Regulation of synthesis of the selenoenzymes cytosolic glutathione peroxidase (GSH-Px), phospholipid hydroperoxide glutathione peroxidase (PHGSH-Px) and type-1 iodothyronine 5'-deiodinase (5'IDI) was investigated in liver, thyroid and heart of rats fed on diets containing 0.405, 0.104 (Se-adequate), 0.052, 0.024 or 0.003 mg of Se/kg. Severe Se deficiency (0.003 mg of Se/kg) caused almost total loss of GSH-Px activity and mRNA in liver and heart. 5'IDI activity decreased by 95% in liver and its mRNA by 50%; in the thyroid, activity increased by 15% and mRNA by 95%. PHGSH-Px activity was reduced by 75% in the liver and 60% in the heart but mRNA levels were unchanged; in the thyroid, PHGSH-Px activity was unaffected by Se depletion but its mRNA increased by 52%. Thus there is differential regulation of the three mRNAs and subsequent protein synthesis within and between organs, suggesting both that mechanisms exist to channel Se for synthesis of a particular enzyme and that there is tissue-specific regulation of selenoenzyme mRNAs. During Se depletion, the levels of selenoenzyme mRNA did not necessarily parallel the changes in enzyme activity, suggesting a distinct mechanism for regulating mRNA levels. Nuclear run-off assays with isolated liver nuclei showed severe Se deficiency to have no effect on transcription of the three genes, suggesting that there is post-transcriptional control of the three selenoenzymes, probably involving regulation of mRNA stability.
Selenium (Se) is a micronutrient essential for human health. Sub-optimal Se status is common, occurring in a significant proportion of the population across the world including parts of Europe and China. Human and animal studies have shown that Se status is a key determinant of the host response to viral infections. In this review, we address the question whether Se intake is a factor in determining the severity of response to COVID-19. Emphasis is placed on epidemiological and animal studies which suggest that Se affects host response to RNA viruses and on the molecular mechanisms by which Se and selenoproteins modulate the inter-linked redox homeostasis, stress response and inflammatory response. Together these studies indicate that Se status is an important factor in determining the host response to viral infections. Therefore, we conclude that Se status is likely to influence human response to the SARS-CoV-2 infection and that Se status is one (of several) risk factors which may impact on the outcome of SARS-CoV-2 infection, particularly in populations where Se intake is sub-optimal or low. We suggest the use of appropriate markers to assess the Se status of COVID-19 patients and possible supplementation may be beneficial in limiting the severity of symptoms, especially in countries where Se status is regarded as sub-optimal.
Obesity and its association with co-morbidities in Africa are on the rise. This systematic review examines evidence of obesity and its association with co-morbidities within the African continent. Comparative studies conducted in Africa on adults 17 years and older with mean body mass index (BMI) ≥ 28 kg/m2 were included. Five electronic databases were searched. Surveys, case–control and cohort studies from January 2000 to July 2010 were evaluated. Of 720 potentially relevant articles, 10 met the inclusion criteria. Prevalence of obesity was higher in urban than rural subjects with significant increases in obesity rates among women. Inflammatory marker levels were significantly elevated among Africans compared with Caucasians. The co-relationship between obesity and chronic diseases was also highlighted. This systematic review demonstrates that while obesity remains an area of significant public health importance to Africans, particularly in urban areas, there is little evidence of proper diagnosis, treatment and/or prevention.
Low selenium (Se) status has been associated with increased risk of colorectal cancer (CRC). Se is present as the amino acid selenocysteine in selenoproteins, such as the glutathione peroxidases. Se incorporation requires specific RNA structures in the 3' untranslated region (3'UTR) of the selenoprotein mRNAs. A single nucleotide polymorphism (SNP) occurs at nucleotide 718 (within the 3'UTR) in the glutathione peroxidase 4 gene. In the present study, Caco-2 cells were transfected with constructs in which type 1 iodothyronine deiodinase coding region was linked to the GPx4 3'UTR with either C or T variant at position 718. Higher reporter activity was observed in cells expressing the C variant compared to those expressing the T variant, under either Se-adequate or Se-deficient conditions. In addition, a disease association study was carried out in cohorts of patients with either adenomatous polyps, colorectal adenocarcinomas and in healthy controls. A higher proportion of individuals with CC genotype at the GPx4 T/C 718 SNP was present in the cancer group, but not in the polyp group, compared with the control group (P < 0.05). The present data demonstrate the functionality of the GPx4 T/C 718 SNP and suggest that T genotype is associated with lower risk of CRC.
Selenium (Se)-containing proteins have important roles in protecting cells from oxidative damage. This work investigated the effects of Se-depletion on the expression of the genes encoding selenoproteins in colonic mucosa from rats fed diets of different Se content and in human intestinal Caco-2 cells grown in Se-adequate or Se-depleted culture medium. Se-depletion produced statistically significant (P < 0.05) falls in glutathione peroxidase (GPX) 1 mRNA (60-83%) and selenoprotein W mRNA (73%) levels, a small but significant fall in GPX4 mRNA (17-25%) but no significant change in GPX2. The data show that SelW expression in the colon is highly sensitive to Se-depletion.
Selenium is an essential nutrient and synthesis of selenoproteins is affected by limited selenium supply. During selenium deficiency there is a differential regulation of selenoprotein synthesis and gene expression; for example, there is a decrease in abundance of mRNA for cytosolic glutathione peroxidase (cGSH-Px) and a preservation of mRNA for phospholipid-hydroperoxide glutathione peroxidase (PHGSH-Px). This difference is not due to an alteration in the rate of transcription but might reflect differences in translation. The aim of the present work was to assess the role of cGSH-Px and PHGSH-Px 3' untranslated regions (UTRs) in the regulation of selenoprotein mRNA stability and translation by using H4-II-E-C3 cells transfected with different constructs containing a type I iodothyronine deiodinase-coding region linked to different selenoprotein mRNA 3' UTRs. Translational efficiency results showed that the efficiency of the 3' UTRs in permitting selenocysteine incorporation is similar in selenium-replete conditions but, when selenium is limiting, the 3' UTR of cGSH-Px is less efficient than the 3' UTR of PHGSH-Px. The results suggest that the 3' UTR of these selenoprotein mRNA species influences their extent of translation when selenium levels are low. The different sensitivity of the 3' UTRs to selenium deficiency can explain the differential effect that selenium deficiency has on cGSH-Px and PHGSH-Px activity and mRNA levels, stability and translation. This might be partly responsible for channelling selenium for synthesis of PHGSH-Px rather than cGSH-Px.
Selenium depletion of H4 hepatoma cells reduced c> tosolic glutathione peroxidase (cGSH-Px) mRNA abundance but had no effect on phospholipid hydroperoxide glutathione peroxidase (PHGSH-Px) mRNA abundance. Actinomycin D chase experiments showed that selenium depletion had no effect on the stability of PHGSH-Px mRNA but decreased the stability of cGSH-Px mRNA. In Se-replete cells puromycin decreased the stability of both cGSH-Px and PHGSH-Px mRNAs. The results suggest that when selenium supply is limiting PHGSH-Px mRNA translation is maintained more than that of cGSH-Px mRNA, and thus more cGSH-Px mRNA is released from polysomes and degraded.
Islet amyloid polypeptide (IAPP) and insulin are expressed in the -cells of the islets of Langerhans. They are co-secreted in response to changes in glucose concentration, and their mRNA levels are also regulated by glucose. The promoters of both genes share similar cisacting sequence elements, and both bind the homeodomain transcription factor PDX1, which plays an important role in the regulation of the insulin promoter and insulin mRNA levels by glucose. Here we examine the role of PDX1 in the regulation of the human IAPP promoter by glucose. The experiments were facilitated by the availability of a human -cell line (NES2Y) that lacks PDX1. NES2Y cells also lack operational K ATP channels, resulting in a loss of control of calcium signaling. We have previously used these cells to show that glucose regulation of the insulin gene is dependent on PDX1, but not calcium. In the mouse -cell line Min6, glucose (16 mM) stimulated a 3.5-4-fold increase in the activity of a ؊222 to ؉450 IAPP promoter construct compared with values observed in 0.5 mM glucose. In NES2Y cells, glucose failed to stimulate transcriptional activation of the IAPP promoter. Overexpression of PDX1 in NES2Y cells failed to reinstate glucose-responsive control of the IAPP promoter. Glucose effects on the IAPP promoter were observed only in the presence of PDX1 when normal calcium signaling was restored by overexpression of the two K ATP channel subunits SUR1 and Kir6.2. The importance of calcium was further emphasized by an experiment in which glucose-stimulated IAPP promoter activity was inhibited by the calcium channel blocker verapamil (50 M). Verapamil was further shown to inhibit the stimulatory effect of glucose on IAPP mRNA levels. These results demonstrate that like the insulin promoter, glucose regulation of the IAPP promoter is dependent on the activity of PDX1, but unlike the insulin promoter, it additionally requires the activity of another, as yet uncharacterized factor(s), the activity of which is calcium-dependent. Islet amyloid polypeptide (IAPP),1 also known as amylin, is a 37-amino acid peptide of the calcitonin gene family (1). IAPP was originally isolated from amyloid deposits in islets of Langerhans from non-insulin-dependent diabetic pancreas and insulinomas (2, 3). It has since been shown to play a role in the normal regulation of glucose metabolism (4, 5).IAPP and insulin are co-secreted in a regulated manner following stimulation with glucose and a variety of other secretagogues (6, 7). Transcription of the IAPP (8, 9) and insulin (10) genes is also stimulated by glucose. In the case of insulin, multiple cis-acting elements located within a relatively short region (Ϫ1 to Ϫ360) upstream of the start site contribute to the regulation of the gene by glucose and other nutrients (11). The homeodomain transcription factor PDX1 (12), which binds to a number of elements termed the A-boxes (13) within this region, plays a particularly important role (14,15). Recently, the cell signaling pathway linking glucose metabolism to the ...
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