Selenoprotein W modulates control of cell cycle entry.

The present study was conducted to identify targets of selenium (Se) provided to cultured human cells in physiologically relevant doses and forms. Breast and prostate epithelial cells were supplemented with Se provided as 100 nM sodium selenite or high-Se serum and gene expression was profiled with DNA microarrays. Pure sodium selenite affected expression of 560 genes in MCF-10A breast cells, including 60 associated with the cell cycle (p = 2.8 x 10(-16)). Selenoprotein W (SEPW1) was the only selenoprotein messenger RNA (mRNA) increased by both sodium selenite (specific) and high-Se serum (physiologic). SEPW1 small interfering RNA inhibited G1-phase progression and increased G1-phase gene transcripts, while decreasing S-phase and G2/M-phase gene transcripts, indicating the cell cycle was interrupted at the G1/S transition. SEPW1 mRNA levels were maximal during G1-phase, dropped after the G1/S transition and increased again after G2/M-phase. SEPW1-underexpressing prostate cells had increased mRNA for BCL2, which can induce a G1 arrest, and decreased mRNA for RBBP8 and KPNA2, which modulate the Rb/p53 checkpoint pathway. These results suggest that SEPW1 and the G1/S transition are physiological targets of Se in breast and prostate epithelial cells.

High-selenium yeast supplementation in free-living North American men: no effect on thyroid hormone metabolism or body composition.

In a prior study, we observed decreased serum 3,3',5-triiodothyronine (T(3)), increased serum thyrotropin and increased body weight in five men fed 297 microg/d of selenium (Se) in foods naturally high in Se while confined in a metabolic research unit. In an attempt to replicate and confirm those observations, we conducted a randomized study of high-Se yeast supplements (300 microg/d) or placebo yeast administered to 42 healthy free-living men for 48 weeks. Serum thyroxine, T(3) and thyrotropin did not change in supplemented or control subjects. Body weight increased in both groups during the 48-week treatment period and remained elevated for the 48-week follow-up period. Body fat increased by 1.2 kg in both groups. Energy intake and voluntary activity levels were not different between the groups and remained unchanged during the treatment period. Dietary intakes of Se, macronutrients and micronutrients were not different between groups and remained unchanged during the treatment period. These results suggest that our previous observation of a hypothyroidal response to high-Se foods was confounded by some aspect of the particular foods used, or were merely chance observations. Because of the high dose and long administration period, the present study suggests that the effects of Se supplements on thyroid hormone metabolism and energy metabolism in healthy North American men with adequate Se status do not represent a significant risk for unhealthy weight gain.

Response of selenium status indicators to supplementation of healthy North American men with high-selenium yeast.

The essential nutrient selenium is required in microgram amounts [recommended dietary allowance (RDA) = 55 microg/day, 699 nmol/day] and has a narrow margin of safety (upper tolerable intake limit = 400 microg/day, 5 micromol/day). We conducted a randomized placebo-controlled study of high-selenium yeast, the form used in most supplements (300 microg/day, 3.8 micromol/day), administered to 42 free-living healthy men for 48 weeks. Dietary intakes of selenium, macronutrients, and micronutrients were not different between groups and did not change during the study. Supplementation more than doubled urinary selenium excretion from 69 to 160 microg/day (876 to 2,032 nmol/day). Urinary excretion was correlated with recent selenium intake estimated from 3-day diet records: urinary selenium excretion = 42 microg/day (533 nmol/day) + 0.132 x dietary selenium intake, p < 0.001. Dietary selenium intake was not significantly correlated with the other indicators of selenium status, presumably because urinary selenium excretion reflected recent intake, and tissue selenium was homeostatically controlled. After 48 weeks of supplementation, plasma selenium was increased 60% from 142 to 228 microg/l (1.8 to 2.9 micromol/l), and erythrocyte selenium was approximately doubled from 261 to 524 microg/l (3.3 to 6.6 micromol/l). Selenium concentrations increased more modestly in hair (56%) and platelets (42%). Platelets were the only blood component in which glutathione peroxidase activity was significantly related to selenium content. Selenium levels decreased rapidly after the end of supplementation, and there were no significant differences in selenium status indicators between groups by week 96. The absorption, distribution, and excretion of selenium from high-Se yeast were similar to selenium in foods.

Beans, as a source of dietary fiber, increase cholecystokinin and apolipoprotein b48 response to test meals in men.

Dry beans lower plasma cholesterol, an effect that has been associated with both the fiber and the protein content of beans. The objective of this study was to determine the acute hormone and lipid responses to a test meal that contained dry beans as a source of dietary fiber. A crossover design was employed in which men consumed the test meal and a control meal in random order. Both meals contained egg, bread, jelly, orange juice, milk and margarine. The high fiber meal contained white beans, whereas the low fiber (control) meal contained rice and dry milk. The men maintained their normal dietary pattern and fasted overnight before the study days. After a fasting blood sample was drawn, the men consumed the test meal and blood samples were collected over the next 6 h. Blood samples were analyzed for cholecystokinin (CCK), insulin and glucose. Plasma was separated into lipoprotein fractions and the triglyceride, cholesterol, apolipoprotein (apo) B100 and B48 content of triglyceride-rich lipoproteins determined. Insulin and glucose responses did not differ significantly between test meals; however, the CCK response was twice as high after the bean-containing meal than after the low fiber meal (P = 0.03). The increase in apo B48 concentration was significantly higher after the bean meal than after the low fiber meal (P < 0.05). Adding beans to a meal to increase fiber content prolongs the postprandial presence of intestinally derived lipoproteins and augments the CCK response to the meal.

A screen for mutations in human homologues of mice exencephaly genes Tfap2alpha and Msx2 in patients with neural tube defects.

BACKGROUND: Very little is known about the identity of genetic factors involved in the complex etiology of nonsyndromic neural tube defects (NTD). Potential susceptibility genes have emerged from the vast number of mutant mouse strains displaying NTD. Reasonable candidates are the human homologues of mice exencephaly genes Tfap2alpha and Msx2, which are expressed in the developing neural tube. METHODS: A single-strand conformation analysis (SSCA) mutation screen of the coding sequences of TFAP2alpha and MSX2 was performed for 204 nonsyndromic NTD patients including cases of anencephaly (n = 10), encephalocele (n = 8), and spina bifida aperta, SBA (n = 183). A selected number of SBA patients was additionally tested for specific mutations in MTHFD, FRalpha, and PAX1 already shown to be related to NTD. RESULTS: Two TFAP2alpha point mutations in individual SBA patients were silent on the amino acid level (C308C, T396T). On nucleic acid level, these mutations change evolutionary conserved codons and thus may influence mRNA processing and translation efficiency. One SBA patient displayed an exonic 9-bp deletion in MSX2 leading to a shortened and possibly less functional protein. None of these mutations was found in 222 controls. Seven polymorphisms detected in TFAP2alpha and MSX2 were equally distributed in patients and controls. Patients with combined heterozygosity of an exonic MSX2 and an intronic TFAP2alpha polymorphism were at a slightly increased risk of NTD (OR 1.71; 95% CI 0.57-5.39). CONCLUSIONS: Although several new genetic variants were found in TFAP2 and MSX2, no statistically significant association was found between NTD cases and the new alleles or their combinations. Further studies are necessary to finally decide if these gene variants may have acted as susceptibility factors in our individual cases.

[Plasma- and tissue concentrations following intramuscular administration of etofenamat. Pharmacokinetics of etofenamat and flufenamic acid in plasma, synovium, and tissues of patients with chronic polyarthritis after administration of an oily solution of etofenamat]. / Plasma- und Gewebespiegel-Studien nach intramuskulärer Applikation von Etofenamat. Pharmakokinetik von Etofenamat und Flufenaminsäure in Plasma, Synovia und Geweben von Patienten mit chronischer Polyarthritis nach Applikation öliger Lösung von Etofenamat.

Studies on Plasma and Tissue Concentrations of Etofenamate following Intramuscular Application/Pharmacokinetics of etofenamate and flutenamic acid in plasma, synovia and tissues of patients with chronic polyarthritis after application of oily etofenamat solution Pharmacokinetics of etofenamate (ETO, CAS 30544-47-9; Rheumon i.m.) and flufenamic acid (FLU, CAS 530-78-9) were investigated in plasma, synovial fluid, and tissues after single intramuscular application of etofenamate to patients with rheumatoid arthritis. 62 patients with indicated operative procedure in the knee-joint received a single dose of etofenamate dissolved in oil before operation. At definite times between 1.5 and 48 h post injectionem samples from 6 patients of each time group were collected. Samples of plasma, synovial fluid, synovial membrane, muscle, bone, hyaline cartilage, and fat tissue and in some cases meniscus cartilage were taken. Concentrations of ETO and its active metabolite, FLU, were determined by HPTLC. In all tissues investigated, concentration/time courses of ETO and FLU were observed. ETO and FLU were measured first in all matrices 1.5 h at the latest 3 h post injectionem. Pharmacokinetics in tissues follows that in plasma. Rate-limiting step is the liberation of drug from the oil depot. For a long period pharmacokinetics of ETO and FLU is mainly determined by the constant liberation from the oil depot (zero order kinetics of liberation). Zero order kinetics is deduced from the linear ascent of the cumulated AUC (in percent) vs. time plot. It is directly related to the liberation of drug from the galenical formulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of antiviral substances against influenza A virus strains by the haemadsorption reduction test.

The haemadsorption reduction test with Ehrlich mouse ascites tumour cells proved to be a simple method for testing the sensitivity of influenza A virus strains to antiviral substances. Ribavirin and 2-deoxy-D-glucose were poorly effective in this system while all virus strains except A/PR/8/34 (H0N1) were highly sensitive to amantadine and rimantadine, the latter being the strongest inhibitor.