Selenium Abstracts 2

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Selenium and mortality in the elderly: results from the EVA study.
            (Akbaraly et al., 2005) Download
BACKGROUND:  Inadequate plasma selenium can adversely affect the maintenance of optimal health; therefore, reported decreases in plasma selenium in an aging population are cause for concern. To further examine this hypothesis, we explored the relationships between plasma selenium and mortality in an elderly population: the EVA (Etude du Vieillissement Artériel) study. METHODS:  The EVA study was a 9-year longitudinal study with 6 periods of follow-up. During the 2-year period from 1991 to 1993 (EVA0), 1389 men and women born between 1922 and 1932 were recruited. The effects of plasma selenium at baseline on mortality were determined by Cox proportional hazards regression analysis, adjusting for the following variables: sociodemographic characteristics, dietary habits, health, and cognitive factors. RESULTS:  During the 9-year follow-up, 101 study participants died. Baseline plasma selenium was higher in individuals who were alive at the end of follow-up [mean (SD), 1.10 (0.20) micromol/L] than in those who died during the follow-up [1.01 (0.20) micromol/L; P <10(-4)]. Mortality rates were significantly higher in individuals with low selenium [increments = 0.2 micromol/L; relative risk (RR) = 1.56 (95% confidence interval, 1.28-1.89)]. After we controlled for various potential confounding factors, this association remained significant [RR = 1.54 (1.25-1.88)]. When the underlying causes of death were considered, we found an association with cancer-related mortality [adjusted RR = 1.79 (1.32-2.44)]. CONCLUSIONS:  Even if it is premature to present selenium as a longevity indicator in an elderly population, our results are in accordance those of large, interventional, randomized trials with selenium, which suggest that this essential trace element plays a role in health maintenance in aging individuals.

Selenium in the immune system.
            (Arthur et al., 2003) Download
Selenium as an essential component of selenocysteine-containing protein is involved in most aspects of cell biochemistry and function. As such, there is much potential for selenium to influence the immune system. For example, the antioxidant glutathione peroxidases are likely to protect neutrophils from oxygen-derived radicals that are produced to kill ingested foreign organisms. When the functions of all selenoproteins are described, only then will it be possible to fully understand their role in maintaining optimal immune function.

Selenium deficiency increases the pathology of an influenza virus infection.
            (Beck et al., 2001) Download
Selenium (Se) deficiency has previously been shown to induce myocarditis in mice infected with a benign strain of coxsackievirus. To determine if Se deficiency would also intensify an infection with influenza virus, Se-deficient and Se-adequate mice were infected with a mild strain of influenza, influenza A/Bangkok/1/79 (H3N2). Infected Se-deficient mice developed much more severe interstitial pneumonitis than did Se-adequate mice. This increase in pathology was associated with significant alterations in mRNA levels for cytokines and chemokines involved in pro-inflammatory responses. These results demonstrate that adequate nutrition is required for protection against viral infection and suggest that nutritional deprivation may be one of many factors that increase the susceptibility of individuals to influenza infection.

Does a role for selenium in DNA damage repair explain apparent controversies in its use in chemoprevention
            (Bera et al., 2013) Download
The trace element selenium is an essential micronutrient that has received considerable attention for its potential use in the prevention of cancer. In spite of this interest, the mechanism(s) by which selenium might function as a chemopreventive remain to be determined. Considerable experimental evidence indicates that one possible mechanism by which selenium supplementation may exert its benefits is by enhancing the DNA damage repair response, and this includes data obtained using cultured cells, animal models as well as in human clinical studies. In these studies, selenium supplementation has been shown to be beneficial in reducing the frequency of DNA adducts and chromosome breaks, consequentially reducing the likelihood of detrimental mutations that ultimately contribute to carcinogenesis. The benefits of selenium can be envisioned as being due, at least in part, to it being a critical constituent of selenoproteins such as glutathione peroxidases and thioredoxin reductases, proteins that play important roles in antioxidant defence and maintaining the cellular reducing environment. Selenium, therefore, may be protective by preventing DNA damage from occurring as well as by increasing the activity of repair enzymes such as DNA glycosylases and DNA damage repair pathways that involve p53, BRCA1 and Gadd45. An improved understanding of the mechanism of selenium's impact on DNA repair processes may help to resolve the apparently contradicting data obtained from decades of animal work, human epidemiology and more recently, clinical supplementation studies.

An increase in selenium intake improves immune function and poliovirus handling in adults with marginal selenium status.
            (Broome et al., 2004) Download
BACKGROUND:  Dietary selenium intakes in many countries, including the United Kingdom, are lower than international recommendations. No functional consequences of these lower intakes have been recognized, although experimental studies suggest that they might contribute to reduced immune function, increased cancer incidence, and increased susceptibility to viral disease. OBJECTIVE:  The objective was to assess whether administration of small selenium supplements to otherwise healthy UK subjects leads to functional changes in immune status and the rates of clearance and mutation of a picornavirus: live attenuated polio vaccine. DESIGN:  Twenty-two adult UK subjects with relatively low plasma selenium concentrations (<1.2 micromol/L, approximately 60% of those screened) received 50 or 100 microg Se (as sodium selenite) or placebo daily for 15 wk in a double-blind study. All subjects received an oral live attenuated poliomyelitis vaccine after 6 wk and enriched stable (74)Se intravenously 3 wk later. RESULTS:  Selenium supplementation increased plasma selenium concentrations, the body exchangeable selenium pool (measured by using (74)Se), and lymphocyte phospholipid and cytosolic glutathione peroxidase activities. Selenium supplements augmented the cellular immune response through an increased production of interferon gamma and other cytokines, an earlier peak T cell proliferation, and an increase in T helper cells. Humoral immune responses were unaffected. Selenium-supplemented subjects also showed more rapid clearance of the poliovirus, and the poliovirus reverse transcriptase-polymerase chain reaction products recovered from the feces of the supplemented subjects contained a lower number of mutations. CONCLUSIONS:  The data indicate that these subjects had a functional selenium deficit with suboptimal immune status and a deficit in viral handling. They also suggest that the additional 100 microg Se/d may be insufficient to support optimal function.

Dietary selenium supplementation modifies breast tumor growth and metastasis.
            (Chen et al., 2013) Download
The survival rate for breast cancer drops dramatically once the disease progresses to the metastatic stage. Selenium (Se) is an essential micronutrient credited with having high anticancer and chemopreventive properties. In our study, we investigated if dietary Se supplementation modified breast cancer development in vivo. Three diets supplemented with sodium selenite, methylseleninic acid (MSA) or selenomethionine (SeMet), as well as a Se-deficient and a Se-adequate diet were fed to mice before mammary gland inoculation of 4T1.2 cells. The primary tumor growth, the numbers of cancer cells present in lungs, hearts, livers, kidneys and femurs and several proinflammatory cytokines were measured. We found that inorganic selenite supplementation provided only short-term delay of tumor growth, whereas the two organic SeMet and MSA supplements provided more potent growth inhibition. These diets also affected cancer metastasis differently. Mice fed selenite developed the most extensive metastasis and had an increased incidence of kidney and bone metastasis. On the other hand, mice fed the SeMet diet showed the least amount of cancer growth at metastatic sites. The MSA diet also provided some protection against breast cancer metastasis although the effects were less significant than those of SeMet. The cytokine profiles indicated that serum levels of interlukin-2, interleukin-6, interferon γ and vascular endothelial growth factor were elevated in SeMet-supplemented mice. There was no significant difference in tumor growth and the patterns of metastasis between the Se-deficient and Se-adequate groups. Our data suggest that organic Se supplementation may reduce/delay breast cancer metastasis, while selenite may exacerbate it.

Review: micronutrient selenium deficiency influences evolution of some viral infectious diseases.
            (Harthill, 2011) Download
Recently emerged viral infectious diseases (VIDs) include HIV/AIDS, influenzas H5N1 and 2009 H1N1, SARS, and Ebola hemorrhagic fevers. Earlier research determined metabolic oxidative stress in hosts deficient in antioxidant selenium (Se) (<1 μMol Se/L of blood) induces both impaired human host immunocompetence and rapidly mutated benign variants of RNA viruses to virulence. These viral mutations are consistent, rather than stochastic, and long-lived. When Se-deficient virus-infected hosts were supplemented with dietary Se, viral mutation rates diminished and immunocompetence improved. Herein is described the role of micronutrient Se deficiency on the evolution of some contemporary RNA viruses and their subsequent VIDs. Distinguishing cellular and biomolecular evidence for several VIDs suggests that environmental conditions conducive to chronic dietary Se deprivation could be monitored for bioindicators of incipient viral virulence and subsequent pathogenesis.

Serum selenium and prognosis in cardiovascular disease: results from the AtheroGene study.
            (Lubos et al., 2010) Download
OBJECTIVE:  Experimental data suggest a protective role of the essential trace element selenium against cardiovascular disease (CVD), whereas epidemiological data remains controversial. We aimed to investigate the impact of serum selenium concentration in patients presenting with stable angina pectoris (SAP) or acute coronary syndrome (ACS) on long term prognosis. METHODS:  Baseline selenium concentration was measured in 1731 individuals (852 with SAP, and 879 with ACS). During a median follow-up of 6.1 years, 190 individuals died from cardiovascular causes. RESULTS:  In those ACS patients who subsequently died of cardiac causes, selenium levels were lower compared to survivors (61.0microg/L versus 71.5microg/L; P<0.0001). In a fully adjusted model, patients in the highest tertile of selenium concentration had a hazard ratio of 0.38 (95% CI: 0.16-0.91; P=0.03) as compared with those in the lowest. No association between selenium levels and cardiovascular outcome was observed in SAP. CONCLUSIONS:  Low selenium concentration was associated with future cardiovascular death in patients with ACS.

Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging.
            (McCann and Ames, 2011) Download
The triage theory proposes that modest deficiency of any vitamin or mineral (V/M) could increase age-related diseases. V/M-dependent proteins required for short-term survival and/or reproduction (i.e., "essential") are predicted to be protected on V/M deficiency over other "nonessential" V/M-dependent proteins needed only for long-term health. The result is accumulation of insidious damage, increasing disease risk. We successfully tested the theory against published evidence on vitamin K. Here, we review about half of the 25 known mammalian selenoproteins; all of those with mouse knockout or human mutant phenotypes that could be used as criteria for a classification of essential or nonessential. Five selenoproteins (Gpx4, Txnrd1, Txnrd2, Dio3, and Sepp1) were classified as essential and 7 (Gpx1, Gpx 2, Gpx 3, Dio1, Dio2, Msrb1, and SelN) nonessential. On modest selenium (Se) deficiency, nonessential selenoprotein activities and concentrations are preferentially lost, with one exception (Dio1 in the thyroid, which we predict is conditionally essential). Mechanisms include the requirement of a special form of tRNA sensitive to Se deficiency for translation of nonessential selenoprotein mRNAs except Dio1. The same set of age-related diseases and conditions, including cancer, heart disease, and immune dysfunction, are prospectively associated with modest Se deficiency and also with genetic dysfunction of nonessential selenoproteins, suggesting that Se deficiency could be a causal factor, a possibility strengthened by mechanistic evidence. Modest Se deficiency is common in many parts of the world; optimal intake could prevent future disease.

Cellular and nephrotoxicity of selenium species.
            (Nagy et al., 2015) Download
PROJECT:  Beside its useful functions at very low concentrations, selenium including supplementary Se sources pose a potential toxicological risk. The toxicity of selenium species was tested in HaCaT cell culture and related nephrotoxicity in mice. PROCEDURE:  The apoptotic shrinkage and necrotic expansion of cells were measured by time-lapse image microscopy. Acute nephrotoxicity was estimated upon administration of various selenium species to mice for two weeks. To confirm or to refute the accumulation of Se in the kidney and its potential chronic effect, Se concentration in kidney tissue and histopathlology were tested. RESULTS:  The comparison of selenium species showed that organic lactomicroSe did not affect cell growth at 5ppm, but inorganic nanoSe severely hampered it at lower concentration (1ppm). The in vivo Se treatment (0.5, 5, 50ppm, corresponding to 4, 40 and 400μg/kg) was misleading as it did neither affect the outward appearance nor the weight of the kidney. Se accumulation was observed after selenate, selenite, SelPlex, selenite and nanoSe administration, while lactomicroSe caused no traceable accumulation. In vivo, ex vivo and in vitro experiments reflected this order of selenium toxicity: selenate>selenite>SelPlex=nanoSe>lactomicroSe. CONCLUSION:  Within the tested species lactomicroSe was the only non-nephrotoxic selenium source recommended for nutritional Se supplementation.

Host nutritional selenium status as a driving force for influenza virus mutations.
            (Nelson et al., 2001) Download
Previous work from our laboratory has demonstrated that infection with influenza A/Bangkok/1/79 (H3N2), a relatively mild strain of the virus, caused much more severe pneumonitis in selenium (Se)-deficient mice than in Se-adequate mice. Here we report that the increased virulence observed in the Se-deficient mice is due to mutations in the influenza virus genome, resulting in a more virulent genotype. Most of the mutations occurred in the gene for the M1 matrix protein, an internal protein that is thought to be relatively stable. A total of 29 nucleotide changes were observed in this gene, and all 29 changes were identical in three separate isolates taken from three different Se-deficient mice. In contrast, only one to three mutations were seen in the genes for the hemagglutinin or neuraminidase proteins, surface antigens that are known to be highly variable. Once the mutations have occurred, even hosts with normal nutritional status are susceptible to the newly virulent strain. This work, in conjunction with our earlier work with coxsackievirus, shows that specific nutritional deficiencies can have a profound impact on the genome of RNA viruses. Poor nutritional status in the host may contribute to the emergence of new viral strains.

Selenium and the prevention of prostate and colorectal cancer.
            (Peters and Takata, 2008) Download
Prostate and colorectal cancers are among the most common cancers and identifying modifiable risk factors are important steps to reduce the burden of these severe diseases. Results from several but mostly small observational studies as well as the secondary analysis of an intervention trial provide support for a chemopreventive effect of selenium on prostate and colorectal cancers. Results suggest effect modification by gender and smoking, but this interpretation is limited by the statistical power of previous studies. Several cancer preventive mechanisms have been described and it is likely that selenium acts through multiple pathways. In particular, the anti-oxidative and anti-inflammatory effects mediated through activity of selenoenzymes are discussed, given the relevance of oxidative stress and inflammation in these cancers. Genetic variation in selenoenzymes may modify the potential chemopreventive effect of selenium and need to be further investigated. Additional large observational studies using biomarkers of selenium intake and intervention trials, such as the Selenium and Vitamin E Cancer Prevention Trial, will be important to further evaluate the potential chemopreventive effect of selenium. Furthermore, characterization of functional effects of polymorphisms in selenoenzymes is needed.

Comparative effects of two different forms of selenium on oxidative stress biomarkers in healthy men: a randomized clinical trial.
            (Richie et al., 2014) Download
Epidemiologic and laboratory studies indicate that dietary selenium protects against prostate cancer. Results from clinical trials suggest that selenium-enriched yeast (SY) but not selenomethionine (SeMet) may be effective at reducing prostate cancer risk. Our objectives were to directly compare for the first time the effects of SeMet and SY on prostate cancer relevant biomarkers in men. We performed a randomized double blind, placebo-controlled trial of SY (200 or 285 μg/day) and SeMet (200 μg/day) administered for 9 months in 69 healthy men. Primary endpoints included blood levels of selenium-containing compounds and oxidative stress biomarkers [urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α) and blood glutathione (GSH)]. Secondary endpoints included plasma glucose and PSA levels. Compliance was high in all groups (>95%). Plasma selenium levels were increased 93%, 54%, and 86% after 9 months in SeMet and low- and high-dose SY groups, respectively, and returned to baseline levels after a 3-month washout (P < 0.05). Levels of 8-OHdG and 8-iso-PGF2α were decreased 34% and 28%, respectively, after 9 months in the high-dose SY group (P < 0.05). These decreases were greatest in individuals with low baseline plasma levels of selenium (<127 ng/mL). No changes in serum PSA or blood glucose and GSH were observed. Overall, we showed for the first time, reductions in biomarkers of oxidative stress following supplementation with SY but not SeMet in healthy men. These findings suggest that selenium-containing compounds other than SeMet may account for the decrease in oxidative stress.

 


References

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Arthur, JR, RC McKenzie, and GJ Beckett (2003), ‘Selenium in the immune system.’, J Nutr, 133 (5 Suppl 1), 1457S-9S. PubMed: 12730442
Beck, MA, et al. (2001), ‘Selenium deficiency increases the pathology of an influenza virus infection.’, FASEB J, 15 (8), 1481-83. PubMed: 11387264
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Nagy, G, et al. (2015), ‘Cellular and nephrotoxicity of selenium species.’, J Trace Elem Med Biol, 30 160-70. PubMed: 25604949
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