A mixture of ammonium perchlorate and sodium chlorate enhances alterations of the pituitary-thyroid axis caused by the individual chemicals in adult male F344 rats.
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Ammonium perchlorate (AP) and sodium chlorate (SC) have been detected in public drinking water supplies in many parts of the United States. These chemicals cause perturbations in pituitary-thyroid homeostasis in animals by competitively inhibiting iodide uptake, thus hindering the synthesis of thyroglobulin and reducing circulating T(4) (thyroxine). Little is known about the short-term exposure effects of mixtures of perchlorate and chlorate. The present study investigated the potential for the response to a mixture of these chemicals on the pituitary-thyroid axis in rats to be greater than that induced by the individual chemicals. Adult male F-344 rats were exposed, via their drinking water, to the nominal concentrations of 0.1, 1.0, 10 mg/L AP or 10, 100, 1000 mg/L SC and their mixtures for 7 days. Serum T(4) levels were significantly (p < 0.05) reduced in rats following exposure to the mixtures, but not after exposure to the individual chemicals. Serum T(3) (triiodothyronine) was not altered by treatment and TSH (thyroid stimulating hormone) was only increased after the high-dose chlorate treatment. Histological examination of the thyroid gland showed colloid depletion and hypertrophy of follicular epithelial cells in high-dose single chemical and all mixture-treated rats, while hyperplasia was observed only in some of the rats treated with mixtures (AP 10 + SC 100, AP 0.1 + SC 1000, and AP 10 + SC 1000 mg/L). These data suggest that short-term exposure to the mixture of AP and SC enhances the effect of either chemical alone on the pituitary-thyroid axis in rats. (+info)
Determination of toxin-induced leakage of different-size nucleotides through the plasma membrane of human diploid fibroblasts.
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Human diploid lung fibroblasts were treated with cytolytic bacterial toxins and the nature of the membrane damage was investigated. [3H] uridine was used for differential labeling of cytoplasmic components of small or large molecular size. Two principal size categories were achieved by labeling the fibroblasts in either early growth phase or stationary phase, a high-molecular weight ribonucleic acid label and a low-molecular-weight nucleotide label. The size of the labeled molecules was determined by perchloric acid precipitation and gel chromatography. Leakage of labeled molecules of different size indicated the size of the "functional pores" in the plasma membrane caused by the test substance. The nonionic detergent Triton X-100 produced large functional pores in the fibroblast membrane as evidenced by rapid leakage of both large and small labeled molecules. Theta-toxin from Clostridium perfringens and the polyene antibiotic filipin both gave rise to considerably small functional pores in the plasma membrane. Although small molecules easily passed the treated membrane, large molecules could not escape from the cells even after prolonged treatment with these substances or by increasing their concentration. By the contrast, the leakage profiles obtained with melittin from bee venom or with delta-toxin from Staphylococcus aureus in each case suggested the formation initially of pores of intermediate size that increased upon prolonged incubation or when higher concentrations were used. (+info)
Uptake and metabolism of iodine is crucial for the development of thyroiditis in obese strain chickens.
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To assess the importance of the role of thyroidal iodine in the pathogenesis of thyroiditis in the obese strain (OS) chicken, a model of spontaneous and severe disease, we studied the effect of antithyroid drugs that reduce thyroidal iodine or prevent its metabolism. Reduction of thyroidal iodine was achieved with KClO4, an inhibitor of iodine transport and mononitrotyrosine (MNT), a drug that promotes loss of thyroidal iodine as iodotyrosines. A regimen consisting of KClO4 and MNT administration beginning in ovo and continuing after hatching reduced thyroidal infiltration to 2% of control values and decreased thyroglobulin antibody (TgAb) production for as long as 9 wk. Untreated birds had severe disease by 5 wk of age. The suppression of disease was independent of TSH, not mediated by generalized immunosuppression and reversed by excess dietary iodine. Two drugs that inhibit the metabolism of iodine, propylthiouracil (PTU) and aminotriazole, reduced thyroidal infiltration and TgAb levels, although to a lesser extent. When splenocytes from OS chickens with thyroiditis were transferred to Cornell strain (CS) chickens, a related strain that develops late onset mild disease, only the recipients that were iodine supplemented developed thyroiditis. In conclusion, autoimmune thyroiditis in an animal model can be prevented by reducing thyroidal iodine or its metabolism and optimal effects require intervention at the embryonic stage. (+info)
In vivo detection of metabolic changes in a mouse model of scrapie using nuclear magnetic resonance spectroscopy.
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In vivo proton nuclear magnetic resonance (NMR) spectroscopy studies of scrapie in a mouse model have shown the appearance of an abnormal peak in the brain early in the incubation period. This abnormal peak was detected weeks before the detection of a protease-resistant form of a membrane protein and vacuolar histopathology in vitro, and several months before clinical signs, and the signal increased in intensity as the disease progressed. In the chronic stage of the disease, a reduction in N-acetyl aspartate levels was observed using in vivo and in vitro proton NMR spectroscopy. (+info)
Modulation of polyene antibiotics self-association by ions from the Hofmeister series.
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The toxicity of the antifungal polyene antibiotic amphotericin B (AMB) has been related to its low solubility, more specifically to a self-associated form termed toxic aggregate. In addition, AMB in aqueous medium gives rise to concentration, ionic strength, and time-dependent polydisperse systems. For this reason different approaches, including the use of several lipid aggregates, have been used in attempts to improve the drug's solubility and increase its therapeutic index. In this context, understanding AMB's self-association properties should help in the preparation of less toxic formulations. Ions from the Hofmeister series alter water properties: while kosmotropes (water structure makers-sulfate, citrate, phosphate) decrease solute solubility, chaotropes (water structure breakers-perchlorate, thiocyanate, trichloroacetate, and the neutral molecule urea) have opposite effects. This work reports a study of the effect of Hofmeister ions and urea on the self-aggregation of AMB and some of its derivatives. Optical absorption and circular dichroism spectra were used to monitor monomeric and aggregated antibiotic. While kosmotropes increased aggregation in a concentration-dependent manner, the opposite was observed for chaotropes. It is shown, for the first time, that thiocyanate and trichloroacetate can induce complete AMB monomerization. The understanding of these processes at the physicochemical and molecular levels and the possibility of modulating the aggregation state of AMB and its derivatives should contribute to elucidate the mechanisms of action and toxicity of this widely used antibiotic and to develop more efficient and less toxic preparations. (+info)
Correlates of osteoclast function in the presence of perchlorate ions in the rat.
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The effects of perchlorate anion (ClO4-) on osteoclast properties were investigated through a number of independent in vivo and in vitro procedures. Intravenous infusion of ClO4- significantly reduced plasma [Ca] in young (50 g) Wistar rats, in the absence of changes in plasma [Mg] or [albumin]. This effect was maximal at 20 min after administration, and at a dose of 600 mumol/rat. Scanning electron-microscope images suggested that the presence of 10 mM-perchlorate reduced both the total area of cortical bone resorbed by freshly disaggregated rat osteoclasts, and the number of osteoclastic excavations in vitro. Similar effects were observed in the presence of 5 mM [Ca2+]. The effects of Ca2+ were potentiated by otherwise ineffective (1 mM) doses of perchlorate. Indo-1 dual-emission microspectrofluorimetry indicated a transient sixfold elevation of cytosolic free [Ca2+], in isolated cultured osteoclasts, with addition of 10 mM-perchlorate. Records of time-lapse video images indicated that this was followed by a marked and sustained cell retraction, by up to 70% of control cell area. Such effects were not observed at thiocyanate concentrations (10 mM) that would have produced comparable lyotropic effects as perchlorate. However, perchlorate did not alter morphometric measures for pseudopodial motility and cell migration. Nor did it influence supernatant concentrations of tartrate-resistant (osteoclastic) acid phosphatase in cultures of resorbing osteoclasts. These findings suggest that perchlorate is a potent inhibitor of osteoclast function, and acts through an influence on intracellular [Ca2+], and in turn upon the degree of cell retraction. (+info)
A facile method for oxidation of primary alcohols to carboxylic acids and its application in glycosaminoglycan syntheses.
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A convenient two-step, one-pot procedure was developed for the conversion of primary alcohols to carboxylic acids. The alcohol was first treated with NaOCl and TEMPO under phase-transfer conditions, followed by NaClO2 oxidation in one pot. This reaction is applicable to a wide range of alcohols and the mild reaction conditions are compatible with many sensitive functional groups, including electron-rich aromatic rings, acid-labile isopropylidene ketal and glycosidic linkages, and oxidation-prone thioacetal, p-methoxybenzyl, and allyl moieties. Several glycosaminoglycans such as heparin, chondroitin, and hyaluronic acid oligosaccharides have been synthesized in high yields by using this new oxidation protocol. (+info)
Energy metabolism in human erythrocytes: the role of phosphoglycerate kinase in cation transport.
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Three models of disturbed erythrocyte metabolism, triose-depleted normal, phosphoglycerate kinase (PGK)-deficient, and pyruvate kinase (PK)-deficient cells, have been studied to examine further the role of PGK in erythrocyte cation transport. Sodium (Na-+) and potassium (K-+) transport were reduced only in cells fully depleted of triose. In such cells the PGK step presumably was inoperative due to total lack of substrate; 2,3-diphosphoglycerate (2,3-DPG) then became the sole substrate source for remaining steps in glycolysis. At increased intracellular Na-+ concentrations which normally stimulate transport and glycolysis, triose-depleted cells had marked impairment of cation transport and ouabain-inhibitable lactate and pyruvate production from 2,3-DPG. PGK-deficient cells and normal cells with high intracellular Na-+ concentrations had similar increases in transport and ouabain-inhibitable lactate production. PK-deficient cells with high intracellular Na-+ concentrations showed an appropriate increase in transport but less stimulation of lactate production. Transport was not related to total cellular adenosine triphosphate (ATP) concentration. These data suggested that normal coupled cation transport occurred despite diminished metabolite flow through PGK, as in PGK- or PK-deficient cells. Transport was diminished only in triose-depleted cells where metabolite flow through PGK was presumably absent. These data, therefore, support the concept that transport and glycolysis interact at the PGK step, although impairment of PGK must be profound before its effect on transport is evident. (+info)