RESUMO
INTRODUCTION: Transfusion-dependent anemia and iron overload are associatedwith reduced survival in myelodysplastic syndrome (MDS). This cross-sectional study aimed to evaluate the prevalence of hepatic and cardiac overload in patients with MDS as measured by T2* magnetic resonance imaging (MRI), and its correlation with survival. METHODS: MDS or chronic myelomonocytic leukemia patients had iron overload evaluated by T2* MRI. HIO was considered when hepatic iron concentration ≥ 2 g/mg. Cardiac iron overload was considered with a T2*-value < 20 ms. RESULTS: Among 71 patients analyzed, median hepatic iron concentration was 3.9 g/mg (range 0.9-16 g/mg), and 68%of patients had hepatic iron overload. Patients with hepatic iron overload had higher mean ferritin levels (1182 ng/mL versus 185 ng/mL, p < 0.0001), transferrin saturation (76% versus 34%, p < 0.0001) and lower survival rates. Median cardiac T2*value was 42 ms (range 19.7-70.1 ms), and only one patienthad a T2* value indicative of cardiac iron overload. CONCLUSIONS: Hepatic iron overload is found in two thirds of patients, even in cases without laboratory signs of iron overload. Hepatic iron overload by T2* MRI is associated with a decreased risk of survival in patients with MDS.
Assuntos
Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/etiologia , Fígado/diagnóstico por imagem , Fígado/patologia , Imageamento por Ressonância Magnética , Síndromes Mielodisplásicas/complicações , Miocárdio/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Transformação Celular Neoplásica , Estudos Transversais , Feminino , Humanos , Incidência , Sobrecarga de Ferro/epidemiologia , Sobrecarga de Ferro/metabolismo , Fígado/metabolismo , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Miocárdio/metabolismo , Prevalência , Avaliação de Sintomas , Adulto JovemRESUMO
Manganese (Mn) is an essential trace element required for the proper functioning of a variety of physiological processes. However, chronic exposures to Mn can cause neurotoxicity in humans, especially when it occurs during critical stages of the central nervous system development. The mechanisms mediating this phenomenon as well as the contribution of Mn speciation and the sensitivity of different types of neuronal cells in such toxicity are poorly understood. This study was aimed to investigate the mechanisms mediating the toxic effects of MnCl(2), Mn(II) citrate, Mn(III) citrate, and Mn(III) pyrophosphate in primary cultures of neocortical (CTX) and cerebellar granular (CGC) neurons. Cell viability, mitochondrial function, and glutathione levels were evaluated after Mn exposure. CGC were significantly more susceptible to Mn-induced toxicity when compared with CTX. Moreover, undifferentiated CGC were more vulnerable to Mn toxicity than mature neurons. Mitochondrial dysfunction was observed after the exposure to all the tested Mn species. Ascorbate protected CGC against Mn-induced neurotoxicity, and this event seemed to be related to the dual role of ascorbate in neurons, acting as antioxidant and metabolic energetic supplier. CTX were protected from Mn-induced toxicity by ascorbate only when coincubated with lactate. These findings reinforce and extend the notion of the hazardous effects of Mn toward neuronal cells. In addition, the present results indicate that Mn-induced neurotoxicity is influenced by brain cell types, their origins, and developmental stages as well as by the chemical speciation of Mn, thus providing important information about Mn-induced developmental neurotoxicity and its risk assessment.
Assuntos
Cerebelo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Manganês/toxicidade , Neurônios/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Ácido Ascórbico/farmacologia , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cerebelo/embriologia , Cerebelo/crescimento & desenvolvimento , Cerebelo/patologia , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Espectroscopia de Ressonância de Spin Eletrônica , Glutationa/metabolismo , Manganês/química , Manganês/farmacocinética , Compostos de Manganês/química , Compostos de Manganês/farmacocinética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Mitocôndrias/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Organogênese/efeitos dos fármacos , Compostos Organometálicos/química , Compostos Organometálicos/farmacocinética , Compostos Organometálicos/toxicidade , Oxirredução , Espectrofotometria Atômica , Espectrofotometria UltravioletaRESUMO
Fluorescence metalosensors provide a means to detect iron in biological systems that is versatile, economical, sensitive and of a high-throughput nature. They rely on relatively high-affinity iron-binding carriers conjugated to highly fluorescent probes that undergo quenching after metal complexation. Metal specificity is determined by probes containing either an iron-binding moiety of high affinity (type A) or of relatively lower affinity (type B) used in combination with a strong specific iron chelator. Due to the heterogeneous nature of biological systems, the apparent metal-binding affinity and complexation stoichiometry ought to be specifically defined. Fluoresceinated moieties coupled to metal-binding cores detect Fe at sub-micromolar concentrations and even sub-microlitre volumes (i.e. cells). Although an ideal probe should also be specific for a particular oxidation state of iron, in physiological conditions that property might be difficult to attain. Quantification of labile iron in cells has relied on the ability of permeant iron chelators to restore the fluorescence of probes quenched by intracellular Fe. Modern design of probes aims to (a) improve probe targeting to specific cell compartments and (b) create probes that respond to metal binding by signal enhancement.
Assuntos
Ferro/análise , Calibragem , Espaço Extracelular/química , Corantes Fluorescentes , Humanos , Quelantes de Ferro/análise , Células K562 , Espectrometria de Fluorescência/métodosRESUMO
BACKGROUND: Labile plasma iron (LPI) associated with iron supplementation has been implicated in complications found in dialysis patients. As LPI can potentially catalyse oxygen radical generation, we determined the presence of labile iron in the parenteral preparations and the frequency of occurrence of LPI in dialysis patients. DESIGN: The capacity to donate iron to apotransferrin (apo-) or to the chelator desferrioxamine (DFO) was measured with fluorescein-Tf (Fl-Tf) and Fl-DFO, respectively. Those probes undergo quenching upon binding to iron. Iron-catalysed generation of oxidant species was determined with dihydrorhodamine. Plasma nontransferrin-bound iron (NTBI), here termed LPI, was determined by mobilization of iron from low-affinity binding sites with oxalate, followed by its quantification with Fl-Tf in the presence of Ga(III). RESULTS: Normal individuals and most (80%) dialysis patients, analysed at least 1 week after iron supplementation showed no detectable (<0.2 microm) LPI. However, approximately 20% of the patients (n = 71) showed significant LPI levels (>0.2 microm), in some cases weeks after iron administration. LPI levels correlated best (r2 = 0.9) with Tf saturation. The iron preparations contained 2-6% low molecular weight and redox-active iron, most of which is chelated by Tf. CONCLUSIONS: Parenteral iron formulations contain a small but significant fraction of redox-active iron, most of which is scavenged by apo-Tf within <1 h. Therefore, oxidant stress associated with iron infusion is likely to be transient. The bulk of the polymeric iron is apparently inaccessible to apo-Tf. Although LPI might return to normal within 2 h of intravenous iron infusion, the long-term persistence of low-level LPI in up to 20% of end stage renal disease (ESRD) patients indicates that complete clearance of the intravenous iron may be more protracted than originally estimated.
Assuntos
Anemia/tratamento farmacológico , Ferro/farmacocinética , Falência Renal Crônica/sangue , Diálise Renal , Transferrina/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/metabolismo , Carboidratos/sangue , Carboidratos/farmacocinética , Química Farmacêutica , Estudos de Coortes , Desferroxamina , Radicais Livres/metabolismo , Humanos , Infusões Parenterais , Ferro/sangue , Ferro/química , Quelantes de Ferro , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Pessoa de Meia-Idade , Peso Molecular , Estresse Oxidativo/efeitos dos fármacosRESUMO
Various divalent rhodium complexes Rh2(L)4 (L = acetate, propionate, butyrate, trifluoroacetate and trifluoroacetamidate) have been found to bind to non-defatted human serum albumin (HSA) at molar ratios about 8:1. The circular dichroism measurements showed that the more liposoluble carboxylates, butyrate and trifluoroacetate, caused the major alterations of the secondary structure of HSA. Stern-Volmer constants for the fluorescence quenching of the buried Trp214 residue by these complexes were also higher for the lipophilic metal compounds. In the case of the rhodium carboxylates it was observed that their denaturating and quenching properties could be explained in terms of their liposolubilities: the higher their lipophilic characters, the higher their abilities to penetrate inside the protein framework leading to structural alterations, and the closer they could get to the Trp residue causing fluorescence quenching. The liposoluble amidate complex, Rh2 (tfc)4, presented an intermediate quenching and did not cause structural alterations in the protein, presumably not penetrating inside the peptidic backbone. This study shows that it is possible to design new antitumor metal complexes which bind, to a large extent, to a transport protein causing little structural damage.
Assuntos
Antineoplásicos/química , Ródio/química , Albumina Sérica/química , Dicroísmo Circular , Humanos , Espectrometria de FluorescênciaRESUMO
The survival of 90% of a tumor-bearing population treated with the complex Rh(2) (CF(3)CONH)(4) was examined and the pharmacological parameter Surv(90) determined. Histopathological alterations raised for this drug in several tissues were studied in Balb-c mice. A Surv(90) dose of 3.8x 10(-5) mol/kg was found.
RESUMO
The rhodium (II) complexes Rh(2)(tfa)(4).2(tfac) and Rh(2)(tfacam)(4) (tfacam = CF(3)CONH-,tfa = CF(3)COO-,tfac = CF(3)CONH(2)) were synthesized and characterized by microanalysis and electronic and vibrational spectroscopies. Rh(2)(tfacam)(4) was tested both in vitro (U937 and K562 human leukemia cells and Ehrlich ascitic tumor cells) and in vivo for cytostatic activity and lethal dose determination, respectively. This is the first rhodium tetra-amidate to have its biological activity evaluated. The LD(50) value for Rh(2)(tfacam)(4) is of the same order as that of cisplatin, and it was verified that the rhodium complex usually needs lower doses than cisplatin to promote the same inhibitory effects.