Preclinical Evaluation of Sodium Selenite in Mice: Toxicological and Tumor Regression Studies after Striatum Implantation of Human Glioblastoma Stem Cells.

Glioblastoma (GBM) is the most aggressive malignant glioma, with a very poor prognosis; as such, efforts to explore new treatments and GBM's etiology are a priority. We previously described human GBM cells (R2J-GS) as exhibiting the properties of cancer stem cells (growing in serum-free medium and proliferating into nude mice when orthotopically grafted). Sodium selenite (SS)-an in vitro attractive agent for cancer therapy against GBM-was evaluated in R2J-GS cells. To go further, we launched a preclinical study: SS was given orally, in an escalation-dose study (2.25 to 10.125 mg/kg/day, 5 days on, 2 days off, and 5 days on), to evaluate (1) the absorption of selenium in plasma and organs (brain, kidney, liver, and lung) and (2) the SS toxicity. A 6.75 mg/kg SS dose was chosen to perform a tumor regression assay, followed by MRI, in R2J-GS cells orthotopically implanted in nude mice, as this dose was nontoxic and increased brain selenium concentration. A group receiving TMZ (5 mg/kg) was led in parallel. Although not reaching statistical significance, the group of mice treated with SS showed a slower tumor growth vs. the control group (p = 0.08). No difference was observed between the TMZ and control groups. We provide new insights of the mechanisms of SS and its possible use in chemotherapy.

Estimating sodium intake from spot urine samples at population level: a validation and application study in French adults.

The aim of this study was to assess the validity of the predictive INTERSALT equation using spot urine samples to estimate 24-h urinary Na (24-hUNa) excretion and daily Na intake among the French adult population. Among 193 French adults ('validation sample'), we assessed the validity by comparing predicted 24-hUNa excretion from spot urine and measured 24-hUNa excretion from 24-h urine collections. Spearman correlation coefficients and Bland-Altman plots were used and we calculated calibration coefficients. In a nationally representative sample of 1720 French adults ('application sample'), the calibrated predictive equation was then applied to the spot urine Na values to estimate 24-hUNa excretion and daily Na intake. In that sample, predicted Na intake was compared with that estimated from 24-h dietary recalls. Results were adjusted and corrected using calibration coefficients. In the validation sample, the measured 24-hUNa excretion was on average 14 % higher than the predicted 24-hUNa (+13 % for men and +16 % for women). Correlation between measured and predicted 24-hUNa excretion was moderate (Spearman r 0·42), and the Bland-Altman plots showed underestimation at lower excretion level and overestimation at higher level. In the application study, estimated daily salt intake was 8·0 g/d using dietary recalls, 8·1 g/d using predicted INTERSALT equation and 9·3 g/d after applying calibration coefficients calculated in the validation study. Despite overall underestimation of 24-hUNa excretion by spot urinary Na, the use of predictive INTERSALT equation remains an acceptable alternative in monitoring global Na intake/excreted in the French population but its use is not advised at the individual level.

Pomegranate peel extract decreases small intestine lipid peroxidation by enhancing activities of major antioxidant enzymes.

BACKGROUND: Pomegranate peel extract (PPE) contains several compounds with antioxidative properties. PPE added to foods may interact with endogenous antioxidants and promote health. However, little is known about the biochemical mechanisms by which PPE exerts their actions on tissues of biological systems in vivo. The purpose of this study was to determine the effects of PPE on activities of antioxidant enzymes. Mice were used to investigate the effects of PPE on plasma levels of malondialdehyde (MDA), tissue MDA content and activities of superoxide dismutase 1 (SOD1), SOD2 and glutathione peroxidase (GPX) in the small intestine, liver and skeletal muscle - different tissues involved in the digestion, absorption and metabolism of dietary nutrients. Control mice were fed a standard diet, whereas treated mice were fed for 40 days with the standard diet containing 5% or 10% PPE. RESULTS: Mice fed the 10% PPE diet exhibited lower plasma MDA concentrations, reduced content of MDA in the small intestine and liver and higher levels of SOD1 and GPX activities in the small intestine compared to mice fed the control diet. CONCLUSIONS: These findings demonstrate that intake of PPE in diet attenuates small intestine lipid peroxidation and strengthens the first line of small intestine antioxidant defense by enhancing enzymatic antioxidative pathways. PPE is worthy of further study as a therapeutic approach to prevent peroxidative stress-induced gut pathogenesis. © 2015 Society of Chemical Industry.

Antioxidant status and the risk of elevated C-reactive protein 12 years later.

BACKGROUND/AIMS: Low-grade inflammation is an independent risk factor for cardiovascular disease. Relationships between the antioxidant status and inflammatory biomarkers could give new insights into cardiovascular disease prevention. We investigated long-term associations between the antioxidant nutrient (vitamin C, α-tocopherol, ß-carotene) status and C-reactive protein (CRP) in a population-based cohort. METHODS: Subjects included in the French SU.VI.MAX trial study who had available data on baseline (1994-1995) blood nutrient concentrations and CRP measurements 12 years later (2007-2009) were included. Associations between baseline antioxidant circulating concentrations and elevated CRP (>3 mg/l) were investigated in multivariate logistic regression models. Subgroup analyses were performed according to gender, supplementation group of the initial trial, smoking status, and alcohol intake. RESULTS: Serum α-tocopherol (n = 2,060) and vitamin C (n = 1,719) concentrations [odds ratio (OR) and 95% confidence interval (95% CI) quintile 5 vs. 1: OR 1.10 (95% CI 0.71-1.73), p for trend = 0.533, vs. OR 0.79 (95% CI 0.48-1.29), p for trend = 0.121, respectively] were not associated with elevated CRP concentrations. The ß-carotene status (n = 2,048) was inversely associated with elevated CRP [adjusted OR quintile 5 vs. 1: OR 0.61 (95% CI 0.38-0.98), p for trend = 0.01]. Subgroup analyses showed that associations were stronger in women (p for trend = 0.004), never smokers (p for trend = 0.009) and subjects in the supplementation group (p for trend = 0.002). CONCLUSIONS: Our results suggest that the ß-carotene status may be inversely associated with low-grade inflammation in the long term.

Docosahexaenoic acid supplementation modifies fatty acid incorporation in tissues and prevents hypoxia induced-atherosclerosis progression in apolipoprotein-E deficient mice.

The n-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), displays anti-inflammatory properties that may prevent atherosclerosis progression. Exposure of apolipoprotein-E deficient (ApoE(-/-)) mice to chronic intermittent hypoxia (CIH) accelerates atherosclerosis progression. Our aim was to assess DHA-supplementation influence on fatty acid incorporation in different tissues/organs and on atherosclerosis progression in ApoE(-/-) mice exposed to CIH. ApoE(-/-) mice were exposed to CIH or normoxia (N) and randomized to four groups (N control, CIH control, N+DHA, and CIH+DHA). DHA-supplementation enhanced DHA and reduced arachidonic acid (AA) contents in tissues/organs. CIH control mice exhibited increased atherosclerosis lesion sizes compared to N control mice. DHA prevented CIH induced atherosclerosis but did not improve atherosclerosis burden in N mice. Aortic matrix metalloproteinase-2 (MMP-2) expression was decreased in CIH+DHA mice (p=0.007). DHA-supplementation prevented CIH-induced atherosclerosis acceleration. This was associated with a decrease of AA incorporation and of aortic MMP-2 gene expression.

Six-day selenium supplementation led to either UVA-photoprotection or toxic effects in human fibroblasts depending on the chemical form and dose of Se.

Selenium (Se) is an essential trace element with a narrow safety zone and unclear effects on skin photoageing. The aim of this work was to investigate the photoageing properties of sodium selenite or selenomethionine (SeMet) after a long term (6 days) Se supplementation in normal human skin fibroblasts (NHSF) subjected to ultraviolet-A (UVA) irradiation inducing 30% cell death. The uptake, toxicity and antioxidant effects of sodium selenite and SeMet were compared to better understand their photoageing properties. SeMet uptake was better than sodium selenite and their uptake by fibroblasts was not via an actively transport process. Sodium selenite induced a higher toxicity than SeMet. At 5 µM, sodium selenite inhibited cell proliferation associated with a blockage in the G2 phase and induced DNA fragmentation leading to caspase-3-dependent apoptosis cell death. At low doses (<1 µM), SeMet and sodium selenite induced glutathione peroxidase-1 (GPX1) activity and selenoproteinW1 (SEPW1) transcript expression but metalloproteinase (MMP)-1 was only induced by sodium selenite. SeMet and sodium selenite did not protect NHSFs from UVA-induced cell death. However, SeMet decreased malondialdehyde (MDA) and protected NHSFs from UVA-induced MMP1 and MMP3. We then observed a large difference in terms of photoprotection according to selenium forms. SeMet may be a potential agent for the prevention and treatment of skin photoageing.

Long-term selenium supplementation in HaCaT cells: importance of chemical form for antagonist (protective versus toxic) activities.

The beneficial effect of selenium (Se) on cancer is known to depend on the chemical form, the dose and the duration of the supplementation. The aim of this work was to explore long term antagonist (antioxidant versus toxic) effects of an inorganic (sodium selenite, Na2SeO3) and an organic (seleno-L-methionine, SeMet) forms in human immortalized keratinocytes HaCaT cells. HaCaT cells were supplemented with Na2SeO3 or SeMet at micromolar concentrations for 144 h, followed or not by UVA radiation. Se absorption, effects of UVA radiation, cell morphology, antioxidant profile, cell cycle processing, DNA fragmentation, cell death triggered and caspase-3 activity were determined. At non-toxic doses (10 µM SeMet and 1 µM Na2SeO3), SeMet was better absorbed than Na2SeO3. The protection of HaCaT from UVA-induced cell death was observed only with SeMet despite both forms increased glutathione peroxidase-1 (GPX1) activities and selenoprotein-1 (SEPW1) transcript expression. After UVA irradiation, malondialdehyde (MDA) and SH groups were not modulated whatever Se chemical form. At toxic doses (100 µM SeMet and 5 µM Na2SeO3), Na2SeO3 and SeMet inhibited cell proliferation associated with S-G2 blockage and DNA fragmentation leading to apoptosis caspase-3 dependant. SeMet only led to hydrogen peroxide production and to a decrease in mitochondrial transmembrane potential. Our study of the effects of selenium on HaCaT cells reaffirm the necessity to take into account the chemical form in experimental and intervention studies.

Effects of light to moderate alcohol consumption on thyroid volume and thyroid function.

OBJECTIVE: To examine a possible relationship between alcohol consumption and thyroid volume and function. SUBJECTS: A total of 1493 subjects (599 males aged 45-60 years and 894 females aged 35-60 years) with no known thyroid disorders who were participating in the SUpplémentation en VItamines et Minéraux AntioXydants (SU.VI.MAX) study. MEASURES: Daily dietary intakes and alcohol consumption in grams per day were based on five 24-h dietary records. Thyroid volume and structure were measured by ultrasonography. At baseline, TSH and free T4 (FT4) were measured. RESULTS: Male and female drinkers consumed (mean +/- SD), respectively, 30.6 +/- 23.3 and 14.2 +/- 13.4 g of ethanol per day. There was a decrease in carbohydrate intake with higher alcohol consumption among both male (P = 0.0001) and female drinkers (P = 0.06). Alcohol intake was associated with higher thyroid volume in males and females independently of iodine status. Multivariate odds ratios (ORs, with 95% confidence intervals) of thyroid enlargement (sex-specific 85th percentile values of > or = 20 ml for males, > or = 14 ml for females) in males and females who drank > or = 45 and > or = 20 g/day, respectively, were 2.22 (1.10-4.47) and 2.11 (1.15-3.90) compared with low drinkers, and 11.75 (2.15-64.12) and 2.03 (1.04-3.96) compared with abstainers. ORs were slightly increased when smokers were excluded. Alcohol intake was associated with low FT4 levels in male drinkers independently of TSH. CONCLUSIONS: An increasing dose-response relationship was found between alcohol intake levels and ORs for thyroid enlargement in both males and females. Alcohol consumption was strongly associated with a higher risk in females.

Comparison of the effects of zinc alone and zinc associated with selenium and vitamin E on insulin sensitivity and oxidative stress in high-fructose-fed rats.

PURPOSE: In the present study, we investigated the effect of an association of micronutrients (zinc (Zn), selenium (Se) and vitamin E (vit E)) on insulin activity and antioxidant status in an animal model of insulin resistance, the high-fructose-fed rat. PROCEDURES: Five experimental groups were compared: a control group (C) receiving a standard diet, a high-fructose-fed group (F) where 58% of the diet carbohydrate was fructose, a high-fructose-fed group supplemented with Zn alone (FZn group), a high-fructose-fed group supplemented micronutrients (Zn, Se and vit E) (FMicro group). A fifth group consumed a high-fructose diet and received metformin in the drinking water (200mg/day/rat) (FMet group). Insulin sensitivity was measured using the euglycemic hyperinsulinic glucose clamp technique. Metabolic parameters, trace elements and antioxidant parameters were measured in blood samples from all groups. RESULTS: High-fructose-fed rats were resistant to insulin as indicated by the lower glucose infusion rate. The insulin sensitivity of FZn, FMicro and FMet groups was higher than that of F group, with the highest insulin sensitivity for the FMicro group. No statistically significant difference in glycemia between the groups was observed. The ratio of reduced to oxidized glutathione was higher in FZn and FMicro groups than in all other groups, as a consequence of decreased oxidized glutathione. CONCLUSION: Our results provide direct evidence that micronutrients have a beneficial effect on insulin sensitivity and some components of the antioxidant defense system in an animal model of insulin resistance.

Protective effects of antioxidant micronutrients (vitamin E, zinc and selenium) in type 2 diabetes mellitus.

Type 2 diabetes (T2D) is a major cause of vascular complications affecting heart, kidney, retina and peripheral nerves. Hyperglycaemia leads to oxidative stress that plays an important role in vascular degenerative lesions observed in diabetes. In this Review we consider whether vitamin E, zinc or selenium are involved in the pathogenesis of diabetes. Concerning vitamin E, major epidemiological studies do not give the expected results in preventing cardiovascular outcomes. The mechanisms of free radical overproduction in diabetes could explain these results. Superoxide anion overproduction originates from mitochondria; in these conditions antioxidant enzymes are more relevant to reduce oxygen species than vitamin E. Zinc has numerous targets to modulate insulin activity, including its antioxidant capacity. Zinc status is decreased in most T2D patients. The effect of zinc supplementation on antioxidant status is raised when complications are associated. Selenium is a major antioxidant trace element and is the co-factor of glutathione peroxidase (Se GSHpx). Low Se GSHpx activity, observed in diabetic patients, is associated with thrombosis and cardiovascular complications.

Interets biologiques et synergiques d'une association de vitamines et d'un oligo-elements antioxydants / Biologic interest and synergy of a vitaminic association and antioxydant trace elements

Le choix d'une association de micronutriments antioxydants a visee de supplementation nutritionnelle est toujours delicat. En effet, une telle association doit permettre d'obtenir... (AU)