Decavanadate toxicity effects following in vivo administration

Very few in vivo animal studies involving vanadium consider the contribution of decavanadate (V10) to vanadium biological effects. Recently, it is been suggested that decameric vanadate may not completely fall apart into other vanadate oligomers before induces changes in cell homeostasis, namely in several stress markers. An acute exposure of different fish species (Halobactrachus didactilus, Lusitanian toadfish, and Sparus aurata, gilthead seabream) to decavanadate, but not to other vanadate oligomers, induced different effects than vanadate in catalase activity, glutathione content, lipid peroxidation, mitochondrial superoxide anion production and vanadium accumulation, whereas both solutions seem to equally depress reactive oxygen species (ROS) production as well as total intracellular reducing power. Vanadium is accumulated in Sparus aurata mitochondria in particular when decavanadate is administrated. Moreover, exposure to different vanadate oligomers induced morphological changes in fish cardiac, hepatic and renal tissues causing tissues lesions in the liver and kidney, but not cardiac tissue. Nevertheless, the results highlight that different vanadate oligomers seem to follow, not only in vitro but also in vivo, different pathways, with different targets and effects. These recent findings, that are now summarized, point out the decameric vanadate species contributions to in vivo effects induced by vanadium in biological systems

Decavanadate induces mitochondrial membrane depolarization and inhibits oxygen consumption

Decavanadate induced rat liver mitochondrial depolarization at very low concentrations, half-depolarization with 39 nM decavanadate, while it was needed a 130-fold higher concentration of monomeric vanadate (5 lM) to induce the same effect. Decavanadate also inhibits mitochondrial repolarization induced by reduced glutathione in vitro, with an inhibition constant of 1 lM, whereas no effect was observed up to 100 lM of monomeric vanadate. The oxygen consumption by mitochondria is also inhibited by lower decavanadate than monomeric vanadate concentrations, i.e. 50% inhibition is attained with 99 nM decavanadate and 10 lM monomeric vanadate. Thus, decavanadate is stronger as mitochondrial depolarization agent than as inhibitor of mitochondrial oxygen consumption. Up to 5 lM, decavanadate does not alter mitochondrial NADH levels nor inhibit neither FOF1-ATPase nor cytochrome c oxidase activity, but it induces changes in the redox steady-state of mitochondrial b-type cytochromes (complex III). NMR spectra showed that decameric vanadate is the predominant vanadate species in decavanadate solutions. It is concluded that decavanadate is much more potent mitochondrial depolarization agent and a more potent inhibitor of mitochondrial oxygen consumption than monomeric vanadate, pointing out the importance to take into account the contribution of higher oligomeric species of vanadium for the biological effects of vanadate solutions

Contribuição de decavanadato para os efeitos IN VIVO e IN VITRO de vanadato no músculo cardíaco

Tese dout., Biologia - Fisiologia Animal, Universidade do Algarve, 2007No presente estudo aborda-se a contribuição da espécie decamérica de vanadato nos efeitos tóxicos in vivo e in vitro de vanadato. Após administração intravenosa de decavanadato em Sparus aurata, o vanadato decamérico induz respostas nos marcadores de stresse oxidativo do tecido cardíaco distintas das promovidas pelo monovanadato, evidenciando a importância de considerar a contribuição dos diferentes oligómeros de vanadato para a toxicidade in vivo de vanadato. Quando administrado na forma de vanadato decamérico, a acumulação de vanádio na mitocôndria sugere este organelo como potencial alvo da toxicidade de vanadato. Estudos in vitro demonstraram que o vanadato decamérico é um potente agente despolarizador da membrana mitocondrial e inibidor do consumo de oxigénio, para além de impedir a repolarização da membrana mitocondrial, em mitocôndrias de coração de peixe e fígado de rato. Verificou-se também que o vanadato decamérico afecta a bioenergética mitocondrial bloqueando a cadeia transportadora de electrões da mitocôndria. Em cardiomiócitos, descreve-se a despolarização da membrana mitocondrial como um evento precursor de morte celular necrótica induzida por vanadato. Conclui-se que, o vanadato decamérico induz efeitos diferentes dos promovidos do monovanadato nos sistemas biológicos, através de diferentes mecanismos, contribuindo, pelo menos em parte, para os efeitos tóxicos induzidos por vanadato na mitocôndria.Fundação para a Ciência e Tecnologia (FCT

The pathways of cell death in cardiomyocytes induced by vanadate

After 24 hours, cardiac myocytes exposure to 10 μM (LD50) vanadate (meta or decavanadate) an increased (30%) of caspase 3-activation was observed, although not significant. On contrary, a significant decrease (40%) of ATP content, characteristic of necrotic cell death was detected. Furthermore, vanadate treatment increased intracellular Ca2+ level from 60 nM to 240 nM, whereas it decreases mitochondria superoxide anion generation and induces mitochondria membrane depolarization (IC50=6.5 μM). In conclusion, micromolar vanadate exposure induces large chances in two major bioenergetic markers in cardiac myocytes: intracellular calcium concentration and superoxide anion mitochondrial production, suggesting a necrotic cell death through a mitochondrial toxic pathway

Vanadate induces necrotic cell death in neonatal rat cardiomyocytes through mitochondrial membrane depolarization

Besides the well-known inotropic effects of vanadium in cardiac muscle, previous studies have shown that vanadate can stimulate cell growth or induce cell death. In this work, we studied the toxicity to neonatal rat ventricular myocytes (cardiomyocytes) of two vanadate solutions containing different oligovanadates distribution, decavanadate (containing decameric vanadate, V10) and metavanadate (containing monomeric vanadate and also di-, tetra-, and pentavanadate). Incubation for 24 h with decavanadate or metavanadate induced necrotic cell death of cardiomyocytes, without significant caspase-3 activation. Only 10 μM total vanadium of either decavanadate (1 μMV10) or metavanadate (10 μM total vanadium) was needed to produce 50% loss of cell viability after 24 h (assessed with MTT and propidium iodide assays). Atomic absorption spectroscopy showed that vanadium accumulation in cardiomyocytes after 24 h was the same when incubation was done with decavanadate or metavanadate. A decrease of 75% of the rate of mitochondrial superoxide anion generation, monitored with dihydroethidium, and a sustained rise of cytosolic calcium (monitored with Fura-2-loaded cardiomyocytes) was observed after 24 h of incubation of cardiomyocytes with decavanadate or metavanadate concentrations close to those inducing 50% loss of cell viability produced. In addition, mitochondrial membrane depolarization within cardiomyocytes, monitored with tetramethylrhodamine ethyl esther or with 3,3′,6,6′-tetrachloro-1,1′,3,3′- tetraethylbenzimidazolcarbocyanine iodide, were observed after only 6 h of incubation with decavanadate or metavanadate. The concentration needed for 50% mitochondrial depolarization was 6.5 ( 1 μM total vanadium for both decavanadate (0.65 μMV10) and metavanadate. In conclusion, mitochondrial membrane depolarization was an early event in decavanadate- and monovanadate-induced necrotic cell death of cardiomyocytes

Vanadate oligomers: in vivo effects in hepatic vanadium accumulation and stress markers

The formation of vanadate oligomeric species is often disregarded in studies on vanadate effects in biological systems, particularly in vivo, even though they may interact with high affinity with many proteins. We report the effects in fish hepatic tissue of an acute intravenous exposure (12, 24 h and 7 days) to two vanadium(V) solutions, metavanadate and decavanadate, containing different vanadate oligomers administered at sub-lethal concentration (5 mM; 1 mg/kg). Decavanadate solution promotes a 5-fold increase (0.135 ± 0.053 lg V 1 dry tissues) in the vanadium content of the mitochondrial fraction 7 days after exposition, whereas no effects were observed after metavanadate solution administration. Reduced glutathione (GSH) levels did not change and the overall reactive oxygen species (ROS) production was decreased by 30% 24 h after decavanadate administration, while for metavanadate, GSH levels increased 35%, the overall ROS production was depressed by 40% and mitochondrial superoxide anion production decreased 45%. Decavanadate intoxication did not induce changes in the rate of lipid peroxidation till 12 h, but later increased 80%, which is similar to the increase observed for metavanadate after 24 h. Decameric vanadate administration clearly induces different effects than the other vanadate oligomeric species, pointing out the importance of taking into account the different vanadate oligomers in the evaluation of vanadium(V) effects in biological systems

Methodology of trace metals analysis in reference, generic and similar medicines: a comparison / Metodologia da análise de metais trace em medicamentos de referência, genéricos e semelhantes: uma comparação

Trace metals are, among the toxic substances, some that cause intoxication of the human organism, they are highly reactive and bioaccumulative; however, living things require small amounts of some metals, including Co, Cu, Mn, Mo, V, Sr and Zn to perform vital functions. Other metals such as mercury, lead and cadmium, have no function to organic systems, and their accumulation may cause several pathologies. Trace metals are also part of pharmaceutical preparations found as contaminants from machinery, handling or medicinal plants’ extracts. The presence of metals in medicines has become a relevant subject to evaluate the degree of exposure and possible consequences for human health. The aim of the work being carried out at the Northeastern Regional Center for Nuclear Sciences in conjunction with the Department of Nuclear Energy is to obtain a qualitative and quantitative analysis of trace metals in medicines and comparing with specific parameters of the Brazilian Legislation. To help regulatory agencies to have a greater control of medicines sold based on the elaborated methodology.  

Vanadium distribution, lipid peroxidation and oxidative stress markers upon decavanadate in vivo administration

The contribution of decameric vanadate species to vanadate toxic effects in cardiac muscle was studied following an intravenous administration of a decavanadate solution (1 mM total vanadium) in Sparus aurata. Although decameric vanadate is unstable in the assay medium, it decomposes with a half-life time of 16 allowing studying its effects not only in vitro but also in vivo. After 1, 6 and 12 h upon decavanadate administration the increase of vanadium in blood plasma, red blood cells and in cardiac mitochondria and cytosol is not affected in comparison to the administration of a metavanadate solution containing labile oxovanadates. Cardiac tissue lipid peroxidation increases up to 20%, 1, 6 and 12 h after metavanadate administration, whilst for decavanadate no effects were observed except 1 h after treatment (+20%). Metavanadate administration clearly differs from decavanadate by enhancing, 12 h after exposure, mitochondrial superoxide dismutase (SOD) activity (+115%) and not affecting catalase (CAT) activity whereas decavanadate increases SOD activity by 20% and decreases ( 55%) mitochondrial CAT activity. At early times of exposure, 1 and 6 h, the only effect observed upon decavanadate administration was the increase by 20% of SOD activity. In conclusion, decavanadate has a different response pattern of lipid peroxidation and oxidative stress markers, in spite of the same vanadium distribution in cardiac cells observed after decavanadate and metavanadate administration. It is suggested that once formed decameric vanadate species has a different reactivity than vanadate, thus, pointing out that the differential contribution of vanadium oligomers should be taken into account to rationalize in vivo vanadate toxicity

Estudantes com deficiência no ensino superior: percepção dos factores facilitadores e inibidores da integração e do sucesso académico

Fundação para a Ciência e a Tecnologia (FCT).Secretariado Nacional para a Reabilitação e Integração de Pessoas com Deficiência

Mortality of Patients with Hematological Malignancy after Admission to the Intensive Care Unit

Background: The admission of patients with malignancies to an intensive care unit (ICU) still remains a matter of substantial controversy. The identification of factors that potentially influence the patient outcome can help ICU professionals make appropriate decisions. Patients and Methods: 90 adult patients with hematological malignancy (leukemia 47.8%, high-grade lymphoma 50%) admitted to the ICU were analyzed retrospectively in this single-center study considering numerous variables with regard to their influence on ICU and day-100 mortality. Results: The median simplified acute physiology score (SAPS) II at ICU admission was 55 (ICU survivors 47 vs. 60.5 for non-survivors). The overall ICU mortality rate was 45.6%. With multivariate regression analysis, patients admitted with sepsis and acute respiratory failure had a significantly increased ICU mortality (sepsis odds ratio (OR) 9.12, 95% confidence interval (CI) 1.1-99.7, p = 0.04; respiratory failure OR 13.72, 95% CI 1.39-136.15, p = 0.025). Additional factors associated with an increased mortality were: high doses of catecholamines (ICU: OR 7.37, p = 0.005; day 100: hazard ratio (HR) 2.96, p < 0.0001), renal replacement therapy (day 100: HR 1.93, p = 0.026), and high SAPS II (ICU: HR 1.05, p = 0.038; day 100: HR 1.2, p = 0.027). Conclusion: The decision for or against ICU admission of patients with hematological diseases should become increasingly independent of the underlying malignant disease