Aromatase inhibition by R 76713: experimental and clinical pharmacology

R 76713 is a new non-steroidal compound which inhibits aromatase in vitro and in vivo with a potency of at least 1000-fold that of aminoglutethimide. In male cynomolgus monkeys peripheral conversion of labeled androstenedione to estrone is decreased by 85%, 4-5 h after a single intravenous dose of 0.003 mg/kg of R 76713, without altering steroid metabolic clearance rates. In rats fed a sodium-depleted diet for 3 weeks, plasma levels of aldosterone and plasma renin activity remain unchanged 2 h after a single oral dose of up to 20 mg/kg of R 76713. This confirms previous data on the selectivity of R 76713 for aromatase inhibition as compared to inhibition of other enzymes involved in steroid biosynthesis. In male volunteers, a single oral dose of 5 or 10 mg of R 76713 lowers median plasma estradiol levels from 70 pM to the detection limit of the assay (30 pM) 4 and 8 h after intake, whereas no important changes are detected after placebo administration. In 15 premenopausal female volunteers receiving a single oral dose of 20 mg of R 76713, mean plasma estradiol levels decrease from 415 pM (before) to 179, 149 and 185 pM respectively 4, 8 and 24 h after intake whereas they remain above 380 pM after placebo (n = 7).     

Effects of selenium supplementation on thyroid hormone metabolism in phenylketonuria subjects on a phenylalanine restricted diet

Type I 5′-deiodinase was recently characterized as a selenocysteine-containing enzyme in humans and other mammals. Up to now, the effect of selenium (Se) supplementation on thyroid hormone metabolism in humans has only been reported in the very peculiar nutritional environment of Central Africa, where combined severe iodine and Se deficiency occurs. In this study, a group of phenylketonuria subjects with a low selenium status, but a normal iodine intake were supplemented with selenium to investigate changes in their thyroid hormone metabolism. After 3 wk of selenium supplementation (1 μg/kg/d), both the concentrations of the prohormone thyroxine (T4) and the metabolic inactive reverse triiodothyronine (rT3) decreased significantly. Clinically, the phenylketonuria subjects remained euthyroid before and after selenium supplementation. The individual changes of plasma Se and glutathione peroxidase activity were closely associated with individual changes of plasma T4 and rT3.     

Evolution of Stronger SARS-CoV-2 Variants as Revealed Through the Lens of Molecular Dynamics Simulations

The Protein Journal - Using molecular dynamics simulations, the protein–protein interactions of the receptor-binding domain of the wild-type and seven variants of the severe acute respiratory...     

Neonatal Thyroid-Stimulating Hormone Concentrations in Belgium: A Useful Indicator for Detecting Mild Iodine Deficiency?

It has been proposed that neonatal thyroid-stimulating hormone (TSH) concentrations are a good indicator of iodine deficiency in the population. A frequency of neonatal TSH concentrations above 5 mU/L below 3% has been proposed as the threshold indicating iodine sufficiency. The objective of the present study was to evaluate feasibility and usefulness of nation-wide neonatal TSH concentration screening results to assess iodine status in Belgium. All newborns born in Belgium during the period 2009–2011 (n = 377713) were included in the study, except those suffering from congenital hypothyroidism and premature neonates. The frequency of neonatal TSH concentrations above 5 mU/L from 2009 to 2011 in Belgium fluctuated between 2.6 and 3.3% in the centres using the same TSH assay. There was a significant inverse association between neonatal TSH level and birth weight. The longer the duration between birth and screening, the lower the TSH level. Neonatal TSH levels were significantly lower in winter than in spring or autumn and significantly lower in spring and summer than in autumn while significantly higher in spring compared to summer. In conclusion, despite that pregnant women in Belgium are mildly iodine deficient, the frequency of neonatal TSH concentrations above 5 mU/L was very low, suggesting that the neonatal TSH threshold proposed for detecting iodine deficiency needs to be re-evaluated. Although neonatal TSH is useful to detect severe iodine deficiency, it should not be recommended presently for the evaluation of iodine status in mildly iodine deficient regions.     

Trypanosoma cruzi: host selenium deficiency leads to higher mortality but similar parasitemia in mice

Selenium is an essential trace element and its deficiency was implicated in heart diseases. We recently showed low Se levels in chronic chagasic patients with cardiomyopathy. Herein, mice were depleted in Se by feeding the mothers with chow containing only 0.005 mg Se/kg and maintaining this diet for offspring, that were further infected with Trypanosoma cruzi. Survival rate was significantly lower in Se deficient than in control mice. Parasitemia was similar in all groups. Necrotic heart lesions were found after infection (high CK-MB levels). No outbreaks of parasite growth were detected in chronic survivors submitted or not to a second Se depletion. The present results confirm our hypothesis that a nutritional deficiency in Se is associated to a higher mortality during T. cruzi infection. The potential beneficial effect of Se supplementation is a perspective. Hypothesis to explain the higher susceptibility of Se-depleted mice to T. cruzi infection are discussed.     

Role of vitamin E in the protection of the resident macrophage membrane against oxidative damage

The variation in tocopherol content of resident peritoneal rat macrophages was investigated during an oxidative stress provided by superoxide anions. Fluorometric measurements showed that phagocytic cells contain 298 +/- 18 ng vit.E/mg prot. The vitamin E level remains nearly constant during 1 h of incubation: 266 +/- 46 ng vit.E/mg prot. HPLC control at 37 degrees C validates our fluorometric measurement. Superoxide anions (O2-.) synthesis was activated by phorbol myristate acetate (PMA) (0.5 microgram/ml), after 1 h of incubation a decrease of 40% of the macrophage tocopherol level was observed and assessed by HLPC control. No tocopherolquinone (TQ) was detected. To clarify this point, tocopherol oxidation was followed spectrophotometrically. Results did not show any appearance of TQ at 265 nm but appearance of a peak at 307 mm. This our results show for the first time that macrophages possess vitamin E which plays a partial role in the protection of their plasma membrane. The lack of detection of TQ is of interest and the study of this unidentified product of oxidation should help us to understand the exact metabolism of vitamin E.     

Iodine deficiency,other trace elements,and goitrogenic factors in the etiopathogeny of iodine deficiency disorders (IDD)

Severe goiter, cretinism, and the other iodine deficiency disorders (IDD) have their main cause in the lack of availability of iodine from the soil linked to a severe limitation of food exchanges. Apart from the degrees of severity of the iodine deficiency, the frequencies and symptomatologies of cretinism and the other IDD are influenced by other goitrogenic factors and trace elements. Thiocyanate overload originating from consumption of poorly detoxified cassava is such deficiency. Very recently, a severe selenium deficiency has also been associated with IDD in the human population, whereas in animals, it has been proven to play a role in thyroid function either through a thyroidal or extrathyroidal mechanism. The former involves oxidative damages mediated by free radicals, whereas the latter implies an inhibition of the deiodinase responsible for the utilization of T4 into T3. One concludes that:

1. Goiter has a multifactorial origin
2. IDD are an important public health problem; and
3. IDD are a good model to study the effects of other trace elements whose actions in many human metabolisms have been somewhat underestimated.