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Evidence that selenium supplementation can reduce cancer risk is difficult to incorporate in nutrition thinking in which 'nutritional essentiality' is the central concept. That concept, which defines nutrient need in terms of indispensability in diets and irreplaceable function in preventing specific deficiency disorders, was not developed to accommodate the function of a nutrient in reducing the risk to chronic disease, particularly when that function is not obligate but may be among several involved in maintaining good health. The findings of Clark et al. (JAMA 276, 1957-1963, 1996; Br J Urol 81, 730-734, 1998) suggest that selenium intakes of approximately twice the levels of the new Recommended Dietary Allowance or more can have such beneficial health effects. Because these intakes are above those required to support its accepted essential biochemical functions and because the maintenance of good general health as much as the prevention of specific deficiency disorders is the goal of public health, it is appropriate to reassess the nutritional essentiality paradigm. This discussion of the development and outcomes of the clinical intervention trials of Larry Clark and colleagues is presented in light of these issues. [ABSTRACT FROM AUTHOR]

Objective: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer.Design: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial.Setting: Seven dermatology clinics in the eastern United States.Patients: A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years.Interventions: Oral administration of 200 microg of selenium per day or placebo.Main Outcome Measures: The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers.Results: After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred.Conclusions: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made [ABSTRACT FROM AUTHOR]

This article provides some personal insight into the author's and his colleague's perspective on the developing background for discussing the priority issues facing the field of nutrition. [ABSTRACT FROM AUTHOR]

Introduction: The safety of novel forms of iron in healthy, iron-replete adults as might occur if used in population-based iron supplementation programs was examined. We tested the hypotheses that supplementation with nanoparticulate iron hydroxide adipate tartrate (IHAT), an iron-enriched Aspergillus oryzae product (ASP), or ferrous sulphate heptahydrate (FS) are safe as indicated by erythrocyte susceptibility to malarial infection, bacterial proliferation, and gut inflammation. Responses to FS administered daily or weekly, and with or without other micronutrients were compared., Methods: Two phases of randomized, double-blinded trials were conducted in Boston, MA. Phase I randomized 160 volunteers to six treatments: placebo, IHAT, ASP, FS, and FS plus a micronutrient powder (MNP) administrated daily at 60 mg Fe/day; and FS administered as a single weekly dose of 420 mg Fe. Phase II randomized 86 volunteers to IHAT, ASP, or FS administered at 120 mg Fe/day. Completing these phases were 151 and 77 participants, respectively. The study was powered to detect effects on primary endpoints: susceptibility of participant erythrocytes to infection by Plasmodium falciparum , the proliferation potential of selected pathogenic bacteria in sera, and markers of gut inflammation. Secondary endpoints for which the study was not powered included indicators of iron status and gastrointestinal symptoms., Results: Supplementation with any form of iron did not affect any primary endpoint. In Phase I, the frequency of gastrointestinal symptoms associated with FS was unaffected by dosing with MNP or weekly administration; but participants taking IHAT more frequently reported abdominal pain (27%, p < 0.008) and nausea (4%, p = 0.009) than those taking FS, while those taking ASP more frequently reported nausea (8%, p = 0.009). Surprisingly, only 9% of participants taking IHAT at 120 mg Fe/day (Phase II) reported abdominal pain and no other group reported that symptom., Discussion: With respect to the primary endpoints, few differences were found when comparing these forms of iron, indicating that 28 days of 60 or 120 mg/day of IHAT, ASP, or FS may be safe for healthy, iron-replete adults. With respect to other endpoints, subjects receiving IHAT more frequently reported abdominal pain and nausea, suggesting the need for further study., Clinical Trial Registration: ClinicalTrials.gov, NCT03212677; registered: 11 July 2017., Competing Interests: DP is an inventor of the IHAT iron supplementation technology, for which she could receive future awards to inventors through the MRC Awards to Inventor scheme. She is also scientific advisor to Nemysis Ltd, who now hold the license for IHAT. She has received honoraria or consultancy fees from Vifor Pharma UK, Shield Therapeutics, Entia Ltd, Danone Nutricia, UN Food and Agriculture Organization (FAO) and Nemysis Ltd, for work concerning iron in health. DP has since moved to full employment in the iron and health industry with Vifor Pharma UK. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lewis, Ortega, Dao, Barger, Mason, Leong, Osburne, Magoun, Nepveux V, Chishti, Schwake, Quynh, Gilhooly, Petty, Guo, Matuszek, Pereira, Reddy, Wang, Wu, Meydani and Combs.)

Optimal selenium (Se) status is necessary for overall health. That status can be affected by food intake pattern, age, sex, and health status. At nutritional levels of intake, Se functions metabolically as an essential constituent of some two dozen selenoproteins, most, if not all, of which have redox functions. Insufficient dietary intake of Se reduces, to varying degrees, the expression of these selenoproteins. Recent clinical and animal studies have indicated that both insufficient and excessive Se intakes may increase risk of type 2 diabetes mellitus (T2D), perhaps by way of selenoprotein actions. In this review, we discuss the current evidence linking Se status and T2D risk, and the roles of 14 selenoproteins and other proteins involved in selenoprotein biosynthesis. Understanding such results can inform the setting of safe and adequate Se intakes., Competing Interests: Declarations of competing interest None., (Copyright © 2022. Published by Elsevier Inc.)

This review traces the discoveries that led to the recognition of selenium (Se) as an essential nutrient and discusses Se-responsive diseases in animals and humans in the context of current understanding of the molecular mechanisms of their pathogeneses. The article includes a comprehensive analysis of dietary sources, nutritional utilization, metabolic functions, and dietary requirements of Se across various species. We also compare the function and regulation of selenogenomes and selenoproteomes among rodents, food animals, and humans. The review addresses the metabolic impacts of high dietary Se intakes in different species and recent revelations of Se metabolites, means of increasing Se status, and the recycling of Se in food systems and ecosystems. Finally, research needs are identified for supporting basic science and practical applications of dietary Se in food, nutrition, and health across species.

Background: Selenium (Se) is a nutritionally essential trace element and health may be improved by increased Se intake. Previous kinetic studies have shown differences in metabolism of organic vs. inorganic forms of Se [e.g., higher absorption of selenomethionine (SeMet) than selenite (Sel), and more recycling of Se from SeMet than Sel]. However, the effects on Se metabolism after prolonged Se supplementation are not known., Objective: To determine how the metabolism and transport of Se changes in the whole-body in response to Se-supplementation by measuring Se kinetics before and after 2 years of Se supplementation with SeMet., Methods: We compared Se kinetics in humans [n = 31, aged 40 ± 3 y (mean ± SEM)] studied twice after oral tracer administration; initially (PK1), then after supplementation for 2 y with 200 µg/d of Se as selenomethionine (SeMet) (PK2). On each occasion, we administered two stable isotope tracers of Se orally: SeMet, the predominant food form, and selenite (Na 2 76 SeO 3, or Sel), an inorganic form. Plasma and RBC were sampled for 4 mo; urine and feces were collected for the initial 12 d of each period. Samples were analyzed for tracers and total Se by isotope dilution GC-MS. Data were analyzed using a compartmental model, we published previously, to estimate fractional transfer between pools and pool masses in PK2., Results: We report that fractional absorption of SeMet or Sel do not change with SeMet supplementation and the amount of Se absorbed increased. The amount of Se excreted in urine increases but does not account for all the Se absorbed. As a result, there is a net incorporation of SeMet into various body pools. Nine of the 11 plasma pools doubled in PK2; two did not change. Differences in metabolism were observed for SeMet and Sel; RBC uptake increased 247% for SeMet, urinary excretion increased from two plasma pools for Sel and from two different pools for SeMet, and recycling to liver/tissues increased from one plasma pool for Sel and from two others for SeMet. One plasma pool increased more in males than females in PK2., Conclusions: Of 11 Se pools identified kinetically in human plasma, two did not increase in size after SeMet supplementation. These pools may be regulated and important during low Se intake., Competing Interests: JM was employed by the company Information Management Services, Inc., and MW was employed by Metabolic Modeling Services. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Patterson, Combs, Taylor, Patterson, Moler and Wastney.)

Background: Thiamin deficiency is a major public health concern in several low- and middle-income countries (LMICs)-current attention to the problem is lacking., Aim: This review discusses prevalence of thiamin insufficiency and thiamin-deficiency disorders (TDDs) in LMICs, outlines programmatic experience with thiamin interventions, and offers recommendations to improve public-health and research attention to thiamin in LMICs., Discussion: Thiamin insufficiency, i.e. low-blood-thiamin status, is endemic among several Southeast Asian countries: Cambodia (70-100% of infants and 27-100% of reproductive-age women); Laos (13% of hospitalized infants); Thailand (16-25% of children and 30% of elderly adults). Thiamin deficiency accounts for up to 45% of under-5 deaths in Cambodia, 34% of infant deaths in Laos, and 17% of infant deaths in Myanmar. Deficiency also exists in Africa, Asia, and the Americas, but these instances have typically been isolated. Exclusively breastfed infants of thiamin-deficient mothers are at highest risk for TDD and related death. Intervention strategies that have been employed to combat thiamin deficiency include food processing, fortification, supplementation, dietary diversification, and dietary behaviors, all of which have shown varying levels of effectiveness., Conclusions: We recommend universal thiamin-fortification of context-specific staple-foods in LMICs as a promising solution, as well as thiamin supplementation, particularly for pregnant and lactating women. Food processing regulations, dietary diversification, and modification of dietary behaviors to increase consumption of thiamin-rich foods may provide benefits in some circumstances, especially in countries without universal fortification programs or in populations dependent on food aid.

Purpose: Pancreatic cancer(PCa) is one of the most lethal cancers with few known consistent nutrition-related risk factors. Epidemiologic associations between the trace element selenium and PCa are inconsistent. This study examined the association of pre-diagnostic serum selenium with incident PCa., Methods: We conducted a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Study (PLCO) cohort of men and women 55-70 years old at baseline (1993-2001). In total, 303 PCa cases developed during the 17-year follow-up period (1993-2009). We selected two controls (n = 606) for each case who were alive at the time the case was diagnosed who were matched on age, sex, race, and date of blood draw. We used conditional logistic regression analysis to calculate the odds ratio (OR) and 95% confidence intervals (CI) adjusting for smoking status and diabetes mellitus., Results: Mean serum selenium concentrations were slightly lower in cases (mean, 95% CI: 139.0 ng/ml, 135.6-138.9) compared to controls (142.5 ng/ml, 140.4-142.4, p = 0.08). Overall, serum selenium was not associated with PCa risk (continuous OR: 0.66; 0.32-1.37). There was no significant interaction by sex, smoking, diabetes, or follow-up time (p > 0.05)., Conclusion: Our results do not support the hypothesis that serum selenium is associated with PCa risk.

Two experiments were conducted to evaluate the efficacy of mineral supplementation to cattle grazing winter-wheat pasture. In experiment 1 (fall), 120 steers and heifers (body weight [BW] = 232 ± 11.4 kg) were assigned randomly to four blocks of replicated pastures during the second week of November in 2008 and 2009 and all herds (6 animals/pasture; 4.9 ha/pasture) were allowed to graze for 84 d. In experiment 2 (spring), 216 steers (BW = 248 ± 7.9 kg) were assigned randomly to five blocks of replicated pastures during the second week of February in 2009 and 2010 and all herds (12 or 6 animals/pasture; 4.9 ha/pasture) were allowed to graze for 84 d. Half the pastures in both experiments received a free-choice mineral mixture (Wheat Pasture Pro; Land O'Lakes Purina Feed, LLC; St. Paul, MN; Ca, 16% and P, 4%); mineral feeders were weighed weekly to determine mineral intake. All pastures were planted in early September of each year (67 kg of seed/ha) and fertilized with 50 kg of urea-N/ha. Standing herbage dry matter was determined midway between weigh dates by clipping wheat forage to the ground along 122 cm of drill rows at 10 locations/pasture. Data were analyzed by ANOVA, with treatment as the fixed effect and pasture, animal sex (experiment 1), and block as random effects. In experiment 1, cattle offered minerals had a 43% faster average daily gain (ADG; P = 0.02, 0.73 kg) than cattle not offered minerals (0.51 kg); hence, supplemented cattle weighed 6% more ( P = 0.04; 286 kg) after 84 d than nonsupplemented cattle (271 kg). In experiment 2, cattle offered the mineral supplement had a faster ADG (20% increase; P = 0.04; 1.00 kg) than cattle not offered minerals (0.83 kg). Further, supplemented cattle weighed 4% more ( P = 0.03; 326 kg) after 84 d than nonsupplemented cattle (312 kg). In both experiments, daily standing herbage dry matter averaged 1,381 kg/animal and never differed ( P ≥ 0.47) between treatments. Mineral intakes averaged 135 (experiment 1) and 124 (experiment 2) g/d, resulting in a cost of supplement to kilogram of added BW gain of $0.53 and $0.64, respectively (assuming a mineral cost of $0.88/kg). Overall, supplementing an appropriate mineral mixture to cattle grazing winter-wheat pasture increased ADG in a cost-effective manner., (Published by Oxford University Press on behalf of the American Society of Animal Science 2019.)

Thiamine is an essential micronutrient that plays a key role in energy metabolism. Many populations worldwide may be at risk of clinical or subclinical thiamine deficiencies, due to famine, reliance on staple crops with low thiamine content, or food preparation practices, such as milling grains and washing milled rice. Clinical manifestations of thiamine deficiency are variable; this, along with the lack of a readily accessible and widely agreed upon biomarker of thiamine status, complicates efforts to diagnose thiamine deficiency and assess its global prevalence. Strategies to identify regions at risk of thiamine deficiency through proxy measures, such as analysis of food balance sheet data and month-specific infant mortality rates, may be valuable for understanding the scope of thiamine deficiency. Urgent public health responses are warranted in high-risk regions, considering the contribution of thiamine deficiency to infant mortality and research suggesting that even subclinical thiamine deficiency in childhood may have lifelong neurodevelopmental consequences. Food fortification and maternal and/or infant thiamine supplementation have proven effective in raising thiamine status and reducing the incidence of infantile beriberi in regions where thiamine deficiency is prevalent, but trial data are limited. Efforts to determine culturally and environmentally appropriate food vehicles for thiamine fortification are ongoing., (© 2018 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.)

Selenium (Se) is a trace metalloid essential for life, but its nutritional and physiological roles during the aging process remain elusive. While telomere attrition contributes to replicative senescence mainly through persistent DNA damage response, such an aging process is mitigated in mice with inherently long telomeres. Here, weanling third generation telomerase RNA component knockout mice carrying short telomeres were fed a Se-deficient basal diet or the diet supplemented with 0.15 ppm Se as sodium selenate to be nutritionally sufficient throughout their life. Dietary Se deprivation delayed wound healing and accelerated incidence of osteoporosis, gray hair, alopecia, and cataract, but surprisingly promoted longevity. Plasma microRNA profiling revealed a circulating signature of Se deprivation, and subsequent ontological analyses predicted dominant changes in metabolism. Consistent with this observation, dietary Se deprivation accelerated age-dependent declines in glucose tolerance, insulin sensitivity, and glucose-stimulated insulin production in the mice. Moreover, DNA damage and senescence responses were enhanced and Pdx1 and MafA mRNA expression were reduced in pancreas of the Se-deficient mice. Altogether, these results suggest a novel model of aging with conceptual advances, whereby Se at low levels may be considered a hormetic chemical and decouple healthspan and longevity., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Resistant starch (RS) has unique digestive and absorptive properties which may provide health benefits. We conducted a study to determine the contributions of cultivar, cooking method and service temperature on the RS contents of potatoes (Solanum tuberosum L.). We hypothesized that the RS content would vary by variety, cooking method and service temperature. Potatoes of three common commercial varieties (Yukon Gold, Dark Red Norland, and Russet Burbank) were subjected to two methods of cooking (baking or boiling) and three service temperatures: hot (65°C), chilled (4°C) and reheated (4°C for 6d; reheated to 65°C) and analyzed the starch content by modification of a commercially available assay. Results showed that RS content (g/100g) varied by cooking method and service temperature but not variety. Baked potatoes had higher RS contents than boiled; chilled potatoes had more RS than either hot or reheated. These results may assist in dietary choices for reducing chronic disease risk., (Published by Elsevier Ltd.)

Background: Selenium is an essential constituent of selenoproteins, which play a substantial role in antioxidant defense and inflammatory cascades. Selenium deficiency is associated with disease states characterized by inflammation, including cardiovascular disease (CVD). Although HIV infection has been associated with low selenium, the role of selenium status in HIV-related CVD is unclear., Objectives: We sought to assess associations between plasma selenium and markers of inflammation, immune activation, and subclinical vascular disease in HIV-infected adults on contemporary antiretroviral therapy (ART) and to determine if statin therapy modifies selenium status., Methods: In the Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN trial, HIV-infected adults on stable ART were randomly assigned 1:1 to rosuvastatin or placebo. Plasma selenium concentrations were determined at entry, week 24, and week 48. Spearman correlation and linear regression analyses were used to assess relations between baseline selenium, HIV-related factors and markers of inflammation, immune activation, and subclinical vascular disease. Changes in selenium over 24 and 48 wk were compared between groups., Results: One hundred forty-seven HIV-infected adults were included. All participants were on ART. Median current CD4+ count was 613, and 76% had HIV-1 RNA ≤48 copies/mL (range: <20-600). Median plasma selenium concentration was 122 μg/L (range: 62-200). At baseline, higher selenium was associated with protease inhibitor (PI) use, lower body mass index, and a higher proportion of activated CD8+ T cells (CD8+CD38+human leukocyte antigen-DR+), but not markers of inflammation or subclinical vascular disease. Over 48 wk, selenium concentrations increased in the statin group (P < 0.01 within group), but the change did not differ between groups (+13.1 vs. +5.3 μg/L; P = 0.14 between groups)., Conclusions: Plasma selenium concentrations were within the normal range for the background population and were not associated with subclinical vascular disease in HIV-infected adults on contemporary ART. The association between current PI use and higher selenium may have implications for ART allocation, especially in resource-limited countries. Also, it appears that statin therapy may increase selenium concentrations; however, larger studies are necessary to confirm this finding. This trial was registered at clinicaltrials.gov as NCT01218802., (© 2015 American Society for Nutrition.)

The essential trace element, selenium (Se), has multiple biological activities, which depend on the level of Se intake. Relatively low Se intakes determine the expression of selenoenzymes in which it serves as an essential constituent. Higher intakes have been shown to have anti-tumorigenic potential; and very high Se intakes can produce adverse effects. This hierarchy of biological activities calls for biomarkers informative at different levels of Se exposure. Some Se-biomarkers, such as the selenoproteins and particularly GPX3 and SEPP1, provide information about function directly and are of value in identifying nutritional Se deficiency and tracking responses of deficient individuals to Se-treatment. They are useful under conditions of Se intake within the range of regulated selenoprotein expression, e.g., for humans <55 μg/day and for animals <20 μg/kg diet. Other Se-biomarkers provide information indirectly through inferences based on Se levels of foods, tissues, urine or feces. They can indicate the likelihood of deficiency or adverse effects, but they do not provide direct evidence of either condition. Their value is in providing information about Se status over a wide range of Se intake, particularly from food forms. There is need for additional Se biomarkers particularly for assessing Se status in non-deficient individuals for whom the prospects of cancer risk reduction and adverse effects risk are the primary health considerations. This would include determining whether supranutritional intakes of Se may be required for maximal selenoprotein expression in immune surveillance cells. It would also include developing methods to determine low molecular weight Se-metabolites, i.e., selenoamino acids and methylated Se-metabolites, which to date have not been detectable in biological specimens. Recent analytical advances using tandem liquid chromatography-mass spectrometry suggest prospects for detecting these metabolites.

Energy deficit and dietary macronutrient intake are thought to independently modulate cognition, mood and sleep. To what extent manipulating the dietary ratio of protein-to-carbohydrate affects mood, cognition and sleep during short-term energy deficit is undetermined. Using a randomized, block design, 39 non-obese young adults (21±1 years, BMI 25±1 kg/m(2)) consumed diets containing 0.8 g, 1.6 g or 2.4 g protein per kg body weight per day for 31 days. Carbohydrate intake was reduced to accommodate higher protein intakes while dietary fat was maintained at 30% of total energy intake. Cognitive performance, mood, self-reported sleep quality, and plasma amino acid concentrations were periodically assessed during a 10-day energy balance period and a subsequent 21-day, 40% energy deficit period. Anger, tension and total mood disturbance increased during the initial ten days of energy deficit (P<0.05), but by the end of the energy deficit returned to levels not different from those measured during energy balance. No effects of dietary protein-to-carbohydrate ratio on cognitive performance, mood or self-reported sleep quality were observed during energy balance or energy deficit. Thus, high-protein, low-carbohydrate, moderate-fat diets do not appear to benefit or impair cognition, mood or sleep in non-obese adults during energy deficit. These findings suggest that energy deficit may initially be psychologically difficult for non-obese individuals attempting to lose weight, but that these changes are transient. Employing strategies that alleviate decrements in mood during this initial period of adaptation may help sustain weight loss efforts., (Published by Elsevier Inc.)

Previous studies in mice have shown that topical L-selenomethionine (SeMet) can prevent UVB-induced skin cancer when applied continuously before, during, and after the radiation exposure. With topical application of SeMet, selenium levels were shown to increase in the skin and liver, as well as in tumor tissue. Thus, possibly, the timing of SeMet application could affect the degree of inhibition of UVB-tumorigenesis (or maybe even enhance tumorigenesis at some stage). The goal of this research was to determine whether topical SeMet best inhibits UV-induced skin cancer if (a) begun before and continued during and after UVB exposure, (b) if begun before UVB-exposure and discontinued when tumors are first clinically detected, or (c) if begun only after tumors are first detected and continued thereafter. Groups of ten Skh: 1 hairless, non-pigmented mice were treated topically with vehicle lotion, or with SeMet (0.05%) in that vehicle lotion applied either (a) before, during, and after UV exposure, (b) before UV radiation and continued only until the first tumor was detected, or (c) only after the first tumor was detected. In all cases, UV irradiation was discontinued at the time of detection of the first tumor. Optimal inhibition of skin cancer was achieved by application of topical SeMet before, during, and after exposure; significant protection was also attained with application only after the onset of tumors. Notably, statistically significant protection was not seen with SeMet application only prior to tumor detection. These results suggest that even beginning SeMet supplementation late in the process of tumorigenesis can help protect from UV-induced photodamage and skin cancer.

We investigated the effect of dietary supplementation with selenium on spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet. Mice were fed a low-fat diet or that diet modified with 45% of calories from corn oil and supplemented with 0 or 2.5mg selenium/4029 kcal as methylseleninic acid. After 6 weeks, mice were each injected 2.5 × 10(5) Lewis lung carcinoma cells subcutaneously. The resulting primary tumor was removed surgically 10 days later; the experiment was terminated after an additional 10 days. High-fat feeding increased pulmonary metastases by 17% compared to the low-fat diet (P < 0.01). Selenium supplementation reduced the metastases by 11% compared to nonsupplemented controls (P < 0.05); the reduction was less for animals fed the high-fat diet (5%) than for those fed the low-fat diet (18%). Supplemental Se lowered plasma concentrations of proteases (urokinase plasminogen activator, P < 0.01; matrix metalloproteinase-9, P < 0.05) and angiogenic factors (vascular endothelial growth factor, P < 0.01; tissue inhibitor of metalloproteinase-1, P < 0.01) compared to nonsupplemented controls. High-fat feeding increased plasma concentrations of adipokines plasminogen activator inhibitor-1, monocyte chemotactic protein-1, tumor necrosis factor-α, and leptin regardless of the level of dietary selenium; supplemental selenium lowered plasma concentrations of plasminogen activator inhibitor-1 (P ≤ 0.05) and monocyte chemotactic protein-1 (P ≤ 0.05) in low-fat fed mice but not in high-fat fed mice. These results indicate that consumption of a high-fat diet abrogated the antimetastatic effects of selenium by increasing the expression of adipose-derived inflammatory cytokines., (Published by Oxford University Press 2014.)

Background: Selenium is found in soils and is essential for human antioxidant defense and immune function. In Malawi, low soil selenium and dietary intakes coupled with low plasma selenium concentrations in HIV infection could have negative consequences for the health of HIV-infected mothers and their exclusively breastfed infants., Objective: We tested the effects of lipid-based nutrient supplements (LNS) that contained 1.3 times the Recommended Dietary Allowance of sodium selenite and antiretroviral drugs (ARV) on maternal plasma and breast-milk selenium concentrations., Design: HIV-infected Malawian mothers in the Breastfeeding, Antiretrovirals, and Nutrition study were randomly assigned at delivery to receive: LNS, ARV, LNS and ARV, or a control. In a subsample of 526 mothers and their uninfected infants, we measured plasma and breast-milk selenium concentrations at 2 or 6 (depending on the availability of infant samples) and 24 wk postpartum., Results: Overall, mean (± SD) maternal (range: 81.2 ± 20.4 to 86.2 ± 19.9 μg/L) and infant (55.6 ± 16.3 to 61.0 ± 15.4 μg/L) plasma selenium concentrations increased, whereas breast-milk selenium concentrations declined (14.3 ± 11.5 to 9.8 ± 7.3 μg/L) from 2 or 6 to 24 wk postpartum (all P < 0.001). Compared with the highest baseline selenium tertile, low and middle tertiles were positively associated with a change in maternal plasma or breast-milk selenium from 2 or 6 to 24 wk postpartum (both P < 0.001). With the use of linear regression, we showed that LNS that contained selenium and ARV were not associated with changes in maternal plasma and breast-milk selenium, but maternal selenium concentrations were positively associated with infant plasma selenium at 2 or 6 and 24 wk postpartum (P < 0.001) regardless of the study arm., Conclusions: Selenite supplementation of HIV-infected Malawian women was not associated with a change in their plasma or breast-milk selenium concentrations. Future research should examine effects of more readily incorporated forms of selenium (ie, selenomethionine) in HIV-infected breastfeeding women.

Background: Although consuming dietary protein above current recommendations during energy deficit (ED) preserves lean body mass, concerns have been raised regarding the effects of high-protein diets on bone health., Objective: The objective was to determine whether calcium homeostasis and bone turnover are affected by high-protein diets during weight maintenance (WM) and ED., Design: In a randomized, parallel-design, controlled trial of 32 men and 7 women, volunteers were assigned diets providing protein at 0.8 [Recommended Dietary Allowance (RDA)], 1.6 (2 × RDA), or 2.4 (3 × RDA) g · kg(-1) · d(-1) for 31 d. Ten days of WM preceded 21 d of ED, during which total daily ED was 40%, achieved by reduced dietary energy intake (∼30%) and increased physical activity (∼10%). The macronutrient composition (protein g · kg(-1) · d(-1) and % fat) was held constant from WM to ED. Calcium absorption (ratio of (44)Ca to (42)Ca) and circulating indexes of bone turnover were determined at day 8 (WM) and day 29 (ED)., Results: Regardless of energy state, mean (±SEM) urinary pH was lower (P < 0.05) at 2 × RDA (6.28 ± 0.05) and 3 × RDA (6.23 ± 0.06) than at the RDA (6.54 ± 0.06). However, protein had no effect on either urinary calcium excretion (P > 0.05) or the amount of calcium retained (P > 0.05). ED decreased serum insulin-like growth factor I concentrations and increased serum tartrate-resistant acid phosphatase and 25-hydroxyvitamin D concentrations (P < 0.01). Remaining markers of bone turnover and whole-body bone mineral density and content were not affected by either the protein level or ED (P > 0.05)., Conclusion: These data demonstrate that short-term consumption of high-protein diets does not disrupt calcium homeostasis and is not detrimental to skeletal integrity. This trial was registered at www.clinicaltrials.gov as NCT01292395.

Impaired S-adenosylmethionine (SAM)-dependent transmethylation and methylation capacity feature in diseases related to obesity or aging, and selenium (Se) metabolism is altered in these states. We tested the hypothesis that SAM metabolism is required for methylation and excretion of Se in a rat model. Four hours after selenite and periodate-oxidized adenosine (POA; an inhibitor of SAM metabolism) were administered, circulating markers of single-carbon status were unchanged, except for decreased circulating phosphatidylcholine (P<.05). In contrast, liver and kidney SAM and S-adenosylhomocysteine were elevated (P<.05 for all). Concentrations of total Se were significantly elevated in both liver (P<.001) and kidney (P<.01), however the degree of accumulation in liver was significantly greater than that of kidney (P<.05). Red blood cell Se levels were decreased (P=.01). Trimethylselenonium levels were decreased in liver and kidney (P=.001 for both tissues) and Se-methyl-N-acetylselenohexosamine selenosugar was decreased in liver (P=.001). Urinary output of both trimethylselenonium (P=.001) and selenosugar (P=.01) was decreased as well. Trimethylselenonium production is more inhibited by POA than is selenosugar production (P<.05). This work indicates that low molecular weight Se metabolism requires SAM-dependent methylation, and disrupting the conversion of SAM to S-adenosylhomocysteine prevents conversion of selenite and intermediate metabolites to final excretory forms, suggesting implications for selenium supplementation under conditions where transmethylation is suboptimal, such as in the case of obese or aging individuals., (© 2013.)

This study was undertaken to characterize the ubiquitin proteasome system (UPS) response to varied dietary protein intake, energy deficit (ED), and consumption of a mixed meal. A randomized, controlled trial of 39 adults consuming protein at 0.8 (recommended dietary allowance [RDA]), 1.6 (2×-RDA), or 2.4 (3×-RDA) g · kg(-1) · d(-1) for 31 d. A 10-d weight maintenance (WM) period was followed by 21 d of 40% ED. Ubiquitin (Ub)-mediated proteolysis and associated gene expression were assessed in the postabsorptive (fasted) and postprandial (fed; 480 kcal, 20 g protein) states after WM and ED by using muscle biopsies, fluorescence-based assays, immunoblot analysis, and real-time qRT-PCR. In the assessment of UPS responses to varied protein intakes, ED, and feeding, the RDA, WM, and fasted measures served as appropriate controls. ED resulted in the up-regulation of UPS-associated gene expression, as mRNA expression of the atrogenes muscle RING finger-1 (MuRF1) and atrogin-1 were 1.2- and 1.3-fold higher (P<0.05) for ED than for WM. However, mixed-meal consumption attenuated UPS-mediated proteolysis, independent of energy status or dietary protein, as the activities of the 26S proteasome subunits β1, β2, and β5 were lower (P<0.05) for fed than for fasted. Muscle protein ubiquitylation was also 45% lower (P<0.05) for fed than for fasted, regardless of dietary protein and energy manipulations. Independent of habitual protein intake and despite increased MuRF1 and atrogin-1 mRNA expression during ED, consuming a protein-containing mixed meal attenuates Ub-mediated proteolysis.

The purpose of this work was to determine the effects of varying levels of dietary protein on body composition and muscle protein synthesis during energy deficit (ED). A randomized controlled trial of 39 adults assigned the subjects diets providing protein at 0.8 (recommended dietary allowance; RDA), 1.6 (2×-RDA), and 2.4 (3×-RDA) g kg(-1) d(-1) for 31 d. A 10-d weight-maintenance (WM) period was followed by a 21 d, 40% ED. Body composition and postabsorptive and postprandial muscle protein synthesis were assessed during WM (d 9-10) and ED (d 30-31). Volunteers lost (P<0.05) 3.2 ± 0.2 kg body weight during ED regardless of dietary protein. The proportion of weight loss due to reductions in fat-free mass was lower (P<0.05) and the loss of fat mass was higher (P<0.05) in those receiving 2×-RDA and 3×-RDA compared to RDA. The anabolic muscle response to a protein-rich meal during ED was not different (P>0.05) from WM for 2×-RDA and 3×-RDA, but was lower during ED than WM for those consuming RDA levels of protein (energy × protein interaction, P<0.05). To assess muscle protein metabolic responses to varied protein intakes during ED, RDA served as the study control. In summary, we determined that consuming dietary protein at levels exceeding the RDA may protect fat-free mass during short-term weight loss.

High-fat (HF) diets can produce obesity and have been linked to the development of nonalcoholic fatty liver disease and changes in the gut microbiome. To test the hypothesis that HF feeding increases certain predominant hind gut bacteria and development of steatohepatitis, C57BL/6 mice were fed an HF (45% energy) or low-fat (LF) (10% energy) diet for 10 wk. At the end of the feeding period, body weights in the HF group were 34% greater than those in the LF group (P < 0.05). These changes were associated with dramatic increases in lipid droplet number and size, inflammatory cell infiltration, and inducible nitric oxide (NO) synthase protein concentration in the livers of mice fed the HF diet. Consistent with the fatty liver phenotype, plasma leptin and tumor necrosis factor-α concentrations were also elevated in mice fed the HF diet, indicative of chronic inflammation. Eight of 12 pairs of polymerase chain reaction (PCR) primers for bacterial species that typically predominate hind gut microbial ecology generated specific PCR products from the fecal DNA samples. The amount of DNA from Lactobacillus gasseri and/or Lactobacillus taiwanensis in the HF group was 6900-fold greater than that in the LF group. Many of these bacteria are bile acid resistant and are capable of bile acid deconjugation. Because bile acids are regulators of hepatic lipid metabolism, the marked increase of gut L. gasseri and/or L. taiwanensis species bacteria with HF feeding may play a role in development of steatohepatitis in this model.

Selenium (Se) is an essential trace element for humans and animals, and several findings suggest that dietary Se intake may be necessary for bone health. Such findings may relate to roles of Se in antioxidant protection, enhanced immune surveillance and modulation of cell proliferation. Elucidation of the mechanisms by which Se supports these cellular processes can lead to a better understanding of the role of this nutrient in normal bone metabolism. This article reviews the current knowledge concerning the molecular functions of Se relevant to bone health.

Changes in dietary selenium and selenoprotein status may influence both anti- and pro-cancer pathways, making the outcome of interventions different from one study to another. To characterize such outcomes in a defined setting, we undertook a controlled hepatocarcinogenesis study involving varying levels of dietary selenium and altered selenoprotein status using mice carrying a mutant (A37G) selenocysteine tRNA transgene (Trsp(tG37) ) and/or a cancer driver TGFα transgene. The use of Trsp(tG37) altered selenoprotein expression in a selenoprotein and tissue specific manner and, at sufficient dietary selenium levels, separate the effect of diet and selenoprotein status. Mice were maintained on diets deficient in selenium (0.02 ppm selenium) or supplemented with 0.1, 0.4 or 2.25 ppm selenium or 30 ppm triphenylselenonium chloride (TPSC), a non-metabolized selenium compound. Trsp(tG37) transgenic and TGFα/Trsp(tG37) bi-transgenic mice subjected to selenium-deficient or TPSC diets developed a neurological phenotype associated with early morbidity and mortality prior to hepatocarcinoma development. Pathology analyses revealed widespread disseminated pyogranulomatous inflammation. Pyogranulomas occurred in liver, lungs, heart, spleen, small and large intestine, and mesenteric lymph nodes in these transgenic and bi-transgenic mice. The incidence of liver tumors was significantly increased in mice carrying the TGFα transgene, while dietary selenium and selenoprotein status did not affect tumor number and multiplicity. However, adenoma and carcinoma size and area were smaller in TGFα transgenic mice that were fed 0.4 and 2.25 versus 0.1 ppm of selenium. Thus, selenium and selenoprotein deficiencies led to widespread pyogranuloma formation, while high selenium levels inhibited the size of TGFα-induced liver tumors.

Prostate cancer is the product of dysregulated homeostasis within the aging prostate. Supplementation with selenium in the form of selenized yeast (Se-yeast) significantly reduced prostate cancer incidence in the Nutritional Prevention of Cancer Trial. Conversely, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed no such cancer-protective advantage using selenomethionine (SeMet). The possibility that SeMet and Se-yeast are not equipotent in promoting homeostasis and cancer risk reduction in the aging prostate has not been adequately investigated; no direct comparison has ever been reported in man or animals. Here, we analyzed data on prostatic responses to SeMet or Se-yeast from a controlled feeding trial of 49 elderly beagle dogs-the only non-human species to frequently develop prostate cancer during aging-randomized to one of five groups: control; low-dose SeMet, low-dose Se-yeast (3 μg/kg); high-dose SeMet, high-dose Se-yeast (6 μg/kg). After seven months of supplementation, we found no significant selenium form-dependent differences in toenail or intraprostatic selenium concentration. Next, we determined whether SeMet or Se-yeast acts with different potency on six markers of prostatic homeostasis that likely contribute to prostate cancer risk reduction-intraprostatic dihydrotestosterone (DHT), testosterone (T), DHT:T, and epithelial cell DNA damage, proliferation, and apoptosis. By analyzing dogs supplemented with SeMet or Se-yeast that achieved equivalent intraprostatic selenium concentration after supplementation, we showed no significant differences in potency of either selenium form on any of the six parameters over three different ranges of target tissue selenium concentration. Our findings, which represent the first direct comparison of SeMet and Se-yeast on a suite of readouts in the aging prostate that reflect flux through multiple gene networks, do not further support the notion that the null results of SELECT are attributable to differences in prostatic consequences achievable through daily supplementation with SeMet, rather than Se-yeast.

Cellular methylation processes enable expression of gluconeogenic enzymes and metabolism of the nutrient selenium. Selenium status has been proposed to relate to type II diabetes risk, and plasma levels of selenoprotein P (SEPP1) have been positively correlated with insulin resistance. Increased expression of gluconeogenic enzymes glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1) has negative consequences for blood glucose management in type II diabetics. Transcriptional regulation of SEPP1 is directed by the same transcription factors that control the expression of G6PC and PCK1, and these factors are activated by methylation of arginine residues. We sought to determine whether expression of SEPP1 and the aforementioned glucoconeogenic enzymes are regulated by protein methylation, the levels of which are reliant upon adequate S-adenosylmethionine (SAM) and inhibited by S-adenosylhomocysteine (SAH). We treated a human hepatocyte cell line, HepG2, with inhibitors of adenosylhomocysteine hydrolase (AHCY) known to increase concentration of SAH before analysis of G6PC, PCK1, and SEPP1 expression. Increasing SAH decreased 1) the SAM/SAH ratio, 2) protein-arginine methylation, and 3) expression of SEPP1, G6PC, and PCK1 transcripts. Furthermore, hormone-dependent induction of gluconeogenic enzymes was reduced by inhibition of protein methylation. When protein-arginine methyltransferase 1 expression was reduced by siRNA treatment, G6PC expression was inhibited. These findings demonstrate that hepatocellular SAM-dependent protein methylation is required for both SEPP1 and gluconeogenic enzyme expression and that inhibition of protein arginine methylation might provide a route to therapeutic interventions in type II diabetes.

Background: Data from human epidemiological studies, cultured mammalian cells, and animal models have supported a potentially beneficial role of selenium (Se) in prostate cancer prevention. In addition, Se-containing proteins including members of the glutathione peroxidase (GPx) family and Selenium-Binding Protein 1 (SBP1) have been linked to either cancer risk or development. For example, SBP1 levels are typically reduced in tumors compared to non-cancerous tissue, with the degree of reduction associated with increasingly poor clinical outcome., Methods: In order to investigate inter-relationships between blood and tissue Se levels and GPx activity, tissue SBP1 levels, and disease aggressiveness using the Gleason score, we measured levels of selenium and selected selenoproteins in fasting serum and histologically normal prostate tissues obtained from 24 men undergoing radical prostatectomy for the treatment of localized prostate cancer., Results: GPx enzyme activity was inversely correlated with SBP1 levels in prostate tissue as determined by densitometry of Western blots obtained using anti-SBP1 antibodies [partial Spearman's correlation coefficients and corresponding P-values overall and in African-Americans = -0.42 (0.08) and -0.53 (0.10), respectively], which is consistent with previous observations in cultured cells and mice. Of particular interest was the positive correlation between tissue GPx activity and Gleason score, with this relationship achieving statistical significance among African-Americans (r = 0.67, P = 0.02)., Conclusion: These studies support the continued investigation of the role of Se and selenoproteins in prostate cancer prevention, development, and prognosis., (Copyright © 2011 Wiley Periodicals, Inc.)

A year-long intervention trial was conducted to characterise the responses of multiple biomarkers of Se status in healthy American adults to supplemental selenomethionine (SeMet) and to identify factors affecting those responses. A total of 261 men and women were randomised to four doses of Se (0, 50, 100 or 200 μg/d as L-SeMet) for 12 months. Responses of several biomarkers of Se status (plasma Se, serum selenoprotein P (SEPP1), plasma glutathione peroxidase activity (GPX3), buccal cell Se, urinary Se) were determined relative to genotype of four selenoproteins (GPX1, GPX3, SEPP1, selenoprotein 15), dietary Se intake and parameters of single-carbon metabolism. Results showed that supplemental SeMet did not affect GPX3 activity or SEPP1 concentration, but produced significant, dose-dependent increases in the Se contents of plasma, urine and buccal cells, each of which plateaued by 9-12 months and was linearly related to effective Se dose (μg/d per kg0·75). The increase in urinary Se excretion was greater for women than men, and for individuals of the GPX1 679 T/T genotype than for those of the GPX1 679 C/C genotype. It is concluded that the most responsive Se-biomarkers in this non-deficient cohort were those related to body Se pools: plasma, buccal cell and urinary Se concentrations. Changes in plasma Se resulted from increases in its non-specific component and were affected by both sex and GPX1 genotype. In a cohort of relatively high Se status, the Se intake (as SeMet) required to support plasma Se concentration at a target level (Se(pl-target)) is: Se(in) = [(Se(pl - target) - Se(pl))/(18.2ng d kg⁰.⁷⁵/ml per mu g)] .

Determining the effect of selenium (Se) chemical form on uptake, transport, and glutathione peroxidase activity in human intestinal cells is critical to assess Se bioavailability at nutritional doses. In this study, we found that two sources of L-selenomethionine (SeMet) and Se-enriched yeast each increased intracellular Se content more effectively than selenite or methylselenocysteine (SeMSC) in the human intestinal Caco-2 cell model. Interestingly, SeMSC, SeMet, and digested Se-enriched yeast were transported at comparable efficacy from the apical to basolateral sides, each being about 3-fold that of selenite. In addition, these forms of Se, whether before or after traversing from apical side to basolateral side, did not change the potential to support glutathione peroxidase (GPx) activity. Although selenoprotein P has been postulated to be a key Se transport protein, its intracellular expression did not differ when selenite, SeMSC, SeMet, or digested Se-enriched yeast was added to serum-contained media. Taken together, our data show, for the first time, that the chemical form of Se at nutritional doses can affect the absorptive (apical to basolateral side) efficacy and retention of Se by intestinal cells; but that, these effects are not directly correlated to the potential to support GPx activity.

Background: Selenium (Se) status in non-deficient subjects is typically assessed by the Se contents of plasma/serum. That pool comprises two functional, specific selenoprotein components and at least one non-functional, non-specific components which respond differently to changes in Se intake. A more informative means of characterizing Se status in non-deficient individuals is needed., Methods: Multiple biomarkers of Se status (plasma Se, serum selenoprotein P [SEPP1], plasma glutathione peroxidase activity [GPX3], buccal cell Se, urinary Se) were evaluated in relation to selenoprotein genotypes (GPX1, GPX3, SEPP1, SEP15), dietary Se intake, and parameters of single-carbon metabolism in a cohort of healthy, non-Se-deficient men (n = 106) and women (n = 155)., Conclusions: Plasma Se concentration was 142.0 ± 23.5 ng/ml, with GPX3 and serum-derived SEPP1 calculated to comprise 20% and 34%, respectively, of that total. The balance, comprised of non-specific components, accounted for virtually all of the interindividual variation in total plasma Se. Buccal cell Se was associated with age and plasma homocysteine (hCys), but not plasma Se. SEPP1 showed a quadratic relationship with body mass index, peaking at BMI 25-30. Urinary Se was greater in women than men, and was associated with metabolic body weight (kg0.75), plasma folate, vitamin B12 and hCys (negatively). One GPX1 genotype (679T/T) was associated with significantly lower plasma Se levels than other allelic variants. Selenium intake, estimated from food frequency questionnaires, did not predict Se status as indicated by any biomarker. These results show that genotype, methyl-group status and BMI contribute to variation in Se biomarkers in Se-adequate individuals.

The present study investigated effects of the physical form of the diet on food intake, growth, and body composition in male C57BL/6 mice. Three-week-old mice were fed isocaloric diets (AIN93G or a modification containing 25% wheat) in powdered or pelleted form. In experiment 1, mice were assigned into 4 groups offered the AIN93G or the wheat-modified diet in powdered or pelleted form. In experiment 2, mice were pair-fed the powdered diets to the ad libitum level of food intake of those fed the pelleted form of the respective diets. Body weight, food intake, and fecal excretion were recorded, and body composition was assessed on mice 1 wk before termination of the experiment. Mice fed the powdered diets showed greater increases in body weight in 2 wk of feeding than did mice fed the pelleted diets. Compared with the pelleted diets, the powdered diets supported an approximately 85% increase in the fat-mass:body-mass ratio and a 2-fold increase in the abdominal-fat-weight:carcass-weight ratio. In addition, mice fed the powdered diet showed significantly greater plasma concentrations of insulin and leptin and significantly lower plasma adiponectin, compared with their pellet-fed counterparts. Food intake of mice fed the powdered diet was 11% greater for the AIN93G and 16% greater for the wheat diet compared with that of the respective pelleted diet. These results demonstrate that C57BL/6 mice responded to the physical form of these diets in terms of food intake, which affected their growth, body composition, and plasma concentrations of insulin and adipocytokines., (Copyright 2011 by the American Association for Laboratory Animal Science)

Selenium (Se) metabolism is affected by its chemical form in foods and by its incorporation (specific vs. nonspecific) into multiple proteins. Modeling Se kinetics may clarify the impact of form on metabolism. Although the kinetics of Se forms have been compared in different participants, or the same participants at different times, direct comparisons of their respective metabolism in the same participants have not been made. The aim of this study was to simultaneously compare kinetics of absorbed Se from inorganic selenite (Sel) and organic selenomethionine (SeMet) in healthy participants (n = 31). After oral administration of stable isotopic tracers of each form, urine and feces were collected for 12 d and blood was sampled over 4 mo. Tracer enrichment was determined by isotope-dilution-GC-MS. Using WinSAAM, a compartmental model was fitted to the data. Within 30 min of ingestion, Se from both forms entered a common pool, and metabolism was similar for several days before diverging. Slowly turning-over pools were required in tissues and plasma for Se derived from SeMet to account for its 3-times-higher incorporation into RBC compared with Se from Sel; these presumably represent nonspecific incorporation of SeMet into proteins. Pool sizes and transport rates were determined and compared by form and gender. The final model consisted of 11 plasma pools, 2 pools and a delay in RBC, and extravascular pools for recycling of Se back into plasma. This model will be used to evaluate changes in Se metabolism following long-term (2 y) Se supplementation.

Background: Selenium, a potential cancer prevention agent currently being tested against prostate cancer in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), plays an integral role in thyroid metabolism. The effects of long-term selenium supplementation on thyroid hormone concentrations are unknown., Objective: The objective was to investigate the effects of long-term selenium supplementation on thyroid hormone concentrations., Design: Twenty-eight healthy adults took 200 microg selenomethionine/d for 28 mo. The thyroid hormones triiodothyronine (T3), thyroxine (T4), and thyrotropin (TSH) were measured in plasma for 4 mo before supplementation and quarterly during supplementation. The assay methods were changed midstudy; the results of the 2 methods were not comparable. Therefore, one analysis was conducted based on the results of the first method, and a second analysis was based on all of the data, adjusted for the change. Serial data collection permitted a test for trends rather than simply a difference between initial and final values., Results: By 9 mo, mean (+/-SEM) plasma selenium concentrations had increased from 1.78 +/- 0.07 micromol/L at baseline to 2.85 +/- 0.11 micromol/L for men and from 1.64 +/- 0.04 to 3.32 +/- 0.1.2 micromol/L for women. T3 concentrations in men increased 5% per year (P = 0.01). T4 and TSH concentrations were unchanged., Conclusions: Selenium supplementation produced no clinically significant changes in thyroid hormone concentrations. A small but statistically significant increase in T3 concentrations was noted in men, with no corresponding decreases in TSH. A subset of SELECT subjects might be monitored periodically for changes during long-term selenium supplementation.

Purpose of Review: To discuss recent research related to anticarcinogenic mechanisms of selenium action in light of the underlying chemical/biochemical functions of the selenium species, likely to be executors of those effects., Recent Findings: Recent studies in a variety of model systems have increased the understanding of the anticarcinogenic mechanisms of selenium compounds. These include effects on gene expression, DNA damage and repair, signaling pathways, regulation of cell cycle and apoptosis, metastasis and angiogenesis. These effects would appear to be related to the production of reactive oxygen species produced by the redox cycling, modification of protein-thiols and methionine mimicry. Three principle selenium metabolites appear to execute these effects: hydrogen selenide, methylselenol and selenomethionine. The fact that various selenium compounds can be metabolized to one or more of these species but differ in anticarcinogenic activity indicates competing pathways of their metabolic and chemical/biochemical disposition. Increasing knowledge of selenoprotein polymorphisms has shown that at least some are related to cancer risk and may affect carcinogenesis indirectly by influencing selenium metabolism., Summary: The anticarcinogenic effects of selenium compounds constitute intermediate mechanisms with several underlying chemical/biochemical mechanisms such as redox cycling, alteration of protein-thiol redox status and methionine mimicry.

Methylselenol has been implicated as an active anticancer selenium (Se) metabolite. However, its in vivo efficacy against prostate cancer (PCa) has yet to be established. Here, we evaluated the growth inhibitory effects of two presumed methylselenol precursors methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in comparison with selenomethionine (SeMet) and selenite in DU145 and PC-3 human PCa xenografts in athymic nude mice. Each Se was given by a daily single oral dose regimen starting the day after the subcutaneous inoculation of cancer cells. We analyzed serum, liver and tumor Se content to confirm supplementation status and apoptosis indices and tumor microvessel density for association with antitumor efficacy. Furthermore, we analyzed lymphocyte DNA integrity to detect genotoxic effect of Se treatments. The data show that MSeA and MSeC exerted a dose-dependent inhibition of DU145 xenograft growth and both were more potent than SeMet and selenite, in spite of less tumor Se retention than in the SeMet-treated mice. Selenite treatment increased DNA single-strand breaks in peripheral lymphocytes, whereas the other Se forms did not. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) and cleaved caspase-3 indices (apoptosis) from MSeC-treated tumors were higher than tumors from control mice or MSeA-treated mice, whereas the microvessel density index was lower in tumors from MSeA-treated mice. In the PC-3 xenograft model, only MSeA was growth inhibitory at a dose of 3 mg/kg body wt. In summary, our data demonstrated superior in vivo growth inhibitory efficacy of MSeA over SeMet and selenite, against two human PCa xenograft models without the genotoxic property of selenite.

To determine whether increased Ca intakes can prevent rickets in a susceptible group of children living in a rickets-endemic area of Bangladesh, we conducted a 13-month long, double-blind, clinical trial with 1-to 5-year-old children who did not present with rickets but ranked in the upper decile of plasma alkaline phosphatase (AP) activity of a screening cohort of 1,749 children. A total of 158 children were randomized to a milk-powder-based dietary supplement given daily, 6 days/week, and providing either 50, 250, or 500 mg Ca, or 500 mg Ca plus multivitamins, iron, and zinc. Upon initial screening, 194 healthy children presented with no rachitic leg signs and had serum AP in the upper decile (>260 u/dl) of the cohort. When 183 of those subjects were re-screened after a 7-month pre-trial period, 23 (12.6%) had developed rachitic leg signs, suggesting an annual risk of 21.5% in this cohort. Of those still not presenting with leg signs and completing 13 months of dietary intervention, none showed rachitic leg signs, none showed significant radiological evidence of active rickets, and all showed carpal ossification normal for age after that intervention. These results are consistent with even the lowest amount of supplemental Ca (50 mg/day) being useful in supporting normal bone development in this high-risk population.

Purpose: Our previous work has shown that methylseleninic acid (MSeA) sensitized hormone refractory prostate cancer (HRPCa) cells to apoptosis induced by paclitaxel (Taxol) through enhancing multiple caspases. This study aimed to (a) determine the general applicability of the sensitization effect for taxane drugs in vitro, (b) establish the enhancement of paclitaxel efficacy by MSeA in vivo, and (c) investigate Bcl-XL and survivin as molecular targets of MSeA to augment apoptosis., Experimental Design: DU145 and PC-3 HRPCa cell lines were used to evaluate the in vitro apoptosis effects of paclitaxel, docetaxel and their combination with MSeA, and the molecular mechanisms. DU145 xenograft growth in athymic nude mice was used to evaluate the in vivo efficacy of paclitaxel and its combination with MSeA. The tumor samples were used to examine Bcl-XL and survivin protein abundance., Results: MSeA combination with paclitaxel or docetaxel exerted a greater than additive apoptosis effect on DU145 and PC-3 cells. In nude mice, paclitaxel and MSeA combination inhibited growth of DU145 subcutaneous xenograft with the equivalent efficacy of a four-time higher dose of paclitaxel alone. MSeA decreased the basal and paclitaxel-induced expression of Bcl-XL and survivin in vitro and in vivo. Ectopic expression of Bcl-XL or survivin attenuated MSeA/paclitaxel-induced apoptosis., Conclusions: MSeA enhanced the efficacy of paclitaxel against HRPCa in vitro and in vivo, at least in part, by down-regulating the basal and paclitaxel-induced expression of both Bcl-XL and survivin to increase caspase-mediated apoptosis. MSeA may be a novel agent to improve taxane combination therapy.

Nonexperimental studies suggest that individuals with higher selenium (Se) status are at decreased risk of cancer. The Nutritional Prevention of Cancer (NPC) study randomized 1,312 high-risk dermatology patients to 200-mcg/day of Se in selenized yeast or a matched placebo; selenium supplementation decreased the risk of lung, colon, prostate, and total cancers but increased the risk of nonmelanoma skin cancer. In this article, we report on a small substudy in Macon, GA, which began in 1989 and randomized 424 patients to 400-mcg/day of Se or to matched placebo. The subjects from both arms had similar baseline Se levels to those treated by 200 mcg, and those treated with 400-mcg attained plasma Se levels much higher than subjects treated with 200 mcg. The 200-mcg/day Se treatment decreased total cancer incidence by a statistically significant 25%; however, 400-mcg/day of Se had no effect on total cancer incidence.

Selenium is an essential dietary component for animals including humans, and there is increasing evidence for the efficacy of certain forms of selenium as cancer-chemopreventive compounds. In addition, selenium appears to have a protective effect at various stages of carcinogenesis including both the early and later stages of cancer progression. Mechanisms for selenium-anticancer action are not fully understood; however, several have been proposed: antioxidant protection, enhanced carcinogen detoxification, enhanced immune surveillance, modulation of cell proliferation (cell cycle and apoptosis), inhibition of tumor cell invasion and inhibition of angiogenesis. Research has shown that the effectiveness of selenium compounds as chemopreventive agents in vivo correlates with their abilities to affect the regulation of the cell cycle, to stimulate apoptosis and to inhibit tumor cell migration and invasion in vitro. This article reviews the status of knowledge concerning selenium metabolism and its anticancer effects with particular reference to the modulation of cell proliferation and the inhibition of tumor cell invasion.

To move closer to the goal of individualized risk prediction for prostate cancer, we used an in vivo canine model to evaluate whether the susceptibility of peripheral blood lymphocytes (PBLs) to oxidative stress-induced DNA damage could identify those individuals with the highest prostatic DNA damage. This hypothesis was tested in a population of 69 elderly male beagle dogs after they had completed a 7-month randomized feeding trial to achieve the broad range of dietary selenium status observed in U.S. men. The alkaline Comet assay was used to directly compare the extent of DNA damage in PBLs with prostatic DNA damage in each dog. Using stepwise logistic regression, the sensitivity of PBLs to oxidative stress challenge with hydrogen peroxide (H(2)O(2)) predicted dogs in the highest tertile of prostatic DNA damage. Dogs with PBLs highly sensitive to H(2)O(2) were 7.6 times [95% confidence interval (95% CI), 1.5-38.3] more likely to have high prostatic DNA damage than those in the H(2)O(2)-resistant group. This risk stratification was observed in multivariate analysis that considered other factors that might influence DNA damage, such as age, toenail selenium concentration, and serum testosterone concentration. Our data show that the sensitivity of PBLs to oxidative stress challenge, but not endogenous DNA damage in PBLs, provides a noninvasive surrogate marker for prostatic DNA damage. These findings lend support to the concept that oxidative stress contributes to genotoxic damage, and that oxidative stress challenge may stratify men for prostate cancer risk.

This study was designed to understand the basis for the efficacy of methylselenocysteine (MSC) in increasing the therapeutic index of irinotecan against human tumor xenografts. Nude mice bearing human head and neck squamous cells carcinoma xenografts (FaDu and A253) were treated orally with different doses of MSC and irinotecan. Plasma, tumor and normal tissue samples were collected at different times after MSC treatments and were analyzed for selenium (Se) concentration using electrothermal atomic absorption spectrophotometry. MSC is highly effective in modulating the therapeutic index of irinotecan. Enhanced irinotecan efficacy was greater in FaDu tumors (100% CR) than in A253 tumors (60% CR), and depended on MSC dose with a minimum effective dose of 0.01 mg/dx28. The highest plasma Se concentration was achieved 1h after a single dose and 28 d after daily treatments of MSC. The ability of FaDu tumors to retain Se was significantly better than A253 tumors, and the highest Se concentration in normal tissue was achieved in the liver. Peak plasma and tissue Se concentrations were functions of the dose and duration of MSC treatment. The MSC-dependent increase in Se level in normal tissues may contribute to the protective effect against irinotecan toxicity observed in those tissues. Intratumoral total Se concentration was not found to be predictive of the combination therapy response rates. There is a critical need to develop a method to measure the active metabolite of MSC, rather than total Se.

Daily supplementation with the essential trace mineral selenium significantly reduced prostate cancer risk in men in the Nutritional Prevention of Cancer Trial. However, the optimal intake of selenium for prostate cancer prevention is unknown. We hypothesized that selenium significantly regulates the extent of genotoxic damage within the aging prostate and that the relationship between dietary selenium intake and DNA damage is non-linear, i.e. more selenium is not necessarily better. To test this hypothesis, we conducted a randomized feeding trial in which 49 elderly beagle dogs (physiologically equivalent to 62-69-year-old men) received nutritionally adequate or supranutritional levels of selenium for 7 months, in order to mimic the range of dietary selenium intake of men in the United States. Our results demonstrate an intriguing U-shaped dose-response relationship between selenium status (toenail selenium concentration) and the extent of DNA damage (alkaline Comet assay) within the prostate. Further, we demonstrate that the concentration of selenium that minimizes DNA damage in the aging dog prostate remarkably parallels the selenium concentration in men that minimizes prostate cancer risk. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a new approach to bridge the gap between laboratory and human studies that can be used to select the appropriate dose of anticancer agents for large-scale human cancer prevention trials. From the U-shaped dose-response, it follows that not all men will necessarily benefit from increasing their selenium intake and that measurement of baseline nutrient status should be required for all individuals in prevention trials to avoid oversupplementation.