Since returning from a lengthy career gap (20-years out of research), my work, has focused on trace elements of importance to health, most notably selenium and iodine (see selected publications below). I am interested in:
I currently collaborate with academics at some 20 other universities and research institutes throughout the world.
The Programme, of which I am Director, has now been running for 11 years during which time it has been extremely successful, achieving a high profile and excellent reputation. We draw a considerable number of students from Europe and from countries as far away as China, Canada and South Africa. Currently there are 145 registered part-time students, the majority of whom are practising clinicians, including consultants, and a substantial number of gastroenterologists.
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Selenium, an essential trace element, is incorporated into selenoproteins with a wide range of health effects. Selenoproteins may reach repletion at a plasma selenium concentration of ~125 μg/L, at which point the concentration of selenoprotein P reaches a plateau; whether sustained concentrations higher than this are beneficial, or indeed detrimental, is unknown.Objective
In a population of relatively low selenium status, we aimed to determine the effect on mortality of long-term selenium supplementation at different dose levels.Design
The Denmark PRECISE study was a single-centre, randomised, double-blinded, placebocontrolled, multi-arm, parallel clinical trial with four groups. Participants were 491 male and female volunteers aged 60-74 years, recruited at Odense University Hospital, Denmark. The trial was initially designed as a 6-month pilot study, but supplemental funding allowed for extension of the study and mortality assessment. Participants were randomly assigned to treatment with 100, 200, or 300 μg selenium/d as selenium-enriched-yeast or placebo-yeast for 5 years from randomization in 1998–1999 and were followed up for mortality for a further 10 years (through March 31, 2015).Results
During 6,871 person-years of follow-up, 158 deaths occurred. In an intention-to-treat analysis, the hazard ratio (95% confidence interval) for all-cause mortality comparing 300 μg selenium/d to placebo was 1.62 (0.66, 3.96) after 5 years of treatment and 1.59 (1.02, 2.46) over the entire follow-up period. The 100 and 200 μg/d doses showed non-significant decreases in mortality during the intervention period that disappeared after treatment cessation. Although we lacked power for endpoints other than all-cause mortality, the effects on cancer and cardiovascular mortality appeared similar.Conclusions
A 300 μg/d dose of selenium taken for 5 years in a country with moderately-low selenium status increased all-cause mortality 10 years later. While our study was not initially designed to evaluate mortality and the sample size was limited, our findings indicate that total selenium intake over 300 μg/d and high-dose selenium supplements should be avoided.
Iodine deficiency is present in certain groups of the UK population, notably in pregnant women; this is of concern as iodine is required for fetal brain development. UK milk is rich in iodine and is the principal dietary iodine source. UK sales of milk-alternative drinks are increasing but data are lacking on their iodine content. As consumers may replace iodine-rich milk with milk-alternative drinks, we aimed to measure the iodine concentration of those available in the UK. Using ICP-MS, we determined the iodine concentration of seven types of milk-alternative drink (soya, almond, coconut, oat, rice, hazelnut, and hemp) by analysing 47 products purchased in November/December 2015. For comparison, winter samples of conventional (n=5) and organic (n=5) cows’ milk were included. The median iodine concentration of all of the unfortified milk-alternative drinks (n=44) was low, at 7.3 μg/kg, just 1.7% of our value for winter conventional cows’ milk (median 438 μg/kg). One brand (not the market leader), fortified its soya, oat, and rice drinks with iodine and those drinks had a higher iodine concentration than unfortified drinks, at 280, 287, 266 μg/kg respectively. The iodine concentration of organic milk (median 324 μg/kg) was lower than that of conventional milk. Although many milk-alternative drinks are fortified with calcium, at the time of this study, just three of 47 drinks were fortified with iodine. Individuals who consume milk-alternative drinks that are not fortified with iodine in place of cows’ milk may be at risk of iodine deficiency unless they consume alternative dietary iodine sources.
Seafood intake in pregnancy has been positively associated with childhood cognitive outcomes which could potentially relate to the high vitamin-D content of oily fish. However, whether higher maternal vitamin D status [serum 25-hydroxy-vitamin D, 25(OH)D] in pregnancy is associated with a reduced risk of offspring suboptimal neurodevelopmental outcomes is unclear. A total of 7065 mother-child pairs were studied from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who had data for both serum total 25(OH)D concentration in pregnancy and at least one measure of offspring neurodevelopment (pre-school development at 6–42 months; “Strengths and Difficulties Questionnaire” scores at 7 years; IQ at 8 years; reading ability at 9 years). After adjustment for confounders, children of vitamin-D deficient mothers (< 50.0 nmol/L) were more likely to have scores in the lowest quartile for gross motor development at 30 months (OR 1.20 95% CI 1.03, 1.40), fine motor development at 30 months (OR 1.23 95% CI 1.05, 1.44), and social development at 42 months (OR 1.20 95% CI 1.01, 1.41) than vitamin-D sufficient mothers (≥ 50.0 nmol/L). No associations were found with neurodevelopmental outcomes, including IQ, measured at older ages. However, our results suggest that deficient maternal vitamin D status in pregnancy may have adverse effects on some measures of motor and social development in children under 4 years. Prevention of vitamin D deficiency may be important for preventing suboptimal development in the first 4 years of life.
The deficiency of Se, an essential micronutrient, has been implicated in adverse pregnancy outcomes. Our study was designed to determine total serum Se, selenoproteins (extracellular glutathione peroxidase (GPx-3), selenoprotein P (SeP)), selenoalbumin (SeAlb) and selenometabolites in healthy women and their newborns at delivery. This cross-sectional study included eighty-three healthy mother–baby couples. Total Se and Se species concentrations were measured in maternal and umbilical cord sera by an in-series coupling of two-dimensional size-exclusion and affinity HPLC. Additional measurements of serum SeP concentration and of serum GPx-3 enzyme activity were carried out using ELISA. Total Se concentration was significantly higher in maternal serum than in cord serum (68·9 (sd 15·2) and 56·1 (sd 14·6) µg/l, respectively; P<0·01). There were significant correlations between selenoprotein and SeAlb concentrations in mothers and newborns, although they also showed significant differences in GPx-3 (11·2 (sd 3·7) v. 10·5 (sd 3·5) µg/l; P<0·01), SeP (42·5 (sd 9·5) v. 28·1 (sd 7·7) µg/l; P<0·01) and SeAlb (11·6 (sd 3·6) v. 14·1 (sd 4·3) µg/l; P<0·01) concentrations in maternal and cord sera, respectively. Serum GPx-3 activity and concentration were positively correlated in mothers (r 0·33; P=0·038) but not in newborns. GPx-3 activity in cord serum was significantly correlated with gestational age (r 0·44; P=0·009). SeAlb concentration was significantly higher in babies, whereas SeP and GPx-3 concentrations were significantly higher in mothers. The differences cannot be explained by simple diffusion; specific transfer mechanisms are probably involved. GPx-3 concentrations in mothers, at delivery, are related to maternal Se status, whereas the GPx-3 activity in cord serum depends on gestational age.
In December, 2016, the Iodine Global Network (IGN) published its new map of global iodine nutrition based on median urinary iodine concentration (mUIC) in school-aged children.1 Notably, the status of the UK, which was classified as mildly iodine deficient in 2014–15 (mUIC 50–99 μg/L), had become adequate by 2016 (mUIC 100–299 μg/L).1 The reason for this apparently rapid improvement lies in the different data sources used; data that showed mild deficiency in 2014–15 came from spot-urine samples from 737 girls aged 14–15 years from nine UK centres (mUIC 80·1 μg/L),2 whereas the 2016 data were based on spot-urine samples from 458 boys and girls aged 4–18 years, which were collected in year 6 of the UK National Diet and Nutrition Survey (NDNS).
Background: Hashimoto's thyroiditis (HT) is considered to be the most common autoimmune disease. It is currently accepted that genetic susceptibility, environmental factors, and immune disorders contribute to its development. With regard to nutritional factors, evidence implicates high iodine intake and deficiencies of selenium and iron with a potential relevance of vitamin D status. To elucidate the role of nutritional factors in the risk, pathogenesis, and treatment of HT, PubMed and the Cochrane Library were searched for publications on iodine, iron, selenium, and vitamin D and risk/treatment of HT. Summary: Chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly iodinated thyroglobulin (Tg) is more immunogenic. Recent introduction of universal salt iodization can have a similar, though transient, effect. Selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases protect the thyroid by removing excessive hydrogen peroxide produced for Tg iodination. Genetic data implicate the anti-inflammatory selenoprotein S in HT risk. There is evidence from observational studies and randomized controlled trials that selenium/selenoproteins can reduce thyroid peroxidase (TPO)-antibody titers, hypothyroidism, and postpartum thyroiditis. Iron deficiency impairs thyroid metabolism. TPO, the enzyme responsible for the production of thyroid hormones, is a heme (iron-containing) enzyme which becomes active at the apical surface of thyrocytes only after binding heme. HT patients are frequently iron deficient, since autoimmune gastritis, which impairs iron absorption, is a common co-morbidity. Treatment of anemic women with impaired thyroid function with iron improves thyroid-hormone concentrations, while thyroxine and iron together are more effective in improving iron status. Lower vitamin D status has been found in HT patients than in controls, and inverse relationships of serum vitamin D with TPO/Tg antibodies have been reported. However, other data and the lack of trial evidence suggest that low vitamin D status is more likely the result of autoimmune disease processes that include vitamin D receptor dysfunction. Conclusions: Clinicians should check patients' iron (particularly in menstruating women) and vitamin D status to correct any deficiency. Adequate selenium intake is vital in areas of iodine deficiency/excess, and in regions of low selenium intake a supplement of 50–100 μg/day of selenium may b
Metabolism is important for cartilage and synovial joint function. Under adverse microenvironmental conditions, mammalian cells undergo a switch in cell metabolism from a resting regulatory state to a highly metabolically activate state to maintain energy homeostasis. This phenomenon also leads to an increase in metabolic intermediates for the biosynthesis of inflammatory and degradative proteins, which in turn activate key transcription factors and inflammatory signalling pathways involved in catabolic processes, and the persistent perpetuation of drivers of pathogenesis. In the past few years, several studies have demonstrated that metabolism has a key role in inflammatory joint diseases. In particular, metabolism is drastically altered in osteoarthritis (OA) and aberrant immunometabolism may be a key feature of many phenotypes of OA. This Review focuses on aberrant metabolism in the pathogenesis of OA, summarizing the current state of knowledge on the role of impaired metabolism in the cells of the osteoarthritic joint. We also highlight areas for future research, such as the potential to target metabolic pathways and mediators therapeutically.
As current treatment options in osteoarthritis are very limited, osteoarthritis patients would benefit greatly from some ability to self-manage their condition. Since diet may potentially affect osteoarthritis, we reviewed the literature on the relationship between nutrition and osteoarthritis risk or progression, aiming to provide guidance for clinicians. For overweight/obese patients, weight-reduction, ideally incorporating exercise, is paramount. The association between metabolic syndrome, type-2 diabetes and osteoarthritis risk or progression may partly explain the apparent benefit of dietary-lipid modification resulting from increased consumption of long-chain n-3 fatty-acids from oily fish/fish-oil supplements. A strong association between osteoarthritis and raised serum cholesterol together with clinical effects in statin users suggest a potential benefit or reduction of cholesterol by dietary means. Patients should ensure that they meet the recommended intakes for micronutrients such as vitamin K which has a role in bone/cartilage mineralization. Evidence for a role of vitamin-D supplementation in osteoarthritis is unconvincing.
Background Though iodine deficiency in pregnancy is a matter of public-health concern, a functional measure of iodine status is lacking. The thyroid-specific protein, thyroglobulin (Tg), which reflects thyroid size, has shown promise as a functional measure in studies of children and adults, but data in pregnancy are sparse. In a cohort of mildly-to-moderately iodine-deficient pregnant women, we aimed to explore whether serum Tg is a sensitive functional biomarker of iodine status and to examine longitudinal change in Tg with gestational age. Method 230 pregnant women were recruited at an ante-natal clinic at 12 weeks of gestation to the Selenium in PRegnancy INTervention (SPRINT) study, in Oxford, UK. Repeated measures of urinary iodine-to-creatinine ratio, serum TSH and Tg at 12, 20, and 35 weeks of gestation were collected. Women were dichotomised by their iodine-to-creatinine ratio, (<150 or ≥150 μg/g) to group them broadly as iodine-deficient or iodine-sufficient. Women with thyroid antibodies were excluded; data and samples were available for 191 women. Results Median Tg concentration was 21, 19, and 23 μg/L in the first, second, and third trimesters, respectively. In a linear mixed model, controlling for confounders, Tg was higher in the <150 μg/g than in the ≥150 μg/g group (p<0.001) but there was no difference in TSH (p=0.27). Gestational week modified the effect of iodine status on TSH (p=0.01) and Tg (p=0.012); Tg did not increase with gestational week in the ≥150 μg/g group but did in the <150 μg/g group, and TSH increased more steeply in the <150 μg/g group. Conclusions Low iodine status (<150 μg/g) in pregnancy is associated with higher serum Tg, suggesting that the thyroid is hyper-stimulated by iodine deficiency, which causes it to enlarge. Tg is a more sensitive biomarker of iodine status in pregnancy than is TSH.
The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.
Iodine, as a component of the thyroid hormones, is crucial for brain development and is therefore especially important during pregnancy when the brain is developing most rapidly. While randomised controlled trials of pregnant women in regions of severe iodine deficiency have shown that prenatal iodine deficiency causes impaired cognition, less is known of the effects in regions of mild deficiency. This is relevant to the UK as the World Health Organisation now classifies the UK as mildly iodine deficient, based on a national study of 14-15 year old schoolgirls in 2011. We have previously published a study using samples and data from the UK-based Avon Longitudinal Study of Parents and Children (ALSPAC) that found an association between low iodine status in early pregnancy (urinary iodine-to-creatinine ratio <150 μg/g) and lower verbal IQ and reading scores in the offspring. Though the women in ALSPAC were recruited in the early 1990s, the results of the study are still relevant as their iodine status was similar to that reported in recent studies of UK pregnant women. This review discusses the evidence that mild-to-moderate iodine deficiency during pregnancy has deleterious effects on child neurodevelopment and relates that evidence to the data on iodine status in the UK. It has highlighted a need for nationwide data on iodine status of pregnant women and that a randomised controlled trial of iodine supplementation in pregnant women in a region of mild-to-moderate iodine deficiency with child outcomes as the primary endpoint is required.
As intra-thyroidal iodine stores should be maximised before conception to facilitate the increased thyroid hormone production during pregnancy, women who are planning to become pregnant should ideally consume 150 μg iodine/d (US RDA). As few UK data exist for this population group, a cross-sectional study was carried out at the University of Surrey to assess the iodine intake and status of women of childbearing age. Total iodine excretion was measured from 24 h urine samples in fifty-seven women; iodine intake was estimated by assuming that 90 % of ingested iodine was excreted. The average iodine intake was also estimated from 48 h food diaries that the participants completed. The median urinary iodine concentration value (63·1 μg/l) indicated the group to be mildly iodine deficient by WHO criteria. By contrast, the median 24 h urinary iodine excretion value (149·8 μg/24 h) indicated a relatively low risk of iodine deficiency. The median estimated iodine intake, extrapolated from urinary excretion, was 167 μg/d, whereas it was lower, at 123 μg/d, when estimated from the 48 h food diaries. Iodine intake estimated from the food diaries and 24 h urinary iodine excretion were strongly correlated (r 0·75, P< 0·001). The intake of milk, eggs and dairy products was positively associated with iodine status. The iodine status of this UK cohort is probably a best-case scenario as the women were mostly nutrition students and were recruited in the winter when milk-iodine content is at its highest; further study in more representative cohorts of UK women is required. The present study highlights the need for revised cut-off values for iodine deficiency that are method- and age group-specific.
Iodine is required for adequate thyroid hormone production, which is essential for brain development, particularly in the first trimester of pregnancy. Milk is the principal source of iodine in UK diets, and while small studies in Europe have shown organic milk to have a lower iodine concentration than conventional milk, no such study has been conducted in Britain. In view of the increasing popularity of organic milk in the UK, we aimed to compare the iodine concentration of retail organic and conventional milk and to evaluate regional influences in iodine levels. Samples of organic milk (n 92) and conventional milk (n 80), purchased from retail outlets in sixteen areas of the UK (southern England, Wales and Northern Ireland), were analysed for iodine using inductively coupled plasma MS. The region of origin of the milk was determined from information on the label. Organic milk was 42·1 % lower in iodine content than conventional milk (median iodine concentration 144·5 v. 249·5 ng/g; P < 0·001). There was no difference in the iodine concentration of either conventional or organic milk by area of purchase. However, a difference was seen in iodine concentration of organic milk by region of origin (P < 0·001). The lower iodine concentration of organic milk has public-health implications, particularly in view of emerging evidence of iodine deficiency in UK population sub-groups, including pregnant women. Individuals who choose organic milk should be aware that their iodine intake may be compromised and should ensure adequate iodine intake from alternative sources.
Use of selenium enriched foods, supplements and fertilizers has increased markedly in recent years in the US and other Western countries because of the perception that the anti-oxidant properties of selenium could potentially reduce the risk of cancer and other chronic diseases. However, concern has been raised recently about possible adverse cardiometabolic effects of high selenium exposure, including an increased risk of diabetes and hyperlipidemia with high selenium intake. Hence, from a public health perspective, the relationship between selenium status and cardiometabolic health should be clarified in order to help guide consumers in their choices of nutritional supplements and enriched food products. Additional experimental evidence is needed to provide new insights into the role of selenium and of specific selenoproteins in human biology, especially to clarify the underlying mechanisms linking selenium to chronic disease endpoints. Further epidemiological studies and randomized clinical trials across populations with different selenium status should be conducted to determine the causal effect of selenium on cardiovascular disease and risk factors. Nevertheless, at the present time the widespread use of selenium supplements or other strategies that artificially increase selenium status above the level required for optimal selenoprotein activity is not justified and should not be encouraged
Knowledge of the plasma selenium levels associated with optimised concentration or activity of specific selenoproteins can provide considerable insights from epidemiological data on the possible involvement of those selenoproteins in health, most notably with respect to cancer. For cohort studies, if selenoproteins such as glutathione peroxidase and selenoprotein P are relevant to cancer, one might only expect to see an effect on risk when the concentrations in the cohort range from below, to above, the level needed to optimise the activity or concentration of these enzymes. Similarly, trials would only show a beneficial effect of supplementation if selenium status were raised from below, to above, the optimal concentration for the selenoproteins likely to be implicated in cancer risk, as occurred in the NPC trial but not in SELECT. The most powerful evidence for the involvement of selenoproteins in human health comes from epidemiological studies that have related single nucleotide polymorphisms in selenoproteins to disease risk. The totality of the evidence currently implicates GPx1, GPx4, SEPS1, Sep15, SEPP1 and TXNRD1 in conditions such as cardiovascular disease, pre-eclampsia and cancer. Future studies therefore need to determine not only selenium status, but genotype, both in selenoproteins and related pathways, when investigating the relationship of selenium with disease risk.
There is a growing appreciation that it is not just the total intake of dietary selenium (Se) that is important to health but that the species of Se ingested may also be important. This review attempts to catalogue what is known about Se species in food sources and supplements and the health effects in which they are implicated. The biosynthetic pathways involved in Se assimilation by plants and the way in which Se species are metabolized in animals are presented in order to give an insight into the species likely to be present in plant and animal foods. Known data on the species of Se in the food chain and in food supplements are tabulated along with their concentrations and the analytical methodology used. The latter is important since identification that is only based on retention time matching with authentic standards must be considered as tentative: for evidence of structural confirmation, fragmentation of the molecular ion in addition to MS data is required. Bioavailability, as normally defined, is higher for organic Se species. Health effects, both beneficial and toxic, thought to be associated with specific Se species are described. Potent antitumour effects have been attributed to the low-molecular-weight species, Se-methyl-selenocysteine and its γ-glutamyl-derivative, found in a number of edible plants of the Allium and Brassica families. There remain considerable gaps in our knowledge of the forms of Se that naturally occur in foods. Without adequate knowledge of Se speciation, false conclusions may be drawn when assessing Se requirements for optimal health.
Dietary advice and intervention clearly have a place in rheumatology and allow patients to have some control over their own disease. Although there is no evidence for efficacy of ‘fad’ diets, 30–40% of rheumatoid patients can benefit from excluding foods individually identified during the reintroduction phase of an elimination diet. A proportion of patients who follow a vegetarian or Mediterranean-type diet will experience benefit. Patients who are either overweight or obese should participate in weight-loss programmes. Those with osteoarthritis need to concentrate on reducing fat mass while maintaining muscle mass. Arthritic patients, other than those with gout, should increase their intake of oily fish and additionally supplement with fish oil for up to 3 months to see whether they experience benefit. All arthritic patients, particularly those with inflammatory disease, should be advised to ensure a good dietary intake of antioxidants, copper and zinc. Supplementation with selenium and vitamin D may be advisable.
BACKGROUND: Selenium is known to be important to the brain. Three small, published studies have suggested an effect of selenium supplementation or deprivation on mood in healthy volunteers. We investigated these findings on a much larger scale. METHODS: In this double-blind, placebo-controlled intervention, 501 UK participants aged 60-74 were randomly allocated to receive 100, 200 or 300 microg selenium/d as high-selenium yeast or placebo yeast. Mood (Profile of Moods States - Bipolar Form [POMS-BI] questionnaire), "quality of life" (Short Form 36 [SF-36] questionnaire) and plasma selenium were measured at baseline and six months. RESULTS: Supplementation significantly increased plasma selenium above baseline values: from an overall mean (SD) of 90(19) ng/g to 91(26), 144(27), 191(41) and 227(53) ng/g in the placebo, 100, 200, 300 microg selenium groups respectively (p < .001). Four hundred forty-eight participants completed the POMS-BI questionnaires at both time points, with no significant differences in total mood or mood-subscale scores seen between doses. After six months of supplementation, mean (SD) total mood scores for the four doses were 163(36), 161(37), 162(33), 162(34), F(3,443) = .25, p = .86. Quality of life was similarly unaffected. CONCLUSIONS: There was no evidence that selenium supplementation benefited mood or quality of life in these elderly volunteers. Though this is at odds with some previous results, our robust study design, much larger sample size and longer supplementation period, together with the evidence that the brain is a privileged site for selenium retention, suggest that this is a reliable finding.
Selenium (Se) is an unusual trace element in having its own codon in mRNA that specifies its insertion into selenoproteins as selenocysteine (Sec), by means of a mechanism requiring a large Sec-insertion complex. This exacting insertion machinery for selenoprotein production has implications for our Se requirements for cancer prevention. If Se may protect against cancer, an adequate intake of Se is desirable. However, the level of intake in Europe and some parts of the world is not adequate for full expression of protective selenoproteins. The evidence for Se as a cancer preventive agent includes that from geographic, animal, prospective and intervention studies. Newly-published prospective studies on oesophageal, gastric-cardia and lung cancer have reinforced previous evidence which is particularly strong for prostate cancer. Interventions with Se have shown benefit in reducing the risk of cancer incidence and mortality in all cancers combined, and specifically in liver, prostate, colorectal and lung cancers. The effect seemed to be strongest in those with the lowest Se status. As the level of Se that appears to be required for optimal effect is higher than that previously understood to be required to maximise the activity of selenoenzymes, the question has been raised as to whether selenoproteins are involved in the anti-cancer process. However, recent evidence showing an association between Se, reduction of DNA damage and oxidative stress together with data showing an effect of selenoprotein genotype on cancer risk implies that selenoproteins are indeed implicated. The likelihood of simultaneous and consecutive effects at different cancer stages still allows an important role for anti-cancer Se metabolites such as methyl selenol formed from γ-glutamyl-selenomethyl-selenocysteine and selenomethylselenocysteine, components identified in certain plants and Se-yeast that have anti-cancer effects. There is some evidence that Se may affect not only cancer risk but also progression and metastasis. Current primary and secondary prevention trials of Se are underway in the USA including the SELECT prostate cancer trial, though a large European trial is still desirable given the likelihood of a stronger effect in populations of lower Se status.
Selenium-enriched yeast (Se-yeast) is a common form of selenium used to supplement dietary intake of this important trace mineral. However, its availability within the EU is under threat owing to concerns expressed by the EC Scientific Committee on Food that Se-yeast supplements are poorly characterised and could potentially cause the build up of selenium in tissues to toxic levels. This review examines the validity of these concerns. Diagrams of the biosynthesis and metabolism of selenium compounds show which species can be expected to occur in Se-yeast preparations. Seyeast manufacture is described together with quality control measures applied by reputable manufacturers. The way in which speciation of Se-yeast is achieved is explained and results on amounts of selenium species in various commercial products are tabulated. In all cases described, selenomethionine is the largest single species, accounting for 54-74% of total selenium. Se-yeast is capable of increasing the activity of the selenoenzymes and its bioavailability has been found to be higher than that of inorganic selenium sources in all but one study. Intervention studies with Seyeast have shown the benefit of this form in cancer prevention, immune response and HIV infection. Of around one dozen supplementation studies, none has shown evidence of toxicity even up to an intake level of 800 μg/d selenium over a period of years. It is concluded that Se-yeast from reputable manufacturers is adequately characterised, of reproducible quality, and that there is no evidence of toxicity even at levels far above the EC Tolerable Upper Intake Level of 300 μg/d.
The essential trace mineral, selenium, is of fundamental importance to human health. As a constituent of selenoproteins, selenium has structural and enzymic roles, in the latter context being best-known as an antioxidant and catalyst for the production of active thyroid hormone. Selenium is needed for the proper functioning of the immune system, and appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Deficiency has been linked to adverse mood states. Findings have been equivocal in linking selenium to cardiovascular disease risk although other conditions involving oxidative stress and inflammation have shown benefits of a higher selenium status. An elevated selenium intake may be associated with reduced cancer risk. Large clinical trials are now planned to confirm or refute this hypothesis. In the context of these health effects, low or diminishing selenium status in some parts of the world, notably in some European countries, is giving cause for concern.
Selenium appears to have a beneficial effect on number of adverse pregnancy health conditions. Higher selenium status has been associated with a lower risk of miscarriage and preterm birth, while there is evidence from randomized controlled trials that selenium supplementation may reduce the risk of pre-eclampsia and post-partum thyroid disease. The ability of selenoproteins to reduce oxidative stress, endoplasmic reticulum stress and inflammation, and to protect the endothelium, control eicosanoid production, regulate vascular tone and reduce infection, is likely to be important in these apparently protective effects.
Selenium (Se) is associated with insulin resistance and may affect endothelial function thereby increasing the risk of type 2 diabetes and associated cardiovascular disease (CVD). However, the molecular mechanisms involved are not clear. The endoplasmic-reticulum (ER) stress response is a mechanism involved in apoptosis induced by high Se in some cancer cells and, also in the pathogenesis of insulin resistance and endothelial dysfunction (ED). Thus, we hypothesised that high Se status causes ED through ER stress response. Endothelial cells (HUVECs) and EA.hy926 cell lines were treated with selenite (0.5-10 µM) for 24 hours in the presence or absence of the ER chemical chaperone, 4-phenylbutryic acid (PBA). ER stress markers were investigated using qPCR and western-blot technique. Endothelial function was assessed by the Griess assay, flow cytometry, Matrigel® and colourimetric assays. Data were expressed as S.E.M (p<0.05) vs. control. High Se concentration (5-10 µM) compared to physiological concentration (0.5–2.0 µM) enhanced mRNA expression of ER-stress markers:- activating transcription factor-4 (ATF4), CAAA/enhanced-binding homologous protein (CHOP) and X-binding box-1 (XBP-1). In addition, high selenite concentration reduced nitric oxide production and angiogenic capacity in endothelial cells. Moreover, high selenite treatment significantly (p<0.05) increased production of reactive oxygen species (ROS) and induced apoptosis through caspase-3/7 activity. Interestingly, PBA completely reversed all the effects of high selenite on endothelial function, indicating the involvement of the ER-stress response. High Se treatment caused endothelial dysfunction through the activation of the ER-stress response. This thesis additionally warns the public to be aware of the risks of the use of Se supplements as a prophylactic agent against oxidative-stress disease.
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