RESUMO
This study aimed to examine the possible association between the oxidative stress parameters and clomiphene citrate resistance in polycystic ovary syndrome. The demographic data, hormone profiles and oxidant and antioxidant values of 50 clomiphene citrate-resistant polycystic ovary syndrome patients (Group 1), 32 clomiphene citrate-sensitive polycystic ovary syndrome patients (Group 2) and 87 non-polycystic ovary syndrome patients (Group 3) were compared. The average age, follicle-stimulating hormone, oestradiol, thyroid-stimulating hormone and prolactin values of the three groups were found to be homogeneous. Ferroxidase, catalase and myeloperoxidase levels were determined to be lower in the clomiphene citrate-resistant group compared to clomiphene citrate-sensitive and non-polycystic ovary syndrome groups (p < .001). As a result, Polycystic ovary syndrome patients with clomiphene resistance had lower antioxidant (catalase and ferroxidase) levels compared to those who were sensitive to clomiphene and who did not have polycystic ovary syndrome. The myeloperoxidase levels also demonstrated the same trend, which might be due to a compensation mechanism.Impact StatementWhat is already known on this subject? In the literature, there are many studies evaluating the association between PCOS and oxidative stress. No research related to antioxidants in clomiphene citrate-sensitive and clomiphene citrate-resistant PCOS patients was found in the relevant literature.What do the results of this study add? In this study, the antioxidants catalase and ferroxidase were found to be lower in PCOS women compared to non-PCOS; however, they were the lowest in clomiphene citrate-resistant PCOS women. Interestingly, myeloperoxidase, which is a part of oxidative stress, was also found to be higher in the non-PCOS group.What are the implications of these findings for clinical practice and/or further research? This study contributes to the literature because it is the first to compare the relation between CC and oxidant and antioxidant markers. These markers will be a guide for PCOS management in patients with CC-R.
Assuntos
Antioxidantes/metabolismo , Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Infertilidade Feminina/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Síndrome do Ovário Policístico/sangue , Adulto , Catalase/efeitos dos fármacos , Ceruloplasmina/efeitos dos fármacos , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Infertilidade Feminina/sangue , Infertilidade Feminina/etiologia , Peroxidase/efeitos dos fármacos , Síndrome do Ovário Policístico/complicações , Prolactina/sangue , Estudos Prospectivos , Tireotropina/sangueAssuntos
Desferroxamina/uso terapêutico , Sideróforos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Ceruloplasmina/deficiência , Ceruloplasmina/efeitos dos fármacos , Feminino , Humanos , Distúrbios do Metabolismo do Ferro/patologia , Estudos Longitudinais , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Doenças Neurodegenerativas/patologiaRESUMO
This study was to examine the effects of copper on the mitochondrial non-specific pore. Three hundred sixty, one-day-old, healthy Arbor Acres (AA) broilers were fed with different concentrations (11, 110, 220, and 330 mg/kg) of copper originated from copper sulfate, tribasic copper chloride (TBCC), or copper methionine. At the indicated time point, the mitochondrial permeability transition (MPT) and copper concentration were analyzed. Results showed that under the same copper concentration, the MPT of broilers fed copper methionine was the greatest, followed by TBCC, then copper sulfate. The effects of copper on MPT were time- and dose-dependent. Furthermore, in vitro in the presence of K(+), 5 µM Cu(2+) could cause permeability transition as compared to 10 µM Cu(2+) in buffer without K(+). Taking these results together, we have shown that hepatocellular MPT may be influenced not only by source and concentration of copper or the raising period of broilers, but also by the existence of K(+).
Assuntos
Cobre/farmacologia , Hepatócitos/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Animais , Ceruloplasmina/efeitos dos fármacos , Ceruloplasmina/metabolismo , Galinhas , Cobre/administração & dosagem , Cobre/metabolismo , Cobre/farmacocinética , Sulfato de Cobre/farmacocinética , Sulfato de Cobre/farmacologia , Relação Dose-Resposta a Droga , Hepatócitos/metabolismo , Hepatócitos/ultraestrutura , Peróxido de Hidrogênio/metabolismo , Indicadores e Reagentes , Metionina/metabolismo , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/ultraestrutura , Modelos Estatísticos , Compostos Organometálicos/metabolismo , Permeabilidade/efeitos dos fármacosRESUMO
Wilson disease is an autosomal recessive disorder with copper metabolism. In Japan, the standard treatment is the administration of copper chelating agents, such as D-penicillamine and trientine. In this study, the authors used zinc acetate to treat Japanese patients with Wilson disease and investigated its efficacy. The 37 patients that comprise this study were found to have Wilson disease using clinical and biochemical tests and were administrated zinc acetate for 48 weeks. The authors followed the clinical symptoms and laboratory findings of the patients by assessing their complete blood counts, biochemical findings, as well as the results of urinalysis and special laboratory tests for copper and zinc metabolism. We also examined side effects of the treatment. Zinc acetate did not aggravate the hepatic or neurological symptoms of any of the patients. Blood biochemical analysis also did not reveal elevation of alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltranspeptidase levels. Zinc treatment did not aggravate the patients' clinical signs and/or laboratory findings. However, it did improve some clinical symptoms of the Wilson disease patients. Although this agent had some side effects, none of them were severe. The authors measured spot urinary copper excretion, which gave an indication of the efficacy of treatment and of the sufficient dosage of zinc. We recommend maintaining a spot urinary copper excretion less than 0.075-µg/mg creatinine. The authors conclude that zinc acetate is an effective and safe treatment for Japanese patients with Wilson disease.
Assuntos
Cobre/metabolismo , Degeneração Hepatolenticular/tratamento farmacológico , Acetato de Zinco/uso terapêutico , Adolescente , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Contagem de Células Sanguíneas , Ceruloplasmina/efeitos dos fármacos , Ceruloplasmina/metabolismo , Criança , Cobre/urina , Feminino , Degeneração Hepatolenticular/sangue , Degeneração Hepatolenticular/metabolismo , Degeneração Hepatolenticular/urina , Humanos , Japão , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Penicilamina/uso terapêutico , Acetato de Zinco/efeitos adversosRESUMO
Cuprizone is used to obtain demyelination in mice. Cuprizone-treated mice show symptoms similar to several neurodegenerative disorders such as severe status spongiosus. Although it has a simple chemical formula, its neurotoxic mechanism is still unknown. In this work, we examined both physico-chemical properties and biological effects of cuprizone. Our results indicate that cuprizone has very complicated and misunderstood solution chemistry. Moreover, we show here the inability of cuprizone to cross neither the intestinal epithelial barrier nor the neuronal cell membrane, as well its high tolerability by cultured neurons. If added to mice diet, cuprizone does not accumulate in liver or in brain. Therefore, its neurotoxic effect is explainable only in terms of its capability to chelate copper, leading to chronic copper deficiency.
Assuntos
Cobre/deficiência , Cuprizona/toxicidade , Inibidores da Monoaminoxidase/toxicidade , Degeneração Neural/etiologia , Síndromes Neurotóxicas , Animais , Encéfalo/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/fisiologia , Ceruloplasmina/efeitos dos fármacos , Fenômenos Químicos , Cobre/metabolismo , Cuprizona/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Fígado/metabolismo , Espectrometria de Massas/métodos , Camundongos , Inibidores da Monoaminoxidase/química , Degeneração Neural/metabolismo , Neuroblastoma , Síndromes Neurotóxicas/complicações , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Oxirredutases/metabolismo , Espectrofotometria Atômica/métodosRESUMO
Ceruloplasmin is a multicopper oxidase required for correct iron homeostasis.Previously, we have identified a ceruloplasmin mutant associated with the iron overload disease aceruloplasminemia, which was unable to acquire copper from the mammalian pump ATP7B but could be produced in an enzymatically active form in yeast. Here, we report the expression of recombinant ceruloplasmin in the yeast Pichia pastoris and the study of the role of five surface-exposed loops in copper incorporation by comparing the efficiencies of mammalian ATP7B and yeast Ccc2p. The possibility to "mix and match" mammalian and yeast multicopper oxidases and copper ATPases can provide clues on the molecular features underlying the process of copper loading in multicopper oxidases.
Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Cobre/farmacologia , Animais , Sítios de Ligação , Ceruloplasmina/química , Ceruloplasmina/efeitos dos fármacos , Cobre/metabolismo , ATPases Transportadoras de Cobre , Teste de Complementação Genética , Humanos , Mamíferos , Modelos Moleculares , Pichia/metabolismo , Conformação Proteica , Isoformas de Proteínas/efeitos dos fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , VertebradosRESUMO
BACKGROUND: Polymorphonuclear leukocytes (PMNs) from subjects with localized aggressive periodontitis (LAgP) present multiple functional abnormalities associated with a phenotypically primed PMN phenotype. Local inflammation is characterized by hypoxia, which leads to increased production of superoxide (O(2)(-)) by PMNs. Ceruloplasmin (CP) is also induced by hypoxia and inflammation. The aim of this study was to investigate the role of CP in O(2)(-) generation in PMNs from healthy subjects and patients with LAgP. METHODS: PMNs were isolated from healthy subjects and those with LAgP (N = 36). Superoxide was measured by cytochrome-C reduction at 550 nm. Intracellular CP expression was analyzed by real-time polymerase chain reaction and Western blotting. Serum levels of CP were measured by enzyme-linked immunosorbent assay. Intracellular iron ion conversion was spectrophotometrically determined by measuring the absorbance of sigma-phenanthroline at 510 nm. RESULTS: O(2)(-) generation was significantly higher in LAgP PMNs before and after stimulation with formyl-methionyl-leucyl-phenylalanine (100 nM). CP expression in PMNs and CP levels in serum were significantly higher in subjects with LAgP compared to the PMNs and serum samples from matched healthy donors (P <0.05). LAgP PMNs also had significantly higher levels of Fe(3+) and lower levels of Fe(2+) compared to healthy PMNs (P <0.05), suggesting increased iron conversion. Exogenous CP treatment of healthy PMNs resulted in significant increases in O(2)(-) generation and iron ion conversion similar to LAgP PMNs. CONCLUSION: LAgP PMNs are primed to express higher levels of CP, leading to hypoxia-mediated O(2)(-) generation in PMNs and increased oxidative stress and neutrophil-mediated tissue injury in LAgP.
Assuntos
Periodontite Agressiva/imunologia , Ceruloplasmina/análise , Neutrófilos/enzimologia , Adolescente , Adulto , Western Blotting , Estudos de Casos e Controles , Ceruloplasmina/efeitos dos fármacos , Ceruloplasmina/metabolismo , Citocromos c/metabolismo , Feminino , Compostos Férricos/análise , Compostos Ferrosos/análise , Humanos , Hipóxia/enzimologia , Hipóxia/metabolismo , Masculino , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Ativação de Neutrófilo/efeitos dos fármacos , Ativação de Neutrófilo/imunologia , Neutrófilos/efeitos dos fármacos , Oxidantes/análise , Oxidantes/metabolismo , Oxirredução , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrofotometria , Superóxidos/análise , Superóxidos/metabolismo , Adulto JovemRESUMO
PURPOSE: Copper chelation reduces the secretion of many angiogenic factors and reduces tumor growth and microvascular density in animal models. ATN-224 is a second-generation analogue of ammonium tetrathiomolybdate. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin, to 5 to 15 mg/dL (normal 16-60) in 14 to 21 days, to determine the pharmacokinetic profile of ATN-224 and to evaluate dose-limiting toxicities. PATIENTS AND METHODS: Cohorts of patients were treated with escalating oral doses of ATN-224 until copper depletion followed by a titrated maintenance dose. RESULTS: Eighteen patients received 78 cycles of ATN-224. Mean baseline ceruloplasmin was 39.6 mg/dL. The maximum administered dose was 330 mg/d where grade 3 fatigue was dose-limiting. At the maximum tolerated dose of 300 mg/d, the median time to achieve target ceruloplasmin was 21 days, and toxicities included grade 3 anemia, grade 3 neutropenia, fatigue, and sulfur eructation. ATN-224 treatment caused a significant reduction (> 90%) in RBC superoxide dismutase 1 activity and circulating endothelial cells. Pharmacokinetic data indicate greater absorption of ATN-224 and more rapid ceruloplasmin reduction when administered with a proton pump inhibitor. Stable disease of > 6 months was observed in 2 patients. CONCLUSIONS: Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/d leads to a reduction of serum ceruloplasmin levels in 80% patients within 21 days. A loading dose of 300 mg/d for 2 weeks followed by a titrated maintenance dose will be the recommended starting dose for phase II study.
Assuntos
Quelantes/efeitos adversos , Quelantes/farmacocinética , Quelantes/uso terapêutico , Terapia por Quelação , Colina/efeitos adversos , Colina/farmacocinética , Colina/uso terapêutico , Cobre/sangue , Molibdênio/efeitos adversos , Molibdênio/farmacocinética , Molibdênio/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Ceruloplasmina/efeitos dos fármacos , Citocinas/sangue , Citocinas/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Superóxido Dismutase/sangue , Superóxido Dismutase/efeitos dos fármacosRESUMO
Ceruloplasmin (glycosylphosphatidylinositol-linked ferroxidase associated with normal astrocytes) can also be secreted by glioma cells, where its function is unknown. Ceruloplasmin is not only present in glioma cells and in human glioma specimens but also is enriched in highly malignant glioma stem-like cells. Hyaluronan is a large extracellular glycosaminoglycan that enhances malignant glioma behaviors by interacting with CD44 receptors and by downstream activation of signaling proteins and transporters associated with malignancy. We examined the relationship between hyaluronan and ceruloplasmin expression in glioma stem-like cells. Antagonism of hyaluronan interactions with short-fragment hyaluronan oligomers decreased ceruloplasmin expression in parental and stem-like glioma cells in vivo and in cell culture, implying that hyaluronan regulates ceruloplasmin expression. Further gain and loss-of-function studies are needed to fully define the relationship between hyaluronan and ceruloplasmin, and ceruloplasmin's effect on malignant behaviors.
Assuntos
Neoplasias Encefálicas/metabolismo , Ceruloplasmina/metabolismo , Glioma/metabolismo , Ácido Hialurônico/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ceruloplasmina/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Resistencia a Medicamentos Antineoplásicos/genética , Matriz Extracelular/metabolismo , Feminino , Glioma/genética , Glioma/fisiopatologia , Humanos , Receptores de Hialuronatos/efeitos dos fármacos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/farmacologia , Invasividade Neoplásica/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Neoplasias da Medula Espinal/tratamento farmacológico , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/metabolismo , Células-Tronco/efeitos dos fármacosRESUMO
OBJECT: Anemia and leukopenia caused by copper deficiency are well-documented consequences of long-term total parenteral nutrition. We measured the serum copper levels of bed-ridden patients receiving enteral feeding, and evaluated optical and ultrastructural features of bone marrow before and after copper supplementation. PATIENTS AND METHODS: Serum samples were obtained from 15 bed-ridden elderly patients receiving tube feeding (TF) and 10 age-matched bed-ridden patients who took food orally (CO), and the copper ceruloplasmin concentration of each sample was measured. Bone marrow samples were obtained from patients who exhibited copper deficiency and leukopenia and/or anemia before and after the copper supplementation, for use in light and electron microscopic analysis. RESULTS: The tube-fed patients had significantly lower mean serum copper and ceruloplasmin concentrations than the control patients. Seven of the 15 tube-fed patients had reduced serum copper concentrations and leukopenia. Six of those 7 patients also had anemia. Copper sulfate was administered to those 7 patients by enteral tube; their copper concentration, anemia and leukopenia improved within 1 month after they were administered copper sulfate. In the bone marrow examination before copper supplementation, light microscopy showed cytoplasmic vacuolization in both myeloid and erythroid precursors, and electron microscopy showed electron-dense deposits in mitochondria and cytoplasm of erythroid and myeloid cells. After copper supplementation, these pathological changes disappeared. CONCLUSIONS: Bicytopenia is likely to occur in tube-fed patients with copper deficiency. Copper deficiency appears to be associated with cytoplasmic vacuolization and electron-dense deposits in mitochondria in erythroid and myeloid cells.
Assuntos
Anemia/etiologia , Cobre/deficiência , Deficiências Nutricionais/complicações , Nutrição Enteral , Leucopenia/etiologia , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/dietoterapia , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Ceruloplasmina/efeitos dos fármacos , Ceruloplasmina/metabolismo , Cobre/administração & dosagem , Cobre/sangue , Deficiências Nutricionais/patologia , Suplementos Nutricionais , Feminino , Humanos , Leucopenia/sangue , Leucopenia/dietoterapia , Masculino , Valores de Referência , Resultado do TratamentoRESUMO
Sapropel was tested for its effect on the permeability of erythrocytic membranes and on the erythrocytic and serum levels of ceruloplasmin, malonic dialdehyde, and dienic conjugates in rats after acute poisoning by carbofos, a malathion insecticide. The increased processes of free radical oxidation during carbofos poisoning were suggested by the higher rates of chemiluminescence of erythrocytes and peripheral blood serum. No significant changes in the parameters of blood oxidative stress in the carbofos-poisoned animals during therapeutic-and-prophylactic use of sapropel indicate that the latter has antioxidative properties. Application of sapropel to normal animals exerted no effect of the studied parameters of oxidative stress. In acute carbofos poisoining, oral sapropel produced a pronounced antioxidative effect, which opens up new vistas for its practical application.
Assuntos
Antioxidantes/metabolismo , Benzopiranos/farmacologia , Malation/intoxicação , Estresse Oxidativo , Intoxicação/terapia , Administração Oral , Animais , Benzopiranos/administração & dosagem , Permeabilidade da Membrana Celular/efeitos dos fármacos , Ceruloplasmina/efeitos dos fármacos , Ceruloplasmina/metabolismo , Membrana Eritrocítica/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Substâncias Húmicas , Malondialdeído/metabolismo , Intoxicação/metabolismo , RatosRESUMO
The purpose of this study was to determine the effects of copper deficiency on key aspects of homocysteine metabolism that involve methionine recycling and transsulfuration. Male weanling Sprague-Dawley rats were fed AIN-93G-based diets containing <1 or approximately 6 mg Cu/kg. After 6 wk (Expt. 1) and 4 wk (Expt. 2) we found that plasma homocysteine was significantly decreased, and plasma glutathione significantly increased, in rats fed the low-Cu diet. Real-time RT-PCR was used to determine the expression of the subunits of glutamate-cysteine ligase (Gcl) in liver that catalyzes the rate-limiting step in glutathione biosynthesis. The expression of Gclc, the catalytic subunit of Gcl, was upregulated by Cu deficiency; Gclm, the modifier subunit, was not affected. Hepatic betaine-homocysteine methyltransferase (Bhmt), which catalyzes one of the two ways that homocysteine can be remethylated to methionine, was downregulated by Cu deficiency. Because Cu deficiency results in upregulation of Gclc and an increase in the biosynthesis of glutathione, it is plausible that the net flux of homocysteine through the transsulfuration pathway is increased. Furthermore, if Bhmt is downregulated, less homocysteine is available for remethylation (methionine recycling) and more is then available to irreversibly enter the transsulfuration pathway where it is lost. The net effect of increased Gclc and decreased Bhmt would be a decrease in homocysteine as a result of Cu deficiency.
Assuntos
Cobre/deficiência , Glutationa/sangue , Homocisteína/sangue , Fígado/metabolismo , Animais , Ceruloplasmina/efeitos dos fármacos , Ceruloplasmina/metabolismo , Cobre/farmacologia , Homocisteína/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , S-Adenosilmetionina/efeitos dos fármacos , S-Adenosilmetionina/metabolismoRESUMO
Oxidative stress is involved in pathogenesis of Raynaud's phenomenon (RP), a hallmark of systemic sclerosis (SSc). Frequent episodes of ischemia-reperfusion may lead to release of free radicals and enhanced lipid peroxidation reflected by elevated levels of malondialdehyde (MDA). The failure of native antioxidants (Catalase [CAT], Superoxide dismutase [SOD], and Ceruloplasmin [CP]) might be crucial in endothelial cells damage in RP. Iloprost (IL) synthetic prostacyclin analogue is currently used in the treatment of SSc patients with RP. The objectives of this study were to compare the serum levels of MDA and CP, CAT and SOD activity in red blood cells hemolysate in SSc patients compared to healthy controls; and to study the effect of 5-days IL infusions on MDA and CP levels, and CAT and SOD activity in SSc patients with RP. Twelve SSc patients were treated with 50 mug IL for 5 days. Blood samples were taken before and after day 1st and after day 5th of IL infusions. Levels of CAT were measured according to the Aebi's method; SOD, according to the Misra and Fridovich method; MDA, according to Slater's method; and CP, according to Ravin's method. Activities of CAT (p < 0.001) and SOD (p < 0.04) were significantly reduced; levels of CP (p < 0.006) and MDA (p < 0.06) were raised in SSc compared to controls. IL infusions caused reduction in MDA (p < 0.0001) levels and enhanced production of SOD (p < 0.006) and CAT (p < 0.003). The levels of CP did not change (p = 0.48). Oxidant status in SSc patients with RP is impaired. Therapy with IL led to normalization of antioxidant activity. We suggest that CAT may be a sensitive and reliable laboratory marker of oxidative stress severity in RP. We found that IL, in addition to its vasoactive properties, has a potential to activate inner antioxidant system. Activation of inner antioxidant activity may explain long-term effect of IL instead of its very short half-life time.
Assuntos
Iloprosta/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Doença de Raynaud/tratamento farmacológico , Escleroderma Sistêmico/complicações , Adulto , Antioxidantes , Catalase/sangue , Catalase/efeitos dos fármacos , Ceruloplasmina/análise , Ceruloplasmina/efeitos dos fármacos , Feminino , Humanos , Malondialdeído/sangue , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Doença de Raynaud/etiologia , Escleroderma Sistêmico/tratamento farmacológico , Superóxido Dismutase/sangue , Superóxido Dismutase/efeitos dos fármacosRESUMO
AIMS: To report on the diagnostic features, management, and clinical outcome after different treatments of Wilson's disease patients followed over a mean period of 15 years. PATIENTS: Thirty-five patients with Wilson's disease referred to the University of Padova's Department of Gastroenterology for diagnosis or treatment were observed for a mean 15 years. The diagnosis was based on clinical symptoms, laboratory tests (ceruloplasmin, urinary, and hepatic copper concentrations), and uptake of the radiostable isotope Cu into the plasma protein pool. Hepatic Cu content was measured by regular follow-up biopsies. Neurologic outcome after therapy was assessed using a newly developed scoring system. RESULTS: Twenty-three (65.7%) patients presented with liver disease; 12 (34.3%) had mixed neurologic and hepatic involvement. All patients had been initially treated with either penicillamine (23) or zinc sulfate (12). The neurologic symptoms became worse or remained stationary in 75% of those treated with penicillamine, whereas zinc treatment improved these symptoms in 90% of treated cases. Both treatments were effective in improving the hepatic symptoms. No differences in hepatic Cu content emerged between follow-up biopsies in either treatment group. Six patients (26%) had to abandon the penicillamine treatment due to side effects. In all, 4 patients underwent liver transplantation, which was successful in 3, with a mean survival after transplantation of 4.6 years; the fourth, who had a severe neurologic impairment, died of central pontine myelinolysis. CONCLUSIONS: Penicillamine and zinc can effectively treat Wilson's disease, though the side effects of penicillamine may be severe enough to prompt its suspension. Liver transplantation remains the treatment of choice for end-stage liver disease.
Assuntos
Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/terapia , Adolescente , Adulto , Alanina Transaminase/sangue , Alanina Transaminase/efeitos dos fármacos , Biomarcadores/sangue , Biomarcadores/urina , Ceruloplasmina/efeitos dos fármacos , Ceruloplasmina/metabolismo , Quelantes/administração & dosagem , Quelantes/efeitos adversos , Criança , Pré-Escolar , Cobre/urina , Feminino , Seguimentos , Degeneração Hepatolenticular/metabolismo , Humanos , Isótopos/urina , Itália/epidemiologia , Transplante de Fígado , Imageamento por Ressonância Magnética , Masculino , Penicilamina/administração & dosagem , Penicilamina/efeitos adversos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Índice de Gravidade de Doença , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Oligoelementos/uso terapêutico , Resultado do Tratamento , Zinco/uso terapêuticoRESUMO
Thirty-two patients with coronary heart disease (CHD)--exertional angina and postinfarction cardiosclerosis with dislipidemia--were treated with dicvertin (2,3-dihydro-3,5,7-trihydroxi-2(3,4-dihydroxiphenyl)-4H-1-benzopyran-4-on), a Russian antioxidant, during two months in a day dose of 80 mg in addition to conventional cardial therapy. The therapy resulted in positive changes including improvement of CHD clinical picture and biochemical serum indices, such as a 6% decrease in cholesterol level, a 12% decrease in low-density lipoproteins cholesterol level, and a 14% increase in high-density lipoproteins cholesterol level. The intensity of lipid peroxidation decreased, the levels of diene conjugates and TBA-reactive products lowered by 38% and 40%, respectively. The fibrinogen level lowered by 20%. The antioxidative status of the patients increased.
Assuntos
Ceruloplasmina/efeitos dos fármacos , Doença das Coronárias/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Flavanonas/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transferrina/efeitos dos fármacos , Antioxidantes/metabolismo , Ceruloplasmina/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença das Coronárias/sangue , Doença das Coronárias/complicações , Dislipidemias/sangue , Dislipidemias/complicações , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Transferrina/metabolismo , Resultado do TratamentoRESUMO
The physiological and production effects of feeding additional vitamin E and ruminally protected vitamin C were examined in cattle challenged with bovine herpesvirus 1 (BHV 1). Forty-eight individually penned 6-mo-old Angus and Angus crossbred heifer calves with a mean BW of 151 kg were allocated randomly to four diets in a 2 x 2 factorial arrangement of treatments. Pelleted diets provided either 15 or 185 IU/kg of DM of vitamin E, with or without 3.7 g of ruminally protected vitamin C/kg of DM. Blood samples were taken at start of the experiment and at wk 4, 5, and 6. At the start of wk 5, half of each of the dietary groups was challenged with BHV 1. Feeding additional vitamin E was associated with greater (P < 0.001) mean plasma alpha-tocopherol. In contrast, feeding ruminally protected vitamin C was not associated with greater (P = 0.59) mean plasma ascorbate concentration; however, feeding ruminally protected vitamin C was associated with lower (P = 0.03) mean blood total superoxide dismutase (Cu/Zn SOD and Mn SOD) concentration. Calves fed additional vitamin E had greater (P = 0.05) mean plasma beta-carotene concentrations. There were interactions between dietary intake of vitamins E and C with respect to serum ceruloplasmin concentration (P = 0.01) and G:F (P = 0.05). Bovine herpesvirus 1 challenge was associated with lower white cell count (P = 0.007), lymphocyte count (P < 0.001), and DMI (P = 0.03). Feeding additional vitamin E to calves challenged with BHV 1 was associated with a lower (P = 0.03) serum ceruloplasmin concentration. There was a non-significant trend towards an interaction (P = 0.06) between the feeding of vitamins E and C, with virus-challenged calves fed additional vitamin E alone having greater plasma retinol concentrations. The feeding of vitamins E and/or C in calves challenged with BHV 1 was associated with alterations in the concentrations of other antioxidants. More severe disease may have translated these cellular effects to changes in health and performance.
Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Bovinos/fisiologia , Herpesvirus Bovino 1/fisiologia , Rinotraqueíte Infecciosa Bovina/fisiopatologia , Vitamina E/farmacologia , Ração Animal/análise , Animais , Antioxidantes/administração & dosagem , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/sangue , Proteínas Sanguíneas/efeitos dos fármacos , Bovinos/virologia , Doenças dos Bovinos/fisiopatologia , Ceruloplasmina/análise , Ceruloplasmina/efeitos dos fármacos , Dieta/veterinária , Suplementos Nutricionais/virologia , Feminino , Contagem de Linfócitos/veterinária , Distribuição Aleatória , Fatores de Tempo , Vitamina A/sangue , Vitamina E/administração & dosagem , Vitamina E/sangue , Aumento de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Oxidative stress has been implicated in the pathogenesis of ageing and menopause, and can arise through the increased production of lipid peroxides and/or a deficiency of antioxidant defence. AIM: To investigate the effects of the menopause and tibolone treatment (2.5 mg/day for six months) on plasma antioxidants and lipid peroxidation. METHODS: Plasma concentrations of ascorbic acid, alpha-tocopherol, total thiol groups, caeruloplasmin, erythrocyte glutathione (GSH) and malondialdehyde (MDA) were measured in 24 postmenopausal and 24 premenopausal healthy women. RESULTS: Data analysis indicates a significant decrease in plasma ascorbic acid, alpha-tocopherol, total thiol groups, [corrected]erythrocyte GSH and a significant increase in lipid peroxides (expressed as MDA concentrations) in postmenopausal women. There was no significant difference between control and study groups in the mean plasma caeruloplasmin concentrations. It was found that there is a significant increase in alpha-tocopherol and significant decrease in lipid peroxide concentrations in postmenopausal after tibolone treatment. CONCLUSIONS: The menopause is associated with an increase in oxidative stress and a decrease of some antioxidants, such as ascorbic acid, alpha-tocopherol, total thiols and erythrocyte GSH. Tibolone treatment leads to a decrease in concentrations of plasma lipid peroxide, probably by stimulating direct and indirect mechanisms of tocopherol regeneration and increasing plasma concentrations of vitamin E. However, due to the relatively small numbers involved this study can be regarded as a pilot. Further studies performed on a larger scale are necessary to establish the exact mechanisms of tibolone in inhibiting oxidative stress in postmenopausal women.
Assuntos
Antioxidantes/metabolismo , Moduladores de Receptor Estrogênico/farmacologia , Menopausa/fisiologia , Norpregnenos/farmacologia , Pós-Menopausa/fisiologia , Adulto , Estudos de Casos e Controles , Ceruloplasmina/efeitos dos fármacos , Ceruloplasmina/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Glutationa/sangue , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/sangue , Menopausa/efeitos dos fármacos , Pessoa de Meia-Idade , Estresse Oxidativo , Pós-Menopausa/efeitos dos fármacos , Pré-Menopausa/fisiologia , Compostos de Sulfidrila/sangue , alfa-Tocoferol/sangueRESUMO
A study was conducted to evaluate the effects of acute and subacute locoweed exposure on serum swainsonine concentrations and selected serum constituents in sheep. Thirteen mixed-breed wethers (BW = 47.5 +/- 9.3 kg) were assigned randomly to 0.2, 0.4, or 0.8 mg of swainsonine x kg BW(-1) x d(-1) treatments. During acute (24 h) and subacute (19 d) exposure, serum swainsonine was detected in all treatments and was greatest (P < 0.03) in the 0.8 mg treatment. Serum alkaline phosphate (ALK-P) activity was increased (P < 0.01) for the 0.8 mg treatment compared with baseline (0 h) by 7 h and continued to increase throughout the initial 22 h following acute exposure to locoweed. A linear increase (P < 0.01) in serum ALK-P activity was noted, with the rate being 3.00 +/- 0.56 U x L(-1) x h(-1). Serum ALK-P activity was increased (P < 0.05) across treatments on d 7 over d -19, -12, 0, 1, 21, and 26; on d 14 over d -19, -12, 0, and 26; and on d 19 over d -19, -12, 0, 1, 21, and 26. By d 20, approximately 48 h after last exposure to swainsonine, serum ALK-P activities were no longer different (P = 0.13) than baseline (d -19, -12, and 0), and by d 26 values had generally returned to baseline. No linear (P = 0.98), quadratic (P = 0.63), or cubic effects of swainsonine with time from exposure were noted for serum aspartate aminotransferase. Similar to serum ALK-P activities, serum aspartate aminotransferase activities were increased (P < 0.05) across treatment levels on d 7, 14, 19, 20, 21, and 26 over those on d -19, -12, 0, and 1. Total serum Fe was decreased (P < 0.05) within the initial 22 h following the swainsonine exposure. On d 21 (48 h after swainsonine feeding ended), serum Fe increased to 472 mg/L. Concentrations of ceruloplasmin were lower (P < 0.10) on d 14 and 19 following exposure to locoweed. Recovery of ceruloplasmin levels coincided with similar changes in serum Fe. There was a linear (slope = 0.33 mg x dL(-1) x d(-1); P < 0.01) effect with time of exposure to locoweed (i.e., swainsonine) on serum triglyceride concentrations. Rapid changes in serum ALK-P and Fe concentrations without parallel changes in other damage markers indicate that acute exposure to swainsonine induces metabolic changes that may impair animal production and health before events of cytotoxicity thought to induce clinical manifestation of locoism.
Assuntos
Dieta/veterinária , Oxytropis , Ovinos/fisiologia , Swainsonina/administração & dosagem , Swainsonina/sangue , Administração Oral , Fosfatase Alcalina/sangue , Fosfatase Alcalina/efeitos dos fármacos , Animais , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/efeitos dos fármacos , Ceruloplasmina/análise , Ceruloplasmina/efeitos dos fármacos , Colesterol/sangue , Relação Dose-Resposta a Droga , Ferro/sangue , Ferro/metabolismo , Masculino , Taxa de Depuração Metabólica/fisiologia , Oxytropis/metabolismo , Distribuição Aleatória , Ovinos/sangue , Hormônios Tireóideos/sangue , Fatores de Tempo , Triglicerídeos/sangueRESUMO
In vivo and in vitro effects of prolactin (PRL) and growth hormone (GH) on plasma levels of lysozyme and ceruloplasmin were examined in the rainbow trout (Oncorhynchus mykiss). Hypophysectomy had no effect on the plasma lysozyme level. Implantation of PRL- or GH-containing cholesterol pellets increased the lysozyme level in a dose-related manner. After hypophysectomy and sham operation, plasma ceruloplasmin was elevated above the level in intact fish, suggesting inflammation caused by the surgery. PRL or GH treatment significantly attenuated the increased level of ceruloplasmin in the operated fish. Expression of lysozyme mRNA was detected in the leucocytes isolated from the peripheral blood by RT-PCR. In vitro administration of PRL or GH showed no effect on the proliferation of isolated leucocytes or on the total protein content; however, lysozyme activity in the medium increased in a dose-related manner. These results suggest that PRL and GH directly stimulate lysozyme production without affecting the proliferation of leucocytes, and the attenuated ceruloplasmin level increased in response to inflammation.
Assuntos
Ceruloplasmina/efeitos dos fármacos , Hormônio do Crescimento/farmacologia , Muramidase/efeitos dos fármacos , Oncorhynchus mykiss/imunologia , Prolactina/farmacologia , Animais , Células Cultivadas , Ceruloplasmina/análise , Relação Dose-Resposta a Droga , Implantes de Medicamento , Hormônio do Crescimento/administração & dosagem , Hormônio do Crescimento/sangue , Hormônio do Crescimento/genética , Hipofisectomia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Muramidase/biossíntese , Muramidase/sangue , Prolactina/administração & dosagem , Prolactina/sangue , Prolactina/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de TempoRESUMO
Selected indices of copper metabolism in weanling rats and fibroblast cultures were progressively altered in response to increased levels of sodium metavanadate. In diets, vanadium was added in amounts ranging from 0 to 80 microg V/g of diet, that is, 0-1.6 micromol V/g of diet. In fibroblast cultures, vanadium ranged from 0 to 400 nmol V/ml. The inhibition of P-ATPase-7A activity by metavanadate, important to copper egress from cells, was a primary focus. In skin, and tendon, the copper concentration was increased in response to increased dietary levels of metavanadate, whereas lysyl oxidase activity, a secreted cuproprotein, was reduced. The reduction in lysyl oxidase activity was also accompanied by reduced redox cycling potential of isolated fractions of lysyl oxidase, presumably due to reduced lysyltyrosyl quinone (LTQ) formation at the active site of lysyl oxidase. In contrast, liver copper concentrations and plasma ceruloplasmin activity were not affected by metavanadate exposure. However, semicarbazide-sensitive benzylamine oxidase (SCBO) activity, which was taken as an indirect measure of vascular adhesive protein-1 (VAP-1), was increased. In cultured fibroblasts, cellular copper was also increased and lysyl oxidase decreased in response to metavanadate. Moreover, the steady-state levels of atp7a and lysyl oxidase mRNAs were not affected by addition of metavanadate to culture medium up to 200 nmol/ml. Taken together, these data suggest that pathways involving copper egress and lysyl oxidase activation are particularly sensitive to metavanadate exposure through processes that are predominately posttranslational.