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
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.
Assuntos
Fluorometria , Quelantes de Ferro/química , Animais , Caenorhabditis elegans , Quelantes de Ferro/síntese química , Estrutura MolecularRESUMO
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.
Assuntos
Antioxidantes/química , Dicetopiperazinas/química , Ácidos Hidroxâmicos/química , Cicloexanos/química , Quelantes de Ferro/química , Sobrecarga de Ferro/metabolismoRESUMO
Iron overload causes progressive and sometimes irreversible damage due to accelerated production of reactive oxygen species. Desferrioxamine (DFO), a siderophore, has been used clinically to remove excess iron. However, the applications of DFO are limited because of its inability to access intracellular labile iron. Cell penetrating peptides (CPPs) have become an efficient delivery vector for the enhanced internalization of drugs into the cytosol. We describe, herein, an efficient method for covalently conjugating DFO to the CPPs TAT(47-57) and Penetratin. Both conjugates suppressed the redox activity of labile plasma iron in buffered solutions and in iron-overloaded sera. Enhanced access to intracellular labile iron compared to the parent siderophore was achieved in HeLa and RBE4 (a model of blood-brain-barrier) cell lines. Iron complexes of both conjugates also had better permeability in both cell models. DFO antioxidant and iron binding properties were preserved and its bioavailability was increased upon CPP conjugation, which opens new therapeutic possibilities for neurodegenerative processes associated with brain iron overload.
Assuntos
Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/síntese química , Desferroxamina/química , Desferroxamina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/síntese química , Fármacos Neuroprotetores/química , Sequência de Aminoácidos , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoproteínas/metabolismo , Ligação Competitiva , Peptídeos Penetradores de Células/metabolismo , Técnicas de Química Sintética , Desferroxamina/metabolismo , Portadores de Fármacos/metabolismo , Fluoresceína/metabolismo , Fluoresceínas/metabolismo , Produtos do Gene tat/química , Células HeLa , Humanos , Ferro/metabolismo , Dados de Sequência Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Permeabilidade , Transferrina/metabolismoRESUMO
Body iron disorders have been reported after myeloablative conditioning in patients undergoing hematopoietic stem cell transplantation (HSCT). There is a concern that labile plasma iron (LPI), the redox-active form of iron, can be involved in the occurrence of toxicity and other complications commonly observed in the early post-HSCT period. In order to better understand the LPI kinetics and its determinants and implications, we undertook sequential LPI determinations before and after conditioning until engraftment in 25 auto-HSCT patients. Increased LPI was present in only 5 patients before starting conditioning. Shortly after conditioning, LPI levels were increased in 23 patients, with peak at day 0, returning to normal range upon engraftment in 21 patients. Overall, LPI levels correlated weakly with serum ferritin and more strongly with transferrin saturation; however, both parameters were apparently not applicable as surrogate markers for increased LPI. Although this was a small cohort, logistic regression suggested that baseline LPI levels could predict occurrence of grade III or IV toxicity. In conclusion, LPI kinetics is influenced by aplasia following conditioning and engraftment. Measuring LPI before starting conditioning can offer an opportunity to predict toxicity and, perhaps, the need for chelation therapy.
Assuntos
Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Sobrecarga de Ferro/etiologia , Ferro/sangue , Condicionamento Pré-Transplante/efeitos adversos , Adulto , Idoso , Antioxidantes/química , Ácido Ascórbico/química , Estudos de Coortes , Deferiprona , Feminino , Corantes Fluorescentes/química , Seguimentos , Humanos , Ferro/química , Quelantes de Ferro/química , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Piridonas/química , Rodaminas/química , Índice de Gravidade de Doença , Adulto JovemRESUMO
Desferrioxamine (DFO) is a potent iron chelator used in the treatment of iron overload (IO) disorders. However, due to its low cell permeability and fast clearance, DFO administration is usually prolonged and of limited use for the treatment of IO in tissues such as the brain. Caffeine is a safe, rapidly absorbable molecule that can be linked to other compounds to improve their cell permeability. In this work, we successfully prepared and described DFO-caffeine, a conjugate with iron scavenging ability, antioxidant properties and enhanced permeation in the HeLa cell model.
Assuntos
Cafeína/farmacologia , Desferroxamina/farmacologia , Quelantes de Ferro/farmacologia , Sobrecarga de Ferro/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Cafeína/administração & dosagem , Permeabilidade da Membrana Celular , Desferroxamina/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Compostos Férricos/metabolismo , Compostos Férricos/toxicidade , Fluoresceínas/análise , Corantes Fluorescentes/análise , Células HeLa , Humanos , Quelantes de Ferro/administração & dosagem , Estrutura Molecular , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/metabolismo , Ácido Nitrilotriacético/toxicidadeRESUMO
Manganese (Mn) is an essential trace element and trivalent Mn complexes have been used as oxidation catalysts and enzyme mimetics. We studied the cytotoxicity of Mn(III) derivatives of citrate, pyrophosphate and salicylene diamine (respectively, MnCit, MnPPi and EUK8) toward HeLa cells stressed by ultraviolet irradiation and the effect of the co-administration of ascorbate and para-amino salicylate (PAS) on cell viability. Metal complexes enhanced the lethality of irradiated cells, and this effect was even more pronounced when ascorbate was co-administered with Mn(III) species. The active role of Mn(III) compounds in the antitumor activity was demonstrated by the treatment of the cells with the chelator PAS, which restored the viability of both non-irradiated and UV-irradiated cells. The association of the Mn(III) metallodrugs with radiation and an antioxidant proved to be a very effective approach to chemotherapy.
Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Manganês/química , Compostos Organometálicos/farmacologia , Fototerapia , Antineoplásicos/química , Antioxidantes/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Compostos Organometálicos/química , Relação Estrutura-AtividadeRESUMO
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
Copper complexes with fluorinated ß-diketones were synthesized and characterized in terms of lipophilicity and peroxide-assisted oxidation of dihydrorhodamine as an indicator of redox activity. The biological activity of the complexes was tested against promastigotes of Leishmania amazonensis. Inhibition of trypanosomatid-specific trypanothione reductase was also tested. It was found that the highly lipophilic and redox-active bis(trifluoroacetylacetonate) derivative had increased toxicity towards promastigotes. These results indicate that it is possible to modulate the activity of metallodrugs based on redox-active metals through the appropriate choice of lipophilic chelators in order to design new antileishmanials. Further work will be necessary to improve selectivity of these compounds against the parasite.
Assuntos
Cobre/química , Inibidores Enzimáticos/farmacologia , Leishmania mexicana/efeitos dos fármacos , Lipídeos/química , NADH NADPH Oxirredutases/antagonistas & inibidores , Compostos Organometálicos/farmacologia , Oxidantes/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cetonas/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Oxidantes/síntese química , Oxidantes/química , Oxirredução/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Relação Estrutura-AtividadeRESUMO
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
BACKGROUND: Increased transferrin saturation (TS) and ferritin are common in hereditary hemochromatosis (HH) but also in chronic liver diseases (CLD). Nontransferrin bound iron (NTBI) is believed to be associated with iron-induced cell damage. We aimed to evaluate NTBI in CLD and their relationship with liver damage. METHODS: Two groups of patients were studied. Group 1 (G1): 94 CLD patients from an Outpatient Hepatology Unit. Group 2 (G2): 36 healthy individuals form a Medical Checkup Clinic. Transferrin iron-binding capacity, TS, ferritin, AST, ALT, and red cell count were performed using standard tests. NTBI was assessed as enhanced labile plasma iron (eLPi). Levels of eLPi less than 0.4 µmol/l were considered within the normal range. RESULTS: Prevalence of increased iron tests (elevated TS and ferritin) was 14% in G1 and 5.5% in G2 ( P = 0.19). Positive NTBI was found in 12 patients (11 in G1 and 1 in G2). Positivity to NTBI was associated with increased iron tests ( P = 0.03), cirrhosis ( P = 0.03) and AST index (ASTI) ( P = 0.03). NTBI was associated with TS of more than 70% ( P = 0.002) but not to elevated ferritin ( P = 0.74). Variables strongly associated with a positive NTBI in univariate analysis (TS > 70%, cirrhosis and ASTI) were submitted to binary regression analysis. TS of more than 70% was the only independent predictive factor ( P = 0.049; odds ratio, 6.8). CONCLUSION: NTBI was associated with TS in CLD, but not with ferritin. NTBI testing could be useful for CLD patients with increased iron tests. Alternatively, a TS of more than 70% can be used as a surrogate marker.
Assuntos
Ferro , Transferrina , Biomarcadores , Ferritinas , Humanos , Cirrose Hepática/diagnóstico , Transferrina/análise , Transferrina/metabolismoRESUMO
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.
Assuntos
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
Desferrioxamine (DFO) and diethylenetriaminepentaacetic acid (DTPA) conjugated with silica gel (IDFOSG and IDTPASG, respectively) were evaluated as adsorbents for chromium in aqueous solutions. Different parameters affecting adsorption such as pH, sorbent dosage, contact time, sample volume and potential of interfering ions have been optimized. The optimum pH for chromium binding was 4 for 100 mg of adsorbents at 5 min of table shaking with 5 mL sample volume of chromium solutions. Langmuir adsorption model described the removal of chromium ions. The adsorption capacity for chromium was 90% for IDFOSG and 83% for IDTPASG in single solutions, and at least 75% in multielemental solutions. Considering the removal efficacy, regeneration and stability, DFO-grafted silica gel was generally superior to its DTPA counterpart and may be applied to the removal of traces of chromium species from natural waters.
Assuntos
Cromo , Poluentes Químicos da Água , Adsorção , Desferroxamina , Concentração de Íons de Hidrogênio , Cinética , Ácido Pentético , Sílica Gel , SoluçõesRESUMO
In this study, Cu(II) complexes with fluorinated ligands were produced aiming at the development of new, less toxic antileishmanial metallodrugs. Complexes of the general formula CuL2 (L = lactate, trifluorolactate, 2-hydroxyisobutyrate, trifluoro-2-hydroxyisobutyrate) were synthesized in methanolic medium, purified by crystallization and characterized by elemental analysis and electronic and infrared spectroscopies. In vitro experiments with Leishmania amazonensis promastigotes showed that the trifluorolactate derivative more active than its non-fluorinated counterpart. Our results indicate that fluorinated chelators may be interesting to increase metal toxicity and/or open new paths for metallodrug chemotherapy against leishmaniasis.
Assuntos
Antiprotozoários/análise , Antiprotozoários/síntese química , Cobre/química , Fluoretos/química , Leishmania/efeitos dos fármacos , Antiprotozoários/uso terapêutico , Técnicas de Cultura de Células , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância de Spin Eletrônica , Halogenação , Hidroxibutiratos/química , Concentração Inibidora 50 , Ácido Láctico/química , Leishmania/crescimento & desenvolvimento , Leishmaniose/tratamento farmacológico , Ligantes , Estrutura Molecular , Espectrofotometria InfravermelhoRESUMO
Iron chelation has already been proposed to be a feasible strategy for cancer therapeutics in that reinforced iron demand is demonstrated in cancer cells, and quite a few iron chelators have been developed for this purpose. Desferrioxamine (DFO), an iron chelator approved by the U.S. Food and Drug Administration (FDA), has been extensively examined to remove extra iron. However, DFO has been found to harbor limited efficacies in combating cancer cells due to poor cellular permeability. In the current study, we synthesized the DFO derivative, named as desferrioxamine-caffeine dimer (DFCAF) by linking DFO to caffeine with high purity and excellent stability. Our data showed that DFCAF displayed greater cellular permeability to chelate intracellular iron in 4T1 breast cancer cells than DFO, posing more inhibition on cell growth and cellular motility/invasion. Importantly, DFCAF was uncovered to remarkably deplete cancer stem cells (CSCs), as characterized by the remarkable decrease of the CD44+/high/CD24-/low and ALDH+/high subpopulation. In parallel, DFCAF was also found to greatly reverse epithelial-mesenchymal transition (EMT), suggesting the potential application to restrain tumor progression and metastasis. Collectively, these data unveiled the improved efficacy to target cancer cells and to deplete CSCs, thus opening a new path for better cancer therapeutics through iron chelation.
Assuntos
Cafeína/farmacologia , Desferroxamina/farmacologia , Quelantes de Ferro/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Desferroxamina/síntese química , Desferroxamina/química , Camundongos , Células Tumorais CultivadasRESUMO
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.
Assuntos
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.
Assuntos
Braquiúros/metabolismo , Compostos Ferrosos/metabolismo , Hepatopâncreas/citologia , Ferro/metabolismo , Metalocenos/metabolismo , Poluentes Químicos da Água/análise , Animais , Braquiúros/química , Braquiúros/efeitos dos fármacos , Braquiúros/fisiologia , Compostos Ferrosos/análise , Compostos Ferrosos/química , Hepatopâncreas/efeitos dos fármacos , Humanos , Ferro/análise , Metalocenos/análise , Metalocenos/químicaRESUMO
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.
Assuntos
Humanos , Criança , Talassemia , Sobrecarga de Ferro , Terapia por QuelaçãoRESUMO
Iron acquisition by bacteria and fungi involves in several cases the promiscuous usage of siderophores. Thus, antibiotic resistance from these microorganisms can be circumvented through a strategy of loading toxic metals into siderophores (Trojan Horse Effect). Desferrioxamine (dfo) and its cell-permeant derivative desferrioxamine-caffeine (dfcaf) were complexed with aluminum or gallium for this purpose. The complexes Me(dfo) and Me(dfcaf) (Me=Al3+ and Ga3+) were synthesized and characterized by mass spectroscopy and cyclic voltammetry. Their relative stabilities were studied through competitive equilibria with fluorescent probes calcein, fluorescein-desferrioxamine and 8-hydroxyquinoline. Me(dfo) and Me(dfcaf) were consistently more toxic than free Me3+ against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans, demonstrating the Trojan Horse Effect. Wide spectrum antimicrobial action can be obtained by loading non-essential or toxic metal ions to microbes via a convenient siderophore carrier.