Summary
Selenium is a trace mineral and an essential nutrient in the human diet. Selenium is found in soil and water and consequently enters the food chain through the root ways of plants and aquatic organisms. Some areas of the world are low in soil selenium resulting in a selenium deficient population and the appearance of an associated heart disease and bone disorders that can be corrected with dietary selenium. Indeed the requirement for dietary selenium was established by these observations and while selenium deficiency is rare in the West, patients requiring long-term intravenous feedings have also show heart disease associated with a deficiency of selenium in the feeding fluids. Subsequently, it has been established that dietary selenium can improve a wide range of human health conditions even in areas with soil replete in selenium.
Keywords: selenium, Se, selenoproteins, dietary, antioxidant
Background
Dietary selenium (Se) functions and mediates health benefits through incorporation into cysteine (MeCyst) prior to protein synthesis forming the 21st amino acid used during protein synthesis (ref). Proteins into which MeCyst is incorporated are known as “selenoproteins” and require dietary selenium to be fully functional. Selenoproteins fulfill vital functions in the body. For example, selenoproteins are: a) essential antioxidant enzymes that fight cancer and other chemical toxicities, b) regulators of thyroid hormone and thyroid function, c) structural proteins in sperm required for fertility, and d) can reduce the virulence associated with certain viral infections including HIV-1. Because the value of Se can only be understood through the activity of selenoproteins, this review takes the unique and challenging approach of presenting the nutritional benefits of selenium by listing and linking selenoprotein function to evidence of health benefits. Table 1 shows a list of the known human selenoproteins and their known roles in human health.
Table 1.
Selenoprotein | Suggested Health Benefit by Study Design | Reference |
---|---|---|
GPx1 | Antioxidant | |
Cell Culture Studies | ||
Protects human cells from UV-induced DNA damage | 19 | |
Animal Studies | ||
Protects mice from colon cancer | 20 | |
Protects rodents from chemical toxicity | 24,25 | |
Protects mice from viral associated cardiomyopathy | 26 | |
Human Clinical Trials | ||
Protects stressed neurons in Parkinson’s Disease | 23 | |
GPx2 | Antioxidant | |
Cell Culture Studies | ||
Reduces metastatic properties of human cancer cells | 5 | |
Animal Studies | ||
Protects mice from intestinal cancer | 4 | |
GPx3 | Antioxidant | |
Human Clinical Trials | ||
Protects people from cerebral clots and stroke | 39–42 | |
Protects people from atherosclerosis and cardiovascular disease | 43–45 | |
GPx4 | Antioxidant | |
Animal Studies | ||
Protects mice from Parkinson’s-like neurodegeneration | 29–31 | |
Supports normal brain development in mice | 32–34 | |
Prevents developmental neurological defects in mice | 48,49 | |
Human Clinical Trials | ||
Vital for sperm production, motility and fertility in men | 46,47 | |
TR1 | Antioxidant | |
Cell Culture Studies | ||
Inhibits HIV replication in human macrophages | 60 | |
Animal Studies | ||
Required for live birth in mice | 50 | |
TR2 | Antioxidant | |
Animal Studies | ||
Required for live birth in mice | 50 | |
D2 | Thyroid Function | |
Animal Studies | ||
Maintains healthy metabolic rate in mice | 54, 55 | |
Sel N | Antioxidant | |
Animal Studies | ||
Supports normal muscle development in mice | 51 | |
Sel P | Antioxidant | |
Animal Studies | ||
Prevents neurodegeneration | 35 | |
Prevents infertility in mice | 58 | |
Human Clinical Trials | ||
Prevents cancers in humans | 6, 7 | |
Protects humans from Alzheimer’s Disease | 38 | |
Sel T | Unknown | |
Cell Culture Studies | ||
Supports neurite/nerve formation in rodent neuronal cells | 52 | |
SPS2 | Synthesis of all other selenoproteins | |
Human Clinical Trials | ||
Maintains healthy metabolic rate in humans | 33 |
It is important to note that understanding selenoprotein functions overlaps with nutritional studies, but does not nearly account for all of the dietary clinical studies that show general health improvements with increased oral selenium intake. Therefore this review will also present most of the recent clinical studies in which selenium was shown to benefit human health. In specific, increased dietary intake of selenium has also been shown to: a) reduce cancer incidence, b) reduce cancer-associated mortality, c) reduce oxidative damage and poisoning associated with chemo- and radiotherapy, d) reduce severity of autoimmune diseases, e) improve mental health, f) improve reproductive performance, g) improve elderly thymus and thyroid function and h) provide various additional health benefits including a slowed progression from HIV-1 infection to AIDS (Table 1).
Selenoprotein Functions
Antioxidant enzymes: Prevention of cancer, toxicities, neurodegeneration, atherosclerosis and stroke
Antioxidant enzymes are required for elimination toxins known as reactive oxygen species (ROS). ROS toxins form naturally in our cells simply from oxygen metabolism and can also form as a result of exposure to chemical pollutants and drugs. These ROS toxins cause damage to DNA, cell membranes, and a variety of other cell structures and leads to “oxidative stress”. We take antioxidants to mitigate the effects of oxidative stress. If we do not have enough antioxidant capacity, oxidative stress can lead to cell death, organ system failure, cancer, inflammatory disease, cardiovascular disease, poor wound healing, hearing impairment and stroke. Selenoproteins constitute one of the most important classes of antioxidant enzymes the glutathione peroxidases (GPx). In the human body there are eight forms of GPxs (GPx1–GPx8) and of these, five (GPx1–GPx4, and GPx6) are selenoproteins [1]. In addition to these well studies antioxidant enzyme systems, at least seven additional selenoproteins (TR1, TR2, TR3, Sel P, Sel R and Sel W) have been suggested to play a role in humans in protecting against oxidative stress and the elimination of ROS toxins.
For example, UV light and the gentotoxic carcinogen azoxymethane are both know to elevate cellular ROS toxins and cause cancer. In studies using in vitro cultures of human breast cancer cells, both the addition of selenium to the culture medium and enhanced expression of GPx1 protected these cells from UV induced DNA damage [2]. Further, mice engineered to lack GPx1 (GPx1 knockouts) were more susceptible to colon abnormalities when treated with the colonic carcinogen, azoxymethane, [3]. GPx2 is primarily express in the gut epithelium and mice engineered to lack GPx2 (GPx2 knockouts) have an increase incidence of intestinal cancer [4]. Further, in vitro cultures of human cancer cells in which production of GPx2 was blocked demonstrated an increase in invasive and migratory properties associated with metastatic potential [5]. In human studies, increased risks for prostate cancer and lung cancer (non-small cell lung carcinoma) have been associated with low Sel P production [6,7]. These studies support the observation that selenium deficient diets may put people at risk for developing cancer and that increasing selenium intake may boost the antioxidant capabilities of selenoproteins in cancer therapy and prevention.
In addition to being more susceptible to DNA damage and cancer, GPX1 knockout mice demonstrate increase rates of sickness and death when exposed to ROS-inducing chemicals such as paraquat [8,9] and also to coxsackievirus-associated cardiac disease [10].
Further, GPx1 may protect the central nervous system from ROS induced neurodegeneration. Microglia and astrocytes protect neurons in the brain from oxidative stress (ROS-induced damage). Studies in rodents have shown that microglia and astrocytes express high levels of GPx1 in rodents [11,12] and humans with Parkinson’s and dementia show microglia with elevated GPx1 activity associated with distressed neurons [13]. GPx4 depletion in the hippocampus of mice has been shown to cause oxidative-damage in brain neurons leading to cell death like that seen in Parkinson’s Disease and b-amyloid production like that seen in Alzheimer’s Disease [14–16]. In addition to preventing neurodegenerative diseases in adults, GPx4 antioxidant activity also supports normal brain development in mice [17–19]. Knockout of the selenoprotein, Sel P, in mice also leads to neurodegeneration [20]. Moreover, elevated Sel P is found in post-mortem analysis of b-amyloid plaques of Alzheimers Disease patients [21] further suggesting a role for oxidative stress in neurodegenerative diseases and the potential for selenium and selenoproteins to prevent their onset.
Selenoproteins are also important for cardiovascular health. Human clinical studies also show that people with low Gpx3 activity have reduced capacity to metabolize ROS toxins and consequently present with increase risk for both arterial and cerebral clots and stroke [22–25]. Further, in a mouse model of atherosclerosis, over-expression of GPx4 leads to reduced lipid peroxidation and associated atherosclerotic plaque [26]. People with specific genetic variants of the selenoprotein, Sel S have also been shown to be at a higher risk for cardiovascular disease and stroke although this increased risk has not been associated with ROS metabolism [27,28].
Thyroid Function
In addition to serving as antioxidant enzymes, selenoproteins are essential to thyroid gland function. The thyroid gland produces thyroid hormone which in turn regulates a variety of metabolic events in humans. Thyroid hormone formation requires selenoproteins and selenoproteins can also regulate thyroid hormone activity by inactivating it. These selenoproteins are the deiodinases enzymes, D1, D2 and D3. The conversion of the thyroid hormone precursor, T4, to the active T3 hormone is mediated by D1 or D2 while both D1 and D3 can inactivate T3 [29]. Mice genetically lacking the D2 selenoprotein exhibit reduced thyroid stimulating hormone regulation and reduced capacity to metabolize fat to keep warm (brown fat thermogenesis) [30,31]. Interestingly the thyroid expresses as many as 11 different selenoproteins to protect this gland from the oxidative stress high levels of ROS hydrogen peroxide which is a byproduct of thyroid hormone synthesis [32]. Indeed, people with mutations in the a gene that encodes for a selenoprotein synthesis factor suffer with thyroid function defects [33].
Fertility
While the two clear categories of selenoprotein activity are antioxidant protection from ROS metabolites and thyroid hormone function, selenoproteins play several diverse important structural and functional roles in cell physiology that are important to human health. GPx4 is an important structural protein of sperm and low sperm GPx activity is associated with reduced viability and motility in men [34,35]. Mice lacking the seloprotein Sel P gene exhibit male infertility [36]. Further, developing mouse embryos that lack GPx4 die in mid gestation from developmental neurological defects [37,38]. Genetic deletion of TR1 and TR2 leads to embryonic lethality in mice [39] and and depletion of the selenoprotein, Sel N leads to muscle malformation in zebrafish embryos [40]. Sel T expression is increased during neurite formation in neuronal cell cultures [41] suggesting a role for this selenoprotein in neuronal development.
Viral Infections
In both mice and humans, reduced activity of GPx as a consequence of selenium deficiency leads to a more virulent coxakie viral infection and heart disease (Keshan Disease) [42–44]. Further, the level of the selenoprotein TR1 is found to be reduced in HIV-1 infected individuals [45]. Further, TR1 inhibits HIV-1 protein Tat which is responsible for transcriptional activity of the virus [46] and selenium deficiency has been associated with a more rapid progression from HIV infection to AIDS [47–49]. In HIV-1 infected patients on anti-retroviral therapy (ART), daily intake of 200 μg selenium increased circulating CD4+ T-cell levels by two to three fold compared to those on ART alone (50).
Clinical Studies with Dietary Selenium
Cancer
In 1996, in randomized clinical studies, the Nutritional Prevention Cancer Study Group reported in the Journal of the American Medical Association that selenium supplementation at 200 micrograms per day reduces the incidence and morbidity from basal and squamous cell carcinomas [51]. Subsequent randomized double blind studies confirmed these observations in 1997 [52] and were extended in placebo controlled studies to include prostate cancer in 1998 [53]. In 2002, randomized clinical trial known at the “Nutritional Prevention of Cancer Trial” was initiated as a multi-institutional investigation and showed that dietary selenium at 200 micrograms per day can reduce the risk of several site specific cancers [54]. By 2003 the Nutritional Prevention of Cancer Trial (NPCT) concluded that selenium supplementation can reduce the incidence of lung cancer in people with selenium deficiency and in blind, placebo controlled trials decreases prostate cancer incidence in selenium-replete patients with low prostate serum markers (PSA) [55]. Further analysis of the NPCT data revealed a reduced risk for colon cancer in patients with low blood selenium levels and also a beneficial effect particularly for smokers [56]. In 2009, a double blind, placebo controlled, prospective study demonstrated that women carrying BRCA1 gene mutations and a predisposition for breast cancer show a reduced risk when taking daily selenium supplements [57]. Most recently, a six month double blind placebo controlled study demonstrated that when taken in combination with silymarin, a milk thistle flavonolignan, selenium reduces the stage progression of prostate cancers [58].
In addition to directly reducing cancer incidences, cancer progression and mortality, dietary selenium has also been shown to alleviate some of the oxidative toxicities associated with cervical, ovarian, head and neck cancer chemo- and radiotherapies [59–62] and also improves the overall nutritional balance in these patients [63].
Immune system
Intake of high levels of selenium protects patients from inflammatory damage associated with sepsis and from rheumatoid arthritis [64,65]. Further, clinical trials show that increased dietary selenium can reduce autoantibody production in autoimmune thyroiditis, Grave’s disease and Psoriasis [66–68].
Reproductive health
Intravenous selenium administration improves the outcomes for preterm infants born in selenium-deficient areas [69,70]. Placebo controlled clinical trials also increase the fertility of men living in low selenium areas leading to successful conception [71]. Dietary selenium also reduces pre-labor membrane rupture and preeclampsia [72,73].
Mental health
Several clinical studies have shown that dietary selenium can improve mood by reducing anxiety and depression [74,75] including post-partum depression [76].
Conclusions
It is clear that selenium is a required dietary nutrient. Selenium is unique in its structural incorporation into proteins (selenoproteins) which in functioning as antioxidants, regulators of thyroid function, and structural proteins, serve to prevent cancer, improve cardiovascular health, prevent stroke and atherosclerosis, prevent neurodegeneration, promote healthy embryonic nervous system and muscle development, improve fertility and the immune response and fight viral infections including HIV-1 (Table 1). Dietary selenium can enhance selenoprotein activity and reduce the risk of various cancers, thyroid disorders, drug toxicities and autoimmune diseases and improve mental health, reproductive outcomes and possibly fight AIDS (Table 1).
Footnotes
Source of support: Departmental sources
References
- 1.Kryukov GV, Castellano S, Novoselov SV, et al. Characterization of mammalian selenoproteomes. Science. 2003;300(5624):1439–43. doi: 10.1126/science.1083516. [DOI] [PubMed] [Google Scholar]
- 2.Baliga MS, Wang H, Zhuo P, et al. Selenium and GPx-1 overexpression protect mammalian cells against UV-induced DNA damage. Biol Trace Elem Res. 2007;115(3):227–42. doi: 10.1007/BF02685998. [DOI] [PubMed] [Google Scholar]
- 3.Carlson BA, Xu XM, Gladyshev VN, Hatfield DL. Selective rescue of selenoprotein expression in mice lacking a highly specialized methyl group in selenocysteine tRNA. J Biol Chem. 2005;280(7):5542–48. doi: 10.1074/jbc.M411725200. [DOI] [PubMed] [Google Scholar]
- 4.Chu FF, Esworthy RS, Chu PG, et al. Bacteria-induced intestinal cancer in mice with disrupted Gpx1 and Gpx2 genes. Cancer Res. 2004;64(3):962–68. doi: 10.1158/0008-5472.can-03-2272. [DOI] [PubMed] [Google Scholar]
- 5.Banning A, Kipp A, Schmitmeier S, et al. Glutathione Peroxidase 2 Inhibits Cyclooxygenase-2-Mediated Migration and Invasion of HT-29 Adenocarcinoma Cells but Supports Their Growth as Tumors in Nude Mice. Cancer Res. 2008;68(23):9746–53. doi: 10.1158/0008-5472.CAN-08-1321. [DOI] [PubMed] [Google Scholar]
- 6.Cooper ML, Adami HO, Gronberg H, et al. Interaction between single nucleotide polymorphisms in selenoprotein P and mitochondrial superoxide dismutase determines prostate cancer risk. Cancer Res. 2008;68:10171–77. doi: 10.1158/0008-5472.CAN-08-1827. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Gresner P, Gromadzinska J, Jablonska E, et al. Expression of selenoprotein-coding genes SEPP1, SEP15 and hGPX1 in non-small cell lung cancer. Lung Cancer. 2009;65(1):34–40. doi: 10.1016/j.lungcan.2008.10.023. [DOI] [PubMed] [Google Scholar]
- 8.Cheng WH, Ho YS, Valentine BA, et al. Cellular glutathione peroxidase is the mediator of body selenium to protect against paraquat lethality in transgenic mice. J Nutr. 1998;128:1070–76. doi: 10.1093/jn/128.7.1070. [DOI] [PubMed] [Google Scholar]
- 9.de Haan JB, Bladier C, Griffiths P, et al. Mice with a homozygous null mutation for the most abundant glutathione peroxidase, GPx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide. J Biol Chem. 1998;273:22528–36. doi: 10.1074/jbc.273.35.22528. [DOI] [PubMed] [Google Scholar]
- 10.Beck MA, Esworthy RS, Ho YS, Chu FF. Glutathione peroxidase protects mice from viral-induced myocarditis. FASEB J. 1998;12:1143–49. doi: 10.1096/fasebj.12.12.1143. [DOI] [PubMed] [Google Scholar]
- 11.Trépanier G, Furling D, Puymirat J, Mirault ME. Immunocytochemical localization of seleno-glutathione peroxidase in the adult mouse brain. Neuroscience. 1996;75(1):231–43. doi: 10.1016/0306-4522(96)00222-9. [DOI] [PubMed] [Google Scholar]
- 12.Lindenau J, Noack H, Asayama K, Wolf G. Enhanced cellular glutathione peroxidase immunoreactivity in activated astrocytes and in microglia during excitotoxin induced neurodegeneration. Glia. 1998;24(2):252–56. [PubMed] [Google Scholar]
- 13.Power JH, Blumbergs PC. Cellular glutathione peroxidase in human brain: cellular distribution, and its potential role in the degradation of Lewy bodies in Parkinson’s disease and dementia with Lewy bodies. Acta Neuropathol. 2009;117(1):63–73. doi: 10.1007/s00401-008-0438-3. [DOI] [PubMed] [Google Scholar]
- 14.Blackinton J, Kumaran R, van der Brug MP, et al. Post-transcriptional regulation of mRNA associated with DJ-1 in sporadic Parkinson disease. Neurosci Lett. 2009;452(1):8–11. doi: 10.1016/j.neulet.2008.12.053. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Seiler A, Schneider M, Forster H, et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 2008;8:237–48. doi: 10.1016/j.cmet.2008.07.005. [DOI] [PubMed] [Google Scholar]
- 16.Chen L, Na R, Gu M, et al. Lipid peroxidation up-regulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer’s disease. J. Neurochem. 2008;107:197–207. doi: 10.1111/j.1471-4159.2008.05603.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Yant LJ, Ran Q, Rao L, et al. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med. 2003;34:496–502. doi: 10.1016/s0891-5849(02)01360-6. [DOI] [PubMed] [Google Scholar]
- 18.Imai H, Hirao F, Sakamoto T, et al. Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene. Biochem Biophys Res Commun. 2003;305:278–86. doi: 10.1016/s0006-291x(03)00734-4. [DOI] [PubMed] [Google Scholar]
- 19.Ufer C, Wang CC, Fahling M, et al. Translational regulation of glutathione peroxidase 4 expression through guanine-rich sequence-binding factor 1 is essential for embryonic brain development. Genes Dev. 2008;22:1838–50. doi: 10.1101/gad.466308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Valentine WM, Abel TW, Hill KE, et al. Neurodegeneration in mice resulting from loss of functional selenoprotein P or its receptor apolipoprotein E receptor 2. J Neuropathol Exp Neurol. 2008;67:68–77. doi: 10.1097/NEN.0b013e318160f347. [DOI] [PubMed] [Google Scholar]
- 21.Bellinger FP, He QP, Bellinger MT, et al. Association of selenoprotein p with Alzheimer’s pathology in human cortex. J Alzheimers Dis. 2008;15:465–72. doi: 10.3233/jad-2008-15313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Freedman JE, Loscalzo J, Benoit SE, et al. Decreased platelet inhibition by nitric oxide in two brothers with a history of arterial thrombosis. J Clin Invest. 1996;97:979–87. doi: 10.1172/JCI118522. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kenet G, Freedman J, Shenkman B, et al. Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke. Arterioscler Thromb Vasc Biol. 1999;19:2017–23. doi: 10.1161/01.atv.19.8.2017. [DOI] [PubMed] [Google Scholar]
- 24.Voetsch B, Jin RC, Bierl C, et al. Promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene: a novel risk factor for arterial ischemic stroke among young adults and children. Stroke. 2007;38:41–49. doi: 10.1161/01.STR.0000252027.53766.2b. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Voetsch B, Jin RC, Bierl C, et al. Role of promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene as a risk factor for cerebral venous thrombosis. Stroke. 2008;39:303–7. doi: 10.1161/STROKEAHA.107.490094. [DOI] [PubMed] [Google Scholar]
- 26.Guo Z, Ran Q, Roberts LJ, II, et al. Suppression of atherogenesis by overexpression of glutathione peroxidase-4 in apolipoprotein E-deficient mice. Free Radic Biol Med. 2008;44:343–52. doi: 10.1016/j.freeradbiomed.2007.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Alanne M, Kristiansson K, Auro K, et al. Variation in the selenoprotein S gene locus is associated with coronary heart disease and ischemic stroke in two independent Finnish cohorts. Hum Genet. 2007;122:355–65. doi: 10.1007/s00439-007-0402-7. [DOI] [PubMed] [Google Scholar]
- 28.Silander K, Alanne M, Kristiansson K, et al. Gender differences in genetic risk profiles for cardiovascular disease. PLoS ONE. 2008;3:e3615. doi: 10.1371/journal.pone.0003615. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Bianco AC, Salvatore D, Gereben B, et al. Biochemistry, cellular and molecularbiology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev. 2002;23:38–89. doi: 10.1210/edrv.23.1.0455. [DOI] [PubMed] [Google Scholar]
- 30.Schneider MJ, Fiering SN, Pallud SE, et al. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Mol Endocrinol. 2001;15:2137–48. doi: 10.1210/mend.15.12.0740. [DOI] [PubMed] [Google Scholar]
- 31.de Jesus LA, Carvalho SD, Ribeiro MO, et al. The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest. 2001;108:1379–85. doi: 10.1172/JCI13803. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Schmutzler C, Mentrup B, Schomburg L, et al. Selenoproteins of the thyroid gland: expression, localization and possible function of glutathione peroxidase 3. Biol Chem. 2007;388:1053–59. doi: 10.1515/BC.2007.122. [DOI] [PubMed] [Google Scholar]
- 33.Dumitrescu AM, Liao XH, Abdullah MS, et al. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet. 2005;37:1247–52. doi: 10.1038/ng1654. [DOI] [PubMed] [Google Scholar]
- 34.Ursini F, Heim S, Kiess M, et al. Dual function of the selenoprotein PHGPx during sperm maturation. Science. 1999;285:1393–96. doi: 10.1126/science.285.5432.1393. [DOI] [PubMed] [Google Scholar]
- 35.Foresta C, Flohe L, Garolla A, et al. Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase. Biol Reprod. 2002;67:967–71. doi: 10.1095/biolreprod.102.003822. [DOI] [PubMed] [Google Scholar]
- 36.Schomburg L, Schweizer U, Holtmann B, et al. Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochem J. 2003;370:397–402. doi: 10.1042/BJ20021853. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Imai H, Hirao F, Sakamoto T, et al. Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene. Biochem Biophys Res Commun. 2003;305:278–86. doi: 10.1016/s0006-291x(03)00734-4. [DOI] [PubMed] [Google Scholar]
- 38.Ufer C, Wang CC, Fahling M, et al. Translational regulation of glutathione peroxidase 4 expression through guanine-rich sequence-binding factor 1 is essential for embryonic brain development. Genes Dev. 2008;22:1838–50. doi: 10.1101/gad.466308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Conrad M, Jakupoglu C, Moreno SG, et al. Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol Cell Biol. 2004;24:9414–23. doi: 10.1128/MCB.24.21.9414-9423.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Jurynec MJ, Xia R, Mackrill JJ, et al. Selenoprotein N is required for ryanodine receptor calcium release channel activity in human and zebrafish muscle. Proc Natl Acad Sci USA. 2008;105:12485–90. doi: 10.1073/pnas.0806015105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Grumolato L, Ghzili H, Montero-Hadjadje M, et al. Selenoprotein T is a PACAP-regulated gene involved in intracellular Ca2+ mobilization and neuroendocrine secretion. FASEB J. 2008;22:1756–68. doi: 10.1096/fj.06-075820. [DOI] [PubMed] [Google Scholar]
- 42.Beck MA, Shi Q, Morris VC, Levander OA. Rapid genomic evolution of a non-virulent Coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates. Nature Medicine. 1995;1:433–36. doi: 10.1038/nm0595-433. [DOI] [PubMed] [Google Scholar]
- 43.Beck MA, Esworthy RS, Ho Y-S, Chu F-F. Glutathione peroxidase protects mice from viral-induced myocarditis. FASEB J. 1998;12:1143–49. doi: 10.1096/fasebj.12.12.1143. [DOI] [PubMed] [Google Scholar]
- 44.Beck MA, Handy J, Levander OA. Host nutritional status: the neglected virulence factor. Trends Microbiol. 2004;12:417–23. doi: 10.1016/j.tim.2004.07.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Gladyshev VN, Stadtman TC, Hatfield DL, Jeang KT. Levels of major selenoproteins in T cells decrease during HIV infection and low molecular mass selenium compounds increase. Proc Natl Acad Sci USA. 1999;96:835–39. doi: 10.1073/pnas.96.3.835. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Kalantari P, Narayan V, Natarajan SK, et al. Thioredoxin reductase-1 negatively regulates HIV-1 transactivating protein Tat-dependent transcription in human macrophages. J Biol Chem. 2008;283:33183–90. doi: 10.1074/jbc.M807403200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Baum MK, Shor-Posner G, Lai S, et al. High risk of HIV-related mortality is associated with selenium deficiency. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;15(5):370–74. doi: 10.1097/00042560-199708150-00007. [DOI] [PubMed] [Google Scholar]
- 48.Campa A, Shor-Posner G, Indacochea F, et al. Mortality risk in selenium-deficient HIV-positive children. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20:508–13. doi: 10.1097/00042560-199904150-00015. [DOI] [PubMed] [Google Scholar]
- 49.Burbano X, Miguez-Burbano MJ, McCollister K, et al. Impact of a selenium chemoprevention clinical trial on hospital admissions of HIV-infected participants. HIV Clin Trials. 2002;3:483–91. doi: 10.1310/A7LC-7C9V-EWKF-2Y0H. [DOI] [PubMed] [Google Scholar]
- 50.Odonukwe NN. The role of Se as adjunct to HAART among HIV-infected individuals who are advanced in their disease. Sixteenth International AIDS Conference; 2006; Toronto, Canada. MoAb0403. [Google Scholar]
- 51.Clark LC, Combs GF, Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA. 1996;276(24):1957–63. Erratum in: JAMA, 1997; 277(19): 1520. [PubMed] [Google Scholar]
- 52.Combs GF, Jr, Clark LC, Turnbull BW. Reduction of cancer mortality and incidence by selenium supplementation. Med Klin (Munich) 1997;92(Suppl 3):42–45. doi: 10.1007/BF03041964. [DOI] [PubMed] [Google Scholar]
- 53.Clark LC, Dalkin B, Krongrad A, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol. 1998;81(5):730–34. doi: 10.1046/j.1464-410x.1998.00630.x. [DOI] [PubMed] [Google Scholar]
- 54.Duffield-Lillico AJ, Reid ME, Turnbull BW, et al. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev. 2002;11(7):630–39. [PubMed] [Google Scholar]
- 55.Duffield-Lillico AJ, Dalkin BL, Reid ME, et al. Nutritional Prevention of Cancer Study Group. Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU Int. 2003;91(7):608–12. doi: 10.1046/j.1464-410x.2003.04167.x. [DOI] [PubMed] [Google Scholar]
- 56.Reid ME, Duffield-Lillico AJ, Sunga A, et al. Selenium supplementation and colorectal adenomas: an analysis of the nutritional prevention of cancer trial. Int J Cancer. 2006;118(7):1777–81. doi: 10.1002/ijc.21529. [DOI] [PubMed] [Google Scholar]
- 57.Dziaman T, Huzarski T, Gackowski D, et al. Selenium supplementation reduced oxidative DNA damage in adnexectomized BRCA1 mutations carriers. Cancer Epidemiol Biomarkers Prev. 2009;18(11):2923–28. doi: 10.1158/1055-9965.EPI-09-0529. [DOI] [PubMed] [Google Scholar]
- 58.Vidlar A, Vostalova J, Ulrichova J, et al. The safety and efficacy of a silymarin and selenium combination in men after radical prostatectomy – a six month placebo-controlled double-blind clinical trial. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010;154(3):239–44. doi: 10.5507/bp.2010.036. [DOI] [PubMed] [Google Scholar]
- 59.Sieja K. Selenium (Se) deficiency in women with ovarian cancer undergoing chemotherapy and the influence of supplementation with this micro-element on biochemical parameters. Pharmazie. 1998;53(7):473–76. [PubMed] [Google Scholar]
- 60.Muecke R, Schomburg L, Glatzel M, et al. German Working Group Trace Elements and Electrolytes in Oncology-AKTE. Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology. Int J Radiat Oncol Biol Phys. 2010;78(3):828–35. doi: 10.1016/j.ijrobp.2009.08.013. [DOI] [PubMed] [Google Scholar]
- 61.Büntzel J, Micke O, Kisters K, et al. Selenium substitution during radiotherapy of solid tumours - laboratory data from two observation studies in gynaecological and head and neck cancer patients. Anticancer Res. 2010;30(5):1783–86. [PubMed] [Google Scholar]
- 62.Kiremidjian-Schumacher L, Roy M, Wishe HI, et al. Supplementation with selenium and human immune cell functions. Biol Trace Elem Res. 1994;41:115–27. doi: 10.1007/BF02917222. [DOI] [PubMed] [Google Scholar]
- 63.Spallholz JE, Boylan LM, Larsen HS. Advances in understanding selenium’s role in the immune system. Ann NY Acad Sci. 1990;587:123–39. doi: 10.1111/j.1749-6632.1990.tb00140.x. [DOI] [PubMed] [Google Scholar]
- 64.Broome CS, McArdle F, Kyle JA, et al. An increase in selenium intake improves immune function and poliovirus handling in adults with marginal selenium status. Am J Clin Nutr. 2004;80:154–62. doi: 10.1093/ajcn/80.1.154. [DOI] [PubMed] [Google Scholar]
- 65.Kiremidjian-Schumacher L, Roy M, Glickman R, et al. Selenium and immunocompetence in patients with headand neck cancer. Biol Trace Elem Res. 2000;73:97–111. doi: 10.1385/BTER:73:2:97. [DOI] [PubMed] [Google Scholar]
- 66.Gärtner R, Gasnier BC, Dietrich JW, et al. Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations. J Clin Endocrinol Metab. 2002;87(4):1687–91. doi: 10.1210/jcem.87.4.8421. [DOI] [PubMed] [Google Scholar]
- 67.Marcocci C, Kahaly GJ, Krassas GE, et al. European Group on Graves’ Orbitopathy” Selenium and the course of mild Graves’ orbitopathy. N Engl J Med. 2011;364(20):1920–31. doi: 10.1056/NEJMoa1012985. [DOI] [PubMed] [Google Scholar]
- 68.Ricketts JR, Rothe MJ, Grant-Kels JM. Nutrition and psoriasis. Clin Dermatol. 2010;28(6):615–26. doi: 10.1016/j.clindermatol.2010.03.027. [DOI] [PubMed] [Google Scholar]
- 69.Bogye G, Alfthan G, Machay T, Zubovics L. Enteral yeast-selenium supplementation in preterm infants. Arch Dis Child Fetal Neonatal Ed. 1998;78(3):F225–26. doi: 10.1136/fn.78.3.f225. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Bogye G, Alfthan G, Machay T. Randomized clinical trial of enteral yeast-selenium supplementation in preterm infants. Biofactors. 1998;8(1–2):139–42. doi: 10.1002/biof.5520080123. [DOI] [PubMed] [Google Scholar]
- 71.Scott R, MacPherson A, Yates RW, et al. The effect of oral selenium supplementation on human sperm motility. Br J Urol. 1998;82(1):76–80. doi: 10.1046/j.1464-410x.1998.00683.x. [DOI] [PubMed] [Google Scholar]
- 72.Tara F, Rayman MP, Boskabadi H, et al. Selenium supplementation and premature (pre-labour) rupture of membranes: a randomised double-blind placebo-controlled trial. J Obstet Gynaecol. 2010;30(1):30–34. doi: 10.3109/01443610903267507. [DOI] [PubMed] [Google Scholar]
- 73.Tara F, Maamouri G, Rayman MP, et al. Selenium supplementation and the incidence of preeclampsia in pregnant Iranian women: a randomized, double-blind, placebo-controlled pilot trial. Taiwan J Obstet Gynecol. 2010;49(2):181–87. doi: 10.1016/S1028-4559(10)60038-1. [DOI] [PubMed] [Google Scholar]
- 74.Benton D, Cook R. Selenium supplementation improves mood in a double-blind crossover trial. Psychopharmacology (Berl) 1990;102(4):549–50. doi: 10.1007/BF02247139. [DOI] [PubMed] [Google Scholar]
- 75.Benton D, Cook R. The impact of selenium supplementation on mood. Biol Psychiatry. 1991;29(11):1092–98. doi: 10.1016/0006-3223(91)90251-g. [DOI] [PubMed] [Google Scholar]
- 76.Mokhber N, Namjoo M, Tara F, et al. Effect of supplementation with selenium on postpartum depression: a randomized double-blind placebo-controlled trial. J Matern Fetal Neonatal Med. 2011;24(1):104–8. doi: 10.3109/14767058.2010.482598. [DOI] [PubMed] [Google Scholar]