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Zinc is required for many critical processes, including intermediary metabolism. In Saccharomyces cerevisiae, the Zap1 activator regulates the transcription of ~ 80 genes in response to Zn supply. Some Zap1-regulated genes are Zn transporters that maintain Zn homeostasis, while others mediate adaptive responses that enhance fitness. One adaptive response gene encodes the 2-cysteine peroxiredoxin Tsa1, which is critical to Zn-deficient (ZnD) growth. Depending on its redox state, Tsa1 can function as a peroxidase, a protein chaperone, or a regulatory redox sensor. In a screen for possible Tsa1 regulatory targets, we identified a mutation (cdc19S492A) that partially suppressed the tsa1Δ growth defect. The cdc19S492A mutation reduced activity of its protein product, pyruvate kinase isozyme 1 (Pyk1), implicating Tsa1 in adapting glycolysis to ZnD conditions. Glycolysis requires activity of the Zn-dependent enzyme fructose-bisphosphate aldolase 1, which was substantially decreased in ZnD cells. We hypothesized that in ZnD tsa1Δ cells, the loss of a compensatory Tsa1 regulatory function causes depletion of glycolytic intermediates and restricts dependent amino acid synthesis pathways, and that the decreased activity of Pyk1S492A counteracted this depletion by slowing the irreversible conversion of phosphoenolpyruvate to pyruvate. In support of this model, supplementing ZnD tsa1Δ cells with aromatic amino acids improved their growth. Phosphoenolpyruvate supplementation, in contrast, had a much greater effect on growth rate of WT and tsa1Δ ZnD cells, indicating that inefficient glycolysis is a major factor limiting yeast growth. Surprisingly however, this restriction was not primarily due to low fructosebisphosphate aldolase 1 activity, but instead occurs earlier in glycolysis. [ABSTRACT FROM AUTHOR]

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Abstract: Quantum-chemical calculations were performed to study the effect of Lewis acid centers introduced to liquid or polymer electrolytes as boric acid esters. Particular attention has been paid to the modeling of solvent effects on ion–ion and anion-acid center interactions. Calculated complexation energies for lithium salts and polymerizable boric acid esters with diols in different solvents were analyzed and related to available conductivity data. [Copyright &y& Elsevier]

Abstract: Objective: Although the global rate of multiple sclerosis (MS) is low, a few studies have documented high costs. Costs are highly variable depending on MS stage. This study was designed to assess the economic burden of Medicare-eligible patients by MS type in the United States using a claims-based classification algorithm to examine cost variation by disease stage. Methods: A sample of 2003 to 2006 Medicare patients was selected. Cases were classified as pre-existing progressive MS or pre-existing relapsing-remitting MS (RRMS); the latter were further subdivided into relapsing, remitting, or stable. Results: The sample had 5044 MS subjects, of whom 34.4% had prevalent progressive MS and 65.6% had prevalent RRMS. There were many chronic, comorbid conditions. The mean all-cause Medicare expenditures (not including self-administered medications) per person-year for MS in 2006 were $23,630 for prevalent progressive patients and $5887 for prevalent RRMS patients. Within the RRMS type, Medicare expenditures per person per month in 2006 were $1418 for relapsing patients, $608 for remitting patients, and $331 for stable patients. Conclusions: There are substantial cost advantages to Medicare for keeping RRMS patients in a stable health state and in keeping them from advancing in disability severity. The overall cost advantage would be diminished by the large cost burden of comorbidity, which would likely remain fixed with improved MS therapies. [Copyright &y& Elsevier]

Despite the progress made in recent years in the field of oncology, the results of glioblastoma treatment remain unsatisfactory. In this paper, cholesterol derivatives - oxysterols - have been investigated in the context of their anti-cancer activity. First, the influence of three oxysterols (7-K, 7β-OH and 25-OH), differing in their chemical structure, on the properties of a model membrane imitating glioblastoma multiforme (GBM) cells was investigated. For this purpose, the Langmuir monolayer technique was applied. The obtained results clearly show that oxysterols modify the structure of the membrane by its stiffening, with the 7-K effect being the most pronounced. Next, the influence of 7-K on the nanomechanical properties of glioblastoma cells (U-251 line) was verified with AFM. It has been shown that 7-K has a dose-dependent cytotoxic effect on glioblastoma cells leading to the induction of apoptosis as confirmed by viability tests. Interestingly, significant changes in membrane structure, characteristic for phospholipidosis, has also been observed. Based on our results we believe that oxysterol-induced apoptosis and phospholipidosis are related and may share common signaling pathways. Dysregulation of lipids in phospholipidosis inhibit cell proliferation and may play key roles in the induction of apoptosis by oxysterols. Moreover, anticancer activity of these compounds may be related to the immobilization of cancer cells as a result of stiffening effect caused by oxysterols. Therefore, we believe that oxysterols are good candidates as new therapeutic molecules as an alternative to the aggressive treatment of GBM currently in use. [Display omitted] • Effect of oxysterols on GBM was studied by Langmuir technique and biological tests. • Oxysterols were found to disrupt the cancer membrane structure. • The most pronounced effect was observed for 7-K. • 7-K induces cell death and phospholipidosis as confirmed by AFM and viability test. • Oxysterols may immobilize GBM cells and thus prevent metastasis. [ABSTRACT FROM AUTHOR]

Aims Impaired awareness of hypoglycemia (IAH) is a limiting factor in the treatment of type 1 diabetes (T1D) and is a challenging condition to reverse. The objective of this study was to test the hypothesis that naltrexone therapy in subjects with T1D and IAH will improve counterregulatory hormone response and recognition of hypoglycemia symptoms during hypoglycemia. Methods We performed a pilot randomized double blind trial of 4 weeks of naltrexone therapy (n = 10) or placebo (n = 12) given orally in subjects with T1D and IAH. Outcome measures included hypoglycemia symptom scores, counterregulatory hormone levels and thalamic activation as measured by cerebral blood flow using MRI during experimental hypoglycemia in all subjects before and after 4 weeks of intervention. Results After 4 weeks of therapy with naltrexone or placebo, no significant differences in response to hypoglycemia were seen in any outcomes of interest within each group. Conclusions In this small study, short-term treatment with naltrexone did not improve recognition of hypoglycemia symptoms or counterregulatory hormone response during experimental hypoglycemia in subjects with T1D and IAH. Whether this lack of effect is related to the small sample size or due to the dose, the advanced stage of study population or the drug itself should be the subject of future investigation. [ABSTRACT FROM AUTHOR]

Zinc is required for the folding and function of many proteins. In Saccharomyces cerevisiae, homeostatic and adaptive responses to zinc deficiency are regulated by the Zap1 transcription factor. One Zap1 target gene encodes the Tsa1 peroxiredoxin, a protein with both peroxidase and protein chaperone activities. Consistent with its regulation, Tsa1 is critical for growth under low zinc conditions. We previously showed that Tsa1's peroxidase function decreases the oxidative stress that occurs in zinc deficiency. In this report, we show that Tsa1 chaperone, and not peroxidase, activity is the more critical function in zinc-deficient cells. Mutations restoring growth to zinc-deficient tsa1 cells inactivated TRR1, encoding thioredoxin reductase. Because Trr1 is required for oxidative stress tolerance, this result implicated the Tsa1 chaperone function in tolerance to zinc deficiency. Consistent with this hypothesis, the tsa1Δ zinc requirement was complemented by a Tsa1 mutant allele that retained only chaperone function. Additionally, growth of tsa1Δ was also restored by overexpression of holdase chaperones Hsp26 and Hsp42, which lack peroxidase activity, and the Tsa1 paralog Tsa2 contributed to suppression by trr1Δ, even though trr1Δ inactivates Tsa2 peroxidase activity. The essentiality of the Tsa1 chaperone suggested that zinc-deficient cells experience a crisis of disrupted protein folding. Consistent with this model, assays of protein homeostasis suggested that zinc-limited tsa1Δ mutants accumulated unfolded proteins and induced a corresponding stress response. These observations demonstrate a clear physiological role for a peroxiredoxin chaperone and reveal a novel and unexpected role for protein homeostasis in tolerating metal deficiency. [ABSTRACT FROM AUTHOR]

In this paper, systematic studies concerning the influence of selected oxysterols on the structure and fluidity of human erythrocyte membrane modeled as Langmuir monolayers have been performed. Three oxidized cholesterol derivatives, namely 7α-hydroxycholesterol (7α-OH) 7β-hydroxycholesterol (7β-OH) and 7-ketocholesterol (7-K) have been incorporated in two different proportions (10 and 50%) into artificial erythrocyte membrane, modeled as two-component (cholesterol:POPC) Langmuir monolayer. All the studied oxysterols were found to alter membrane fluidity and the effect was more pronounced for higher oxysterol content. 7α-OH increased membrane fluidity while opposite effect was observed for 7β-OH and 7-K. Experiments performed on model systems have been verified in biological studies on red blood cells (RBC). Consistent results have been found, i.e. under the influence of 7α-OH, the elasticity of erythrocytes increased, and in the presence of other investigated oxysterols - decreased. The strongest effect was noticed for 7-K. Change of membrane elasticity was associated with the change of erythrocytes shape, being most noticeable under the influence of 7-K. Unlabelled Image • Influence of B-ring-substituted oxysterols on RBC was determined. • Results from Langmuir monolayers are consistent with biological experiments on RBCs. • The investigated oxysterols (7-K, 7α-OH and 7β-OH) alter RBC elasticity. • The strongest influence on RBC has been observed for 7-K. [ABSTRACT FROM AUTHOR]