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Roles for selenium and selenoprotein P in the development, progression, and prevention of intestinal disease.
Short SP, Pilat JM, Williams CS
(2018) Free Radic Biol Med 127: 26-35
MeSH Terms: Animals, Disease Progression, Humans, Intestinal Diseases, Selenium, Selenoprotein P
Show Abstract · Added April 15, 2019
Selenium (Se) is a micronutrient essential to human health, the function of which is mediated in part by incorporation into a class of proteins known as selenoproteins (SePs). As many SePs serve antioxidant functions, Se has long been postulated to protect against inflammation and cancer development in the gut by attenuating oxidative stress. Indeed, numerous studies over the years have correlated Se levels with incidence and severity of intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). Similar results have been obtained with the Se transport protein, selenoprotein P (SELENOP), which is decreased in the plasma of both IBD and CRC patients. While animal models further suggest that decreases in Se or SELENOP augment colitis and intestinal tumorigenesis, large-scale clinical trials have yet to show a protective effect in patient populations. In this review, we discuss the function of Se and SELENOP in intestinal diseases and how research into these mechanisms may impact patient treatment.
Copyright © 2018 Elsevier Inc. All rights reserved.
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1 Members
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6 MeSH Terms
Antioxidant supplementation and atrial arrhythmias in critically ill trauma patients.
Mirhoseini MF, Hamblin SE, Moore WP, Pouliot J, Jenkins JM, Wang W, Chandrasekhar R, Collier BR, Patel MB
(2018) J Surg Res 222: 10-16
MeSH Terms: Adult, Antioxidants, Arrhythmias, Cardiac, Ascorbic Acid, Critical Care, Critical Illness, Dietary Supplements, Female, Humans, Male, Middle Aged, Oxidative Stress, Retrospective Studies, Selenium, Trauma Centers, Vitamin D, Wounds and Injuries
Show Abstract · Added June 26, 2018
BACKGROUND - The purpose of this study is to determine if antioxidant supplementation influences the incidence of atrial arrhythmias in trauma intensive care unit (ICU) patients.
MATERIALS AND METHODS - In this retrospective pre-post study, critically ill injured patients aged ≥18 years, admitted to a single-center trauma ICU for ≥48 hours were eligible for inclusion. The control group consists of patients admitted from January 2000 to September 2005, before routine antioxidant supplementation in our ICU. The antioxidant group consists of patients admitted from October 2005 to June 2011 who received an antioxidant protocol for ≥48 hours. The primary outcome is the incidence of atrial arrhythmias in the first 2 weeks of hospitalization or before discharge.
RESULTS - Of the 4699 patients, 1622 patients were in the antioxidant group and 2414 patients were in the control group. Adjusted for age, sex, year, injury severity, past medical history, and medication administration, the unadjusted incidence of atrial arrhythmias was 3.02% in the antioxidant group versus 3.31% in the control group, with no adjusted difference in atrial arrhythmias among those exposed to antioxidants (odds ratio: 1.31 [95% confidence interval: 0.46, 3.75], P = 0.62). Although there was no change in overall mortality, the expected adjusted survival of patients in those without antioxidant therapy was lower (odds ratio: 0.65 [95% confidence interval: 0.43, 0.97], P = 0.04).
CONCLUSIONS - ICU antioxidant supplementation did not decrease the incidence of atrial arrhythmias, nor alter the time from admission to development of arrhythmia. A longer expected survival time was observed in the antioxidant group compared with the control group but without a change in overall mortality between groups.
Published by Elsevier Inc.
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17 MeSH Terms
Selenoproteins in Tumorigenesis and Cancer Progression.
Short SP, Williams CS
(2017) Adv Cancer Res 136: 49-83
MeSH Terms: Animals, Antioxidants, Carcinogenesis, Disease Progression, Humans, Neoplasms, Oxidation-Reduction, Oxidative Stress, Selenium, Selenoproteins
Show Abstract · Added April 15, 2019
Selenium is a micronutrient essential to human health and has long been associated with cancer prevention. Functionally, these effects are thought to be mediated by a class of selenium-containing proteins known as selenoproteins. Indeed, many selenoproteins have antioxidant activity which can attenuate cancer development by minimizing oxidative insult and resultant DNA damage. However, oxidative stress is increasingly being recognized for its "double-edged sword" effect in tumorigenesis, whereby it can mediate both negative and positive effects on tumor growth depending on the cellular context. In addition to their roles in redox homeostasis, recent work has also implicated selenoproteins in key oncogenic and tumor-suppressive pathways. Together, these data suggest that the overall contribution of selenoproteins to tumorigenesis is complicated and may be affected by a variety of factors. In this review, we discuss what is currently known about selenoproteins in tumorigenesis with a focus on their contextual roles in cancer development, growth, and progression.
© 2017 Elsevier Inc. All rights reserved.
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MeSH Terms
Competition between the Brain and Testes under Selenium-Compromised Conditions: Insight into Sex Differences in Selenium Metabolism and Risk of Neurodevelopmental Disease.
Pitts MW, Kremer PM, Hashimoto AC, Torres DJ, Byrns CN, Williams CS, Berry MJ
(2015) J Neurosci 35: 15326-38
MeSH Terms: Age Factors, Animals, Brain, Castration, Dizocilpine Maleate, Epilepsy, Reflex, Exploratory Behavior, Female, Gene Expression Regulation, Glutamate Decarboxylase, Lyases, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Neurodevelopmental Disorders, Selenium, Selenoprotein P, Sex Factors, Transcription Factors
Show Abstract · Added March 29, 2016
UNLABELLED - Selenium (Se) is essential for both brain development and male fertility. Male mice lacking two key genes involved in Se metabolism (Scly(-/-)Sepp1(-/-) mice), selenoprotein P (Sepp1) and Sec lyase (Scly), develop severe neurological dysfunction, neurodegeneration, and audiogenic seizures that manifest beginning in early adulthood. We demonstrate that prepubescent castration of Scly(-/-)Sepp1(-/-) mice prevents behavioral deficits, attenuates neurodegeneration, rescues maturation of GABAergic inhibition, and increases brain selenoprotein levels. Moreover, castration also yields similar neuroprotective benefits to Sepp1(-/-) and wild-type mice challenged with Se-deficient diets. Our data show that, under Se-compromised conditions, the brain and testes compete for Se utilization, with concomitant effects on neurodevelopment and neurodegeneration.
SIGNIFICANCE STATEMENT - Selenium is an essential trace element that promotes male fertility and brain function. Herein, we report that prepubescent castration provides neuroprotection by increasing selenium-dependent antioxidant activity in the brain, revealing a competition between the brain and testes for selenium utilization. These findings provide novel insight into the interaction of sex and oxidative stress upon the developing brain and have potentially significant implications for the prevention of neurodevelopmental disorders characterized by aberrant excitatory/inhibitory balance, such as schizophrenia and epilepsy.
Copyright © 2015 the authors 0270-6474/15/3515326-13$15.00/0.
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1 Members
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23 MeSH Terms
Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage.
Barrett CW, Reddy VK, Short SP, Motley AK, Lintel MK, Bradley AM, Freeman T, Vallance J, Ning W, Parang B, Poindexter SV, Fingleton B, Chen X, Washington MK, Wilson KT, Shroyer NF, Hill KE, Burk RF, Williams CS
(2015) J Clin Invest 125: 2646-60
MeSH Terms: Animals, Antioxidants, Apoptosis, Colitis, Colonic Neoplasms, DNA Damage, Genomic Instability, Haploinsufficiency, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutagenesis, Site-Directed, Neoplastic Stem Cells, Oxidative Stress, Protein Structure, Tertiary, Selenium, Selenoprotein P, Tumor Microenvironment, Tumor Suppressor Proteins
Show Abstract · Added July 10, 2015
Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions.
0 Communities
6 Members
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20 MeSH Terms
Regulation of Selenium Metabolism and Transport.
Burk RF, Hill KE
(2015) Annu Rev Nutr 35: 109-34
MeSH Terms: Animals, Biological Availability, Biological Transport, Biomarkers, Diet, Dietary Supplements, Health Status, Homeostasis, Humans, Kidney Tubules, Proximal, LDL-Receptor Related Proteins, Liver, Low Density Lipoprotein Receptor-Related Protein-2, Nutritional Requirements, Organ Specificity, Selenium, Selenocysteine, Selenomethionine, Selenoprotein P, Selenoproteins
Show Abstract · Added September 28, 2015
Selenium is regulated in the body to maintain vital selenoproteins and to avoid toxicity. When selenium is limiting, cells utilize it to synthesize the selenoproteins most important to them, creating a selenoprotein hierarchy in the cell. The liver is the central organ for selenium regulation and produces excretory selenium forms to regulate whole-body selenium. It responds to selenium deficiency by curtailing excretion and secreting selenoprotein P (Sepp1) into the plasma at the expense of its intracellular selenoproteins. Plasma Sepp1 is distributed to tissues in relation to their expression of the Sepp1 receptor apolipoprotein E receptor-2, creating a tissue selenium hierarchy. N-terminal Sepp1 forms are taken up in the renal proximal tubule by another receptor, megalin. Thus, the regulated whole-body pool of selenium is shifted to needy cells and then to vital selenoproteins in them to supply selenium where it is needed, creating a whole-body selenoprotein hierarchy.
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1 Members
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20 MeSH Terms
Selenoprotein P is the major selenium transport protein in mouse milk.
Hill KE, Motley AK, Winfrey VP, Burk RF
(2014) PLoS One 9: e103486
MeSH Terms: Animals, Animals, Newborn, Biological Transport, Electrophoresis, Polyacrylamide Gel, Female, Glutathione Peroxidase, In Situ Hybridization, Male, Mammary Glands, Animal, Mice, Inbred C57BL, Mice, Knockout, Milk, Selenium, Selenoprotein P, Weaning, Weight Gain
Show Abstract · Added September 28, 2015
Selenium is transferred from the mouse dam to its neonate via milk. Milk contains selenium in selenoprotein form as selenoprotein P (Sepp1) and glutathione peroxidase-3 (Gpx3) as well as in non-specific protein form as selenomethionine. Selenium is also present in milk in uncharacterized small-molecule form. We eliminated selenomethionine from the mice in these experiments by feeding a diet that contained sodium selenite as the source of selenium. Selenium-replete dams with deletion of Sepp1 or Gpx3 were studied to assess the effects of these genes on selenium transfer to the neonate. Sepp1 knockout caused a drop in milk selenium to 27% of the value in wild-type milk and a drop in selenium acquisition by the neonates to 35%. In addition to decreasing milk selenium by eliminating Sepp1, deletion of Sepp1 causes a decline in whole-body selenium, which likely also contributes to the decreased transfer of selenium to the neonate. Deletion of Gpx3 did not decrease milk selenium content or neonate selenium acquisition by measurable amounts. Thus, when the dam is fed selenium-adequate diet (0.25 mg selenium/kg diet), milk Sepp1 transfers a large amount of selenium to neonates but the transfer of selenium by Gpx3 is below detection by our methods.
0 Communities
1 Members
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16 MeSH Terms
Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration.
Burk RF, Hill KE, Motley AK, Winfrey VP, Kurokawa S, Mitchell SL, Zhang W
(2014) FASEB J 28: 3579-88
MeSH Terms: Animals, Animals, Congenic, Biological Transport, Blood-Brain Barrier, Brain, Capillaries, Choroid Plexus, Endocytosis, Endothelial Cells, Female, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-2, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Degeneration, Neurons, Pregnancy, Selenium, Selenoprotein P
Show Abstract · Added September 28, 2015
Selenoprotein P (Sepp1) and its receptor, apolipoprotein E receptor 2 (apoER2), account for brain retaining selenium better than other tissues. The primary sources of Sepp1 in plasma and brain are hepatocytes and astrocytes, respectively. ApoER2 is expressed in varying amounts by tissues; within the brain it is expressed primarily by neurons. Knockout of Sepp1 or apoER2 lowers brain selenium from ∼120 to ∼50 ng/g and leads to severe neurodegeneration and death in mild selenium deficiency. Interactions of Sepp1 and apoER2 that protect against this injury have not been characterized. We studied Sepp1, apoER2, and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediates Sepp1 uptake at the blood-brain barrier. When Sepp1(-/-) or apoER2(-/-) mice developed severe neurodegeneration caused by mild selenium deficiency, brain selenium was ∼35 ng/g. In extreme selenium deficiency, however, brain selenium of ∼12 ng/g was tolerated when both Sepp1 and apoER2 were intact in the brain. These findings indicate that tandem Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons. One interaction is at the blood-brain barrier, and the other is within the brain. We postulate that Sepp1 inside the blood-brain barrier is taken up by neurons via apoER2, concentrating brain selenium in them.
© FASEB.
0 Communities
1 Members
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21 MeSH Terms
Isoform-specific binding of selenoprotein P to the β-propeller domain of apolipoprotein E receptor 2 mediates selenium supply.
Kurokawa S, Bellinger FP, Hill KE, Burk RF, Berry MJ
(2014) J Biol Chem 289: 9195-207
MeSH Terms: Amino Acid Sequence, Animals, Endocytosis, Female, HEK293 Cells, Humans, Ligands, Low Density Lipoprotein Receptor-Related Protein-1, Male, Mice, Molecular Sequence Data, Protein Isoforms, Protein Structure, Tertiary, Selenium, Selenocysteine, Selenoprotein P, Sequence Alignment, Substrate Specificity
Show Abstract · Added March 10, 2014
Sepp1 supplies selenium to tissues via receptor-mediated endocytosis. Mice, rats, and humans have 10 selenocysteines in Sepp1, which are incorporated via recoding of the stop codon, UGA. Four isoforms of rat Sepp1 have been identified, including full-length Sepp1 and three others, which terminate at the second, third, and seventh UGA codons. Previous studies have shown that the longer Sepp1 isoforms bind to the low density lipoprotein receptor apoER2, but the mechanism remains unclear. To identify the essential residues for apoER2 binding, an in vitro Sepp1 binding assay was developed using different Sec to Cys substituted variants of Sepp1 produced in HEK293T cells. ApoER2 was found to bind the two longest isoforms. These results suggest that Sepp1 isoforms with six or more selenocysteines are taken up by apoER2. Furthermore, the C-terminal domain of Sepp1 alone can bind to apoER2. These results indicate that apoER2 binds to the Sepp1 C-terminal domain and does not require the heparin-binding site, which is located in the N-terminal domain. Site-directed mutagenesis identified three residues of Sepp1 that are necessary for apoER2 binding. Sequential deletion of extracellular domains of apoER2 surprisingly identified the YWTD β-propeller domain as the Sepp1 binding site. Finally, we show that apoER2 missing the ligand-binding repeat region, which can result from cleavage at a furin cleavage site present in some apoER2 isoforms, can act as a receptor for Sepp1. Thus, longer isoforms of Sepp1 with high selenium content interact with a binding site distinct from the ligand-binding domain of apoER2 for selenium delivery.
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18 MeSH Terms
Plasma selenium biomarkers in low income black and white americans from the southeastern United States.
Hargreaves MK, Liu J, Buchowski MS, Patel KA, Larson CO, Schlundt DG, Kenerson DM, Hill KE, Burk RF, Blot WJ
(2014) PLoS One 9: e84972
MeSH Terms: Adult, African Continental Ancestry Group, Aged, Biomarkers, European Continental Ancestry Group, Female, Humans, Male, Middle Aged, Selenium, Southeastern United States
Show Abstract · Added March 10, 2014
Biomarkers of selenium are necessary for assessing selenium status in humans, since soil variation hinders estimation of selenium intake from foods. In this study, we measured the concentration of plasma selenium, selenoprotein P (SEPP1), and glutathione peroxidase (GPX3) activity and their interindividual differences in 383 low-income blacks and whites selected from a stratified random sample of adults aged 40-79 years, who were participating in a long-term cohort study in the southeastern United States (US). We assessed the utility of these biomarkers to determine differences in selenium status and their association with demographic, socio-economic, dietary, and other indicators. Dietary selenium intake was assessed using a validated food frequency questionnaire designed for the cohort, matched with region-specific food selenium content, and compared with the US Recommended Dietary Allowances (RDA) set at 55 µg/day. We found that SEPP1, a sensitive biomarker of selenium nutritional status, was significantly lower among blacks than whites (mean 4.4 ± 1.1 vs. 4.7 ± 1.0 mg/L, p = 0.006), with blacks less than half as likely to have highest vs. lowest quartile SEPP1 concentration (Odds Ratio (OR) 0.4, 95% Confidence Interval (CI) 0.2-0.8). The trend in a similar direction was observed for plasma selenium among blacks and whites, (mean 115 ± 15.1 vs. 118 ± 17.7 µg/L, p = 0.08), while GPX3 activity did not differ between blacks and whites (136 ± 33.3 vs. 132 ± 33.5 U/L, p = 0.320). Levels of the three biomarkers were not correlated with estimated dietary selenium intake, except for SEPP1 among 10% of participants with the lowest selenium intake (≤ 57 µg/day). The findings suggest that SEPP1 may be an effective biomarker of selenium status and disease risk in adults and that low selenium status may disproportionately affect black and white cohort participants.
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4 Members
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11 MeSH Terms