: We evaluated 136 patients, 92% major thalassaemic, with a median age of 18 years, and median baseline ferritin 2.033ng/ml (range: 59-14,123). Iron overload distribution was: liver (99%), pancreas (74%) and heart (36%). After a median of 1.2 years of follow-up, the iron overload in the myocardium reduced from 2,63 Fe mg/g to 2,05 (p 0.003). The optimal R2* pancreas cut-off was 148 Hertz, achieving 78% sensitivity and 73% specificity. However, when combining the R2* pancreas cut off ≤ 50 Hertz and a ferritin ≤ 1222 ng/ml, we could reach a negative predictive value (NPV) of 98% for cardiac siderosis. Only 28% were undergoing combined chelation at baseline assessment, which increased up to 50% on follow up evaluation. CONCLUSIONS: Chelation therapy significantly reduced cardiac siderosis in thalassaemic patients. In patients with moderate/severe liver iron concentration undergoing chelation therapy, ferritin levels and myocardium iron improved earlier than the liver siderosis.
RESUMO
Phytochelators have been studied as templates for designing new drugs for chelation therapy. This work evaluated key chemical and biological properties of five candidate phytochelators for iron overload diseases: maltol, mimosine, morin, tropolone, and esculetin. Intra- and extracellular iron affinity and antioxidant activity, as well as the ability to scavenge iron from holo-transferrin, were studied in physiologically relevant settings. Tropolone and mimosine (and, to a lesser extent, maltol) presented good binding capacity for iron, removing it from calcein, a high-affinity fluorescent probe. Tropolone and mimosine arrested iron-mediated oxidation of ascorbate with the same efficiency as the standard iron chelator DFO. Also, both were cell permeant and able to access labile pools of iron in HeLa and HepG2 cells. Mimosine was an effective antioxidant in cells stressed by iron and peroxide, being as efficient as the cell-permeant iron chelator deferiprone. These results reinforce the potential of those molecules, especially mimosine, as adjuvants in treatments for iron overload.
Assuntos
Quelantes de Ferro , Sobrecarga de Ferro , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Desferroxamina , Humanos , Ferro/metabolismo , Quelantes de Ferro/farmacologia , Mimosina/uso terapêutico , Piridonas/uso terapêutico , Tropolona/uso terapêuticoRESUMO
The nematode Caenorhabditis elegans (C. elegans) is a convenient tool to evaluate iron metabolism as it shares great orthology with human proteins involved in iron transport, in addition to being transparent and readily available. In this work, we describe how wild-type (N2) C. elegans nematodes in the first larval stage can be loaded with acetomethoxycalcein (CAL-AM) and study it as a whole-organism model for both iron speciation and chelator permeability of the labile iron pool (LIP). This model may be relevant for high throughput assessment of molecules intended for chelation therapy of iron overload diseases.
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Fluorometria , Quelantes de Ferro/química , Animais , Caenorhabditis elegans , Quelantes de Ferro/síntese química , Estrutura MolecularRESUMO
BACKGROUND: The purpose of the present study was to investigate the antioxidant and antimicrobial activities of a conventional preservative system containing desferrioxamine mesylate (DFO) and optimize the composition of the system through mathematical models. METHODS: Different combinations of ethylenediaminetetraacetic acid (EDTA), sodium metabisulfite (SM), DFO and methylparaben (MP) were prepared using factorial design of experiments. The systems were added to ascorbic acid (AA) solution and the AA content over time, at room temperature and at 40 °C was determined by volumetric assay. The systems were also evaluated for antioxidant activity by a fluorescence-based assay. Antimicrobial activity was assessed by microdilution technique and photometric detection against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Aspergillus brasiliensis. A multi-criteria decision approach was adopted to optimize all responses by desirability functions. RESULTS: DFO did not extend the stability of AA over time, but displayed a better ability than EDTA to block the pro-oxidant activity of iron. DFO had a positive interaction with MP in microbial growth inhibition. The mathematical models showed adequate capacity to predict the responses. Statistical optimization aiming to meet the quality specifications of the ascorbic acid solution indicated that the presence of DFO in the composition allows to decrease the concentrations of EDTA, SM and MP. CONCLUSION: DFO was much more effective than EDTA in preventing iron-catalyzed oxidation. In addition, DFO improved the inhibitory response of most microorganisms tested. The Quality by Design concepts aided in predicting an optimized preservative system with reduced levels of conventional antioxidants and preservatives, suggesting DFO as a candidate for multifunctional excipient.
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Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Desferroxamina/química , Conservantes Farmacêuticos/química , Anti-Infecciosos/química , Antioxidantes/química , Ácido Ascórbico/química , Aspergillus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Ácido Edético/química , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Teóricos , Parabenos/química , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Sulfitos/químicaRESUMO
The hydroxamate class of compounds is well known for its pharmacological applications, especially in the context of chelation therapy. In this work we investigate the performance of the fungal hydroxamates pyridoxatin (PYR), desferriastechrome (DAC) and desferricoprogen (DCO) as mitigators of stress caused by iron overload (IO) both in buffered medium and in cells. Desferrioxamine (DFO), the gold standard for IO treatment, was used as comparison. It was observed that all the fungal chelators (in aqueous medium) or PYR and DAC (in cells) are powerful iron scavengers. However only PYR and DCO (in aqueous medium) or PYR (in cells) were also antioxidant against two forms of iron-dependent oxidative stress (ascorbate or peroxide oxidation). These findings reveal that PYR is an interesting alternative to DFO for iron chelation therapy, since it has the advantage of being cell permeable and thus potentially orally active.
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Antioxidantes/química , Dicetopiperazinas/química , Ácidos Hidroxâmicos/química , Cicloexanos/química , Quelantes de Ferro/química , Sobrecarga de Ferro/metabolismoRESUMO
Drugs bearing metal-coordinating moieties can alter biological metal distribution. In this work, a complex between iron(II) and diflunisal was prepared in the solid state, exhibiting the following composition: [Fe(diflunisal)2(H2O)2], (Fe(dif)2). The ability of diflunisal to alter labile pools of both plasmatic and cellular iron was investigated in this work. We found out that diflunisal does not increase the levels of redox-active iron in plasma of iron overloaded patients. However, diflunisal efficiently carries iron into HeLa or HepG2 cells, inducing an iron-catalyzed oxidative stress.
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Complexos de Coordenação/síntese química , Compostos Ferrosos/química , Ferro/química , Sulfetos/química , Catálise , Complexos de Coordenação/química , Compostos Ferrosos/farmacocinética , Células HeLa , Células Hep G2 , Humanos , Estrutura Molecular , Estresse Oxidativo , Células Tumorais CultivadasRESUMO
The field of nanotechnology had enormous developments, resulting in new methods for the controlled synthesis of a wide variety of nanoscale materials with unique properties. Efficient methods such as thermal decomposition for efficient size control have been developed in recent years for the synthesis of oleic acid (OA)-coated magnetite (Fe3O4) nanoparticles (MNP-OA). These nanostructures can be a source of pollution when emitted in the aquatic environment and could be accumulated by vulnerable marine species such as crustaceans. In this work, we synthesized and characterized MNP-OA of three different diameters (5, 8, and 12 nm) by thermal decomposition. These nanoparticles were remarkably stable after treatment with high affinity iron chelators (calcein, fluorescent desferrioxamine, and fluorescent apotransferrin); however, they displayed pro-oxidant activity after being challenged with ascorbate under two physiological buffers. Free or nanoparticle iron displayed low toxicity to four types of hepatopancreatic cells (E, R, F, and B) of the mangrove crab Ucides cordatus; however, they were promptly bioavailable, posing the risk of ecosystem disruption due to the release of excess nutrients.
Assuntos
Braquiúros/efeitos dos fármacos , Hepatopâncreas/efeitos dos fármacos , Nanopartículas de Magnetita , Ácido Oleico/farmacocinética , Animais , Disponibilidade Biológica , Braquiúros/fisiologia , Desferroxamina/metabolismo , Ecossistema , Ecotoxicologia , Fluoresceínas/química , Hepatopâncreas/citologia , Ferro/análise , Ferro/metabolismo , Quelantes de Ferro/química , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/toxicidade , Masculino , Ácido Oleico/química , Tamanho da Partícula , Polissorbatos/química , Transferrina/metabolismo , Áreas AlagadasRESUMO
The mangrove crab Ucides cordatus is a bioindicator of aquatic contamination. In this work, the iron availability and redox activity of saccharide-coated mineral iron supplements (for both human and veterinary use) and ferrocene derivatives in Saline Ucides Buffer (SUB) medium were assessed. The transport of these metallodrugs by four different hepatopancreatic cell types (embryonic (E), resorptive (R), fibrillar (F), and blister (B)) of U. cordatus were measured. Organic coated iron minerals (iron supplements) were stable against strong chelators (calcein and transferrin). Ascorbic acid efficiently mediated the release of iron only from ferrocene compounds, leading to redox-active species. Ferrous iron and iron supplements were efficient in loading iron to all hepatopancreatic cell types. In contrast, ferrocene derivatives were loaded only in F and B cell types. Acute exposition to the iron compounds resulted in cell viability of 70-95%, and to intracellular iron levels as high as 0.40 µmol L-1 depending upon the compound and the cell line. The easiness that iron from iron metallodrugs was loaded/transported into U. cordatus hepatopancreatic cells reinforces a cautionary approach to the widespread disposal and use of highly bioavailable iron species as far as the long-term environmental welfare is concerned.