Daily nutrition varies considerably among individuals. The number of vegetarians is increasing co... more Daily nutrition varies considerably among individuals. The number of vegetarians is increasing continuously due to ethical, environmental, religious or other reasons. There is growing concern over their nutritional status with respect to micronutrient deficiencies. Among the essential trace elements, Se is of prime importance as it is part of the active site in selenoproteins. European soil and plants are relatively poor sources of Se, while farm animals are generally supplemented with Se in order to improve their health and avoid deficiency syndromes. We therefore wondered whether German vegetarians display a measurable Se deficiency. To this end, we compared young vegetarians (n 54) and omnivores (n 53). We assessed their Se status by measuring extracellular glutathione peroxidase 3 (GPX3) activity, and concentrations of total serum Se and circulating Se-transport protein selenoprotein P (SEPP). GPX3 activities were not different between the groups, whereas both total Se and SEPP concentrations were reduced to 79•5 and 71•2 % in vegetarians compared with omnivores. When splitting the group of vegetarians into vegans (n 26) and vegetarians consuming egg and milk products (n 28), analyses of the Se-dependent biomarkers did not reveal significant differences. We conclude that low serum Se is mirrored by circulating SEPP concentrations, but not by GPX3 activities in marginally supplied individuals. The specific dietary Se sources, divergent metabolic routes of selenomethionine v. selenocysteine and the different saturation kinetics of GPX3 and SEPP probably underlie our contradictory findings. Whether German vegetarians and vegans need to be considered as a Se-deficient group depends on the biomarker chosen.
Liver-specific inactivation of Trsp, the gene for selenocysteine tRNA, removes SePP (selenoprotei... more Liver-specific inactivation of Trsp, the gene for selenocysteine tRNA, removes SePP (selenoprotein P) from plasma, causing serum selenium levels to fall from 298 µg/l to 50 µg/l and kidney selenium to decrease to 36 % of wild-type levels. Likewise, glutathione peroxidase activities decreased in plasma and kidney to 43 % and 18 % respectively of wild-type levels. This agrees nicely with data from SePP knockout mice, supporting a selenium transport role for hepatically expressed SePP. However, brain selenium levels remain unaffected and neurological defects do not occur in the liver-specific Trsp knockout mice, while SePP knockout mice suffer from neurological defects. This indicates that a transport function in plasma is exerted by hepatically derived SePP, while in brain SePP fulfils a second, hitherto unexpected, essential role.
The importance of autoantibodies (AABs) against adrenergic/muscarinic receptors in heart failure ... more The importance of autoantibodies (AABs) against adrenergic/muscarinic receptors in heart failure (HF) is not well-understood. We investigated the prevalence and clinical/prognostic associations of four AABs recognizing the M2-muscarinic receptor or the β1-, β2-, or β3-adrenergic receptor in a large and well-characterized cohort of patients with HF. Methods and results Serum samples from 2256 patients with HF from the BIOSTAT-CHF cohort and 299 healthy controls were analysed using newly established chemiluminescence immunoassays. The primary outcome was a composite of all-cause mortality and HF rehospitalization at 2-year follow-up, and each outcome was also separately investigated. Collectively, 382 (16.9%) patients and 37 (12.4%) controls were seropositive for ≥1 AAB (P = 0.045). Seropositivity occurred more frequently only for anti-M2 AABs (P = 0.025). Amongst patients with HF, seropositivity was associated with the presence of comorbidities (renal disease, chronic obstructive pulmonary disease, stroke, and atrial fibrillation) and with medication use. Only anti-β1 AAB seropositivity was associated with the primary outcome [hazard ratio (95% confidence interval): 1.37 (1.04-1.81), P = 0.024] and HF rehospitalization [1.57 (1.13-2.19), P = 0.010] in univariable analyses but remained associated only with HF rehospitalization after multivariable adjustment for the BIOSTAT-CHF risk model [1.47 (1.05-2.07), P = 0.030]. Principal component analyses showed considerable overlap in B-lymphocyte activity between seropositive and seronegative patients, based on 31 circulating biomarkers related to B-lymphocyte function. Conclusions AAB seropositivity was not strongly associated with adverse outcomes in HF and was mostly related to the presence of comorbidities and medication use. Only anti-β1 AABs were independently associated with HF rehospitalization. The exact clinical value of AABs remains to be elucidated.
Selenoprotein P (Sepp) is a remarkable selenoprotein. Among all mammalian selenoproteins, it is t... more Selenoprotein P (Sepp) is a remarkable selenoprotein. Among all mammalian selenoproteins, it is the only one containing more than one selenocysteine, and ten in humans. Sepp is a plasma protein mainly originating in the liver, but it is also expressed in other organs, notably the brain, placenta, and the lactating mamma. The main function of Sepp is transport of selenium (Se) to target tissues. Hepatocytes thus convert nutritional selenocompounds into Sepp for transport and distribution, and the mother’s milk contains Sepp as an essential gift to the offspring. The fact that about 25 % of all selenoprotein mRNAs in hepatocytes code for Sepp alone highlights its central position in the body’s Se homeostasis. Selenium status of an individual is thus reflected by the serum concentration of Sepp. Endocytic receptors of the lipoprotein receptor-related protein (Lrp) family participate in targeting cell-specific Sepp uptake and retention. A Sepp-cycle exists in brain, testes, and kidney and appears to preserve tissue Se during times of poor nutritional supply, explaining the long known hierarchical differences in tissue-specific Se retention in deficiency. Individual genotype differences may modulate these processes exerting an influence on the relative expression levels of selenoproteins, response to Se intake, and individual risk for Se-dependent diseases.
The essential trace element selenium, which is a crucial cofactor in the most important endogenou... more The essential trace element selenium, which is a crucial cofactor in the most important endogenous antioxidative systems of the human body, is attracting more and more the attention of both laypersons and expert groups. The interest of oncologists mainly focuses in the following clinical aspects: radioprotection of normal tissues, radiosensitizing in malignant tumors, antiedematous effect, prognostic impact of selenium, and effects in primary and secondary cancer prevention. Selenium is a constituent of the small group of selenocysteine-containing selenoproteins and elicits important structural and enzymatic functions. Selenium deficiency has been linked to increased infection risk and adverse mood states. It has been shown to possess cancer-preventive and cytoprotective activities in both animal models and humans. It is well established that Se has a key role in redox regulation and antioxidant function, and hence in membrane integrity, energy metabolism and protection against DNA damage. Recent clinical trials have shown the importance of
Journal of Trace Elements in Medicine and Biology, Oct 1, 2015
The German, Austrian and Swiss nutrition societies are the joint editors of the 'reference values... more The German, Austrian and Swiss nutrition societies are the joint editors of the 'reference values for nutrient intake'. They have revised the reference values for the intake of selenium and published them in February 2015. The saturation of selenoprotein P (SePP) in plasma is used as a criterion for the derivation of reference values for selenium intake in adults. For persons from selenium-deficient regions (China) SePP saturation was achieved with a daily intake of 49 g of selenium. When using the reference body weights the D-A-CH reference values are based upon, the resulting estimated value for selenium intake is 70 g/day for men and 60 g/day for women. The estimated value for selenium intake for children and adolescents is extrapolated using the estimated value for adults in relation to body weight. For infants aged 0 to under 4 months the estimated value of 10 g/day was derived from the basis of selenium intake via breast milk. For infants aged 4 to under 12 months this estimated value was used and taking into account the differences regarding body weight an estimated value of 15 g/day was derived. For lactating women compared to non-lactating women a higher reference value of 75 g/day is indicated due to the release of selenium with breast milk. The additional selenium requirement for pregnant women is negligible, so that no increased reference value is indicated.
Selenoprotein P (SePP) is a unique selenoprotein in many respects. It carries up to ten selenocys... more Selenoprotein P (SePP) is a unique selenoprotein in many respects. It carries up to ten selenocysteine moieties, which have been inserted cotranslationally with the help of two separate SECIS elements in its mRNA. The majority of serum SePP is secreted by the liver where hepatocytes convert nutritional selenocompounds into SePP for transport and distribution. Therefore, serum concentration of SePP is a useful biomarker for the selenium status of an individual. Recently, two endocytic receptors, i.e., Lrp2/megalin and Lrp8/ApoE receptor 2, have been identified which participate in target cell-specific SePP uptake and retention. A SePP-cycle has been proposed based on a tissue-specific sequence of reversible biosynthesis, secretion, and reuptake. Brain, testes, and kidney appear to use the SePP-cycle in order to preserve tissue selenium in times of poor nutritional supply. In how far individual genotype differences and common disease signals impair this pathway and disturb normal selenium metabolism and its hierarchical distribution by affecting SePP biosynthesis, secretion of isoforms and reuptake is a central research issue in basic science and biomedicine.
International Journal of Radiation Oncology Biology Physics, Nov 1, 2010
Purpose: We assessed whether adjuvant supplementation with selenium improves the selenium status ... more Purpose: We assessed whether adjuvant supplementation with selenium improves the selenium status and reduces side effects of patients treated by radiotherapy (RT) for cervical and uterine cancer. Methods and Materials: Whole-blood selenium concentrations were measured in patients with cervical cancer (n = 11) and uterine cancer (n = 70) after surgical treatment, during RT, at the end of RT, and 6 weeks after RT. Patients with initial selenium concentrations of less than 84mg/L were randomized before RT either to receive 500 mg of selenium (in the form of sodium selenite [selenaseÒ, biosyn Arzneimittel GmbH, Fellbach, Germany]) by mouth on the days of RTand 300 mg of selenium on the days without RT or to receive no supplement during RT. The primary endpoint of this multicenter Phase 3 study was to assess the efficiency of selenium supplementation during RT; the secondary endpoint was to decrease radiation-induced diarrhea and other RT-dependent side effects. Results: A total of 81 patients were randomized. We enrolled 39 in the selenium group (SG) and 42 in the control group (CG). Selenium levels did not differ between the SG and CG upon study initiation but were significantly higher in the SG at the end of RT. The actuarial incidence of diarrhea of Grade 2 or higher according to Common Toxicity Criteria (version 2) in the SG was 20.5% compared with 44.5% in the CG (p = 0.04). Other blood parameters, Eastern Cooperative Oncology Group performance status, and self-reported quality of life were not different between the groups. Conclusions: Selenium supplementation during RT is effective in improving blood selenium status in seleniumdeficient cervical and uterine cancer patients and reduces the number of episodes and severity of RT-induced diarrhea.
SARS-CoV-2 infections cause the current coronavirus disease (COVID-19) pandemic and challenge the... more SARS-CoV-2 infections cause the current coronavirus disease (COVID-19) pandemic and challenge the immune system with ongoing inflammation. Several redox-relevant micronutrients are known to contribute to an adequate immune response, including the essential trace elements zinc (Zn) and selenium (Se). In this study, we tested the hypothesis that COVID-19 patients are characterised by Zn deficiency and that Zn status provides prognostic information. Serum Zn was determined in serum samples (n = 171) collected consecutively from patients surviving COVID-19 (n = 29) or non-survivors (n = 6). Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study were used for comparison. Zn concentrations in patient samples were low as compared to healthy subjects (mean ± SD; 717.4 ± 246.2 vs 975.7 ± 294.0 μg/L, P < 0.0001). The majority of serum samples collected at different time points from the non-survivors (25/34, i.e., 73.5%) and almost half of the samples collected from the survivors (56/137, i.e., 40.9%) were below the threshold for Zn deficiency, i.e., below 638.7 μg/L (the 2.5th percentile in the EPIC cohort). In view that the Se status biomarker and Se transporter selenoprotein P (SELENOP) is also particularly low in COVID-19, we tested the prevalence of a combined deficit, i.e., serum Zn below 638.7 μg/L and serum SELENOP below 2.56 mg/L. This combined deficit was observed in 0.15% of samples in the EPIC cohort of healthy subjects, in 19.7% of the samples collected from the surviving COVID-19 patients and in 50.0% of samples from the non-survivors. Accordingly, the composite biomarker (SELENOP and Zn with age) proved as a reliable indicator of survival in COVID-19 by receiver operating characteristic (ROC) curve analysis, yielding an area under the curve (AUC) of 94.42%. We conclude that Zn and SELENOP status within the reference ranges indicate high survival odds in COVID-19, and assume that correcting a diagnostically proven deficit in Se and/or Zn by a personalised supplementation may support convalescence.
The essential trace element selenium (Se) is of central importance for human health and particula... more The essential trace element selenium (Se) is of central importance for human health and particularly for a regular functioning of the immune system. In the context of the current pandemic, Se deficiency in patients with COVID-19 correlated with disease severity and mortality risk. Selenium has been reported to be associated with the immune response following vaccination, but it is unknown whether this also applies to SARS-CoV-2 vaccines. In this observational study, adult health care workers (n = 126) who received two consecutive anti-SARS-CoV-2 vaccinations by BNT162b2 were followed for up to 24 weeks, with blood samples collected at the first and second dose and at three and 21 weeks after the second dose. Serum SARS-CoV-2 IgG titres, neutralising antibody potency, total Se and selenoprotein P concentrations, and glutathione peroxidase 3 activity were quantified. All three biomarkers of Se status were significantly correlated at all the time points, and participants who reported supplemental Se intake displayed higher Se concentrations. SARS-CoV-2 IgG titres and neutralising potency were highest three weeks after the second dose and decreased towards the last sampling point. The humoral immune response was not related to any of the three Se status biomarkers. Supplemental Se intake had no effect at any time point on the vaccination response as measured by serum SARS-CoV-2 IgG levels or neutralising potency. Overall, no association was found between Se status or supplemental Se intake and humoral immune response to COVID-19 mRNA vaccination.
Purpose We aimed to examine the prospective association between manganese, iron, copper, zinc, io... more Purpose We aimed to examine the prospective association between manganese, iron, copper, zinc, iodine, selenium, selenoprotein P, free zinc, and their interplay, with incident type 2 diabetes (T2D), cardiovascular disease (CVD) and colorectal cancer (CRC). Methods Serum trace element (TE) concentrations were measured in a case-cohort study embedded within the EPIC-Potsdam cohort, consisting of a random sub-cohort (n = 2500) and incident cases of T2D (n = 705), CVD (n = 414), and CRC (n = 219). TE patterns were investigated using principal component analysis. Cox proportional hazard models were fitted to examine the association between TEs with T2D, CVD and CRC incidence. Results Higher manganese, zinc, iodine and selenium were associated with an increased risk of developing T2D (HR Q5 vs Q1: 1.56, 1.09–2.22; HR per SD, 95% CI 1.18, 1.05–1.33; 1.09, 1.01–1.17; 1.19, 1.06–1.34, respectively). Regarding CVD, manganese, copper and copper-to-zinc ratio were associated with an increased r...
Selenium and copper are essential trace elements for humans, needed for the biosynthesis of enzym... more Selenium and copper are essential trace elements for humans, needed for the biosynthesis of enzymes contributing to redox homeostasis and redox-dependent signaling pathways. Selenium is incorporated as selenocysteine into the active site of redox-relevant selenoproteins including glutathione peroxidases (GPX) and thioredoxin reductases (TXNRD). Copper-dependent enzymes mediate electron transfer and other redox reactions. As selenoprotein expression can be modulated e.g. by H 2 O 2 , we tested the hypothesis that copper status affects selenoprotein expression. To this end, hepatocarcinoma HepG2 cells and mice were exposed to a variable copper and selenium supply in a physiologically relevant concentration range, and transcript and protein expression as well as GPX and TXNRD activities were compared. Copper suppressed selenoprotein mRNA levels of GPX1 and SELENOW, downregulated GPX and TXNRD activities and decreased UGA recoding efficiency in reporter cells. The interfering effects were successfully suppressed by applying the copper chelators bathocuproinedisulfonic acid or tetrathiomolybdate. In mice, a decreased copper supply moderately decreased the copper status and negatively affected hepatic TXNRD activity. We conclude that there is a hitherto unknown interrelationship between copper and selenium status, and that copper negatively affects selenoprotein expression and activity most probably via limiting UGA recoding. This interference may be of physiological relevance during aging, where a particular shift in the selenium to copper ratio has been reported. An increased concentration of copper in face of a downregulated selenoprotein expression may synergize and negatively affect the cellular redox homeostasis contributing to disease processes.
A decline of immune responses and dynamic modulation of the redox status are observed during agin... more A decline of immune responses and dynamic modulation of the redox status are observed during aging and are influenced by trace elements such as copper, iodine, iron, manganese, selenium, and zinc. So far, analytical studies have focused mainly on single trace elements. Therefore, we aimed to characterize age-specific profiles of several trace elements simultaneously in serum and organs of adult and old mice. This allows for correlating multiple trace element levels and to identify potential patterns of age-dependent alterations. In serum, copper and iodine concentrations were increased and zinc concentration was decreased in old as compared to adult mice. In parallel, decreased copper and elevated iron concentrations were observed in liver. The age-related reduction of hepatic copper levels was associated with reduced expression of copper transporters, whereas the increased hepatic iron concentrations correlated positively with proinflammatory mediators and Nrf2-induced ferritin H levels. Interestingly, the age-dependent inverse regulation of copper and iron was unique for the liver and not observed in any other organ. The physiological importance of alterations in the iron/copper ratio for liver function and the aging process needs to be addressed in further studies.
BACKGROUND Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed usi... more BACKGROUND Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed using serum concentrations of thyroid-stimulating hormone (TSH), which is sufficient in most cases. However, in certain conditions, such as resistance to TH due to mutations in THRB (RTHb) or TSH-releasing pituitary adenoma (TSHoma), TSH may be insufficient for a correct diagnosis, even in combination with serum TH concentrations. Likewise, under TH replacement therapy, these parameters can be misleading and do not always allow optimal treatment. Hence, additional biomarkers to assess challenging clinical conditions would be highly beneficial. METHODS Data from untargeted multi-omics analyses of plasma samples from experimental thyrotoxicosis in human and mouse were exploited to identify proteins that might represent possible biomarkers of TH function. Subsequent mouse studies were used to identify the tissue of origin and the involvement of the two different TH receptors (TR). For in depth characterisation of the underlying cellular mechanisms, primary mouse cells were used. RESULTS The analysis of the plasma proteome data sets revealed 16 plasma proteins that were concordantly differentially abundant under thyroxine treatment compared to euthyroid controls across the two species. These originated predominantly from liver, spleen and bone. Independent studies in a clinical cohort and different mouse models identified CD5L as the most robust putative biomarker under different serum TH states and treatment periods. In vitro studies revealed that CD5L originates from pro-inflammatory M1 macrophages, which are similar to liver residing Kupffer cells, and is regulated by an indirect mechanism requiring the secretion of a yet unknown factor from hepatocytes. In agreement with the role of TRα1 in immune cells and the TRβ dependent hepatocyte-derived signalling, the in vivo regulation of Cd5l expression depended on both TR isoforms. CONCLUSION Our results identify several novel targets of TH action in serum with CD5L as the most robust marker. Although further studies will be needed to validate the specificity of these targets, CD5L seems to be a promising candidate to assess TH action in hepatocyte-macrophage crosstalk.
Daily nutrition varies considerably among individuals. The number of vegetarians is increasing co... more Daily nutrition varies considerably among individuals. The number of vegetarians is increasing continuously due to ethical, environmental, religious or other reasons. There is growing concern over their nutritional status with respect to micronutrient deficiencies. Among the essential trace elements, Se is of prime importance as it is part of the active site in selenoproteins. European soil and plants are relatively poor sources of Se, while farm animals are generally supplemented with Se in order to improve their health and avoid deficiency syndromes. We therefore wondered whether German vegetarians display a measurable Se deficiency. To this end, we compared young vegetarians (n 54) and omnivores (n 53). We assessed their Se status by measuring extracellular glutathione peroxidase 3 (GPX3) activity, and concentrations of total serum Se and circulating Se-transport protein selenoprotein P (SEPP). GPX3 activities were not different between the groups, whereas both total Se and SEPP concentrations were reduced to 79•5 and 71•2 % in vegetarians compared with omnivores. When splitting the group of vegetarians into vegans (n 26) and vegetarians consuming egg and milk products (n 28), analyses of the Se-dependent biomarkers did not reveal significant differences. We conclude that low serum Se is mirrored by circulating SEPP concentrations, but not by GPX3 activities in marginally supplied individuals. The specific dietary Se sources, divergent metabolic routes of selenomethionine v. selenocysteine and the different saturation kinetics of GPX3 and SEPP probably underlie our contradictory findings. Whether German vegetarians and vegans need to be considered as a Se-deficient group depends on the biomarker chosen.
Liver-specific inactivation of Trsp, the gene for selenocysteine tRNA, removes SePP (selenoprotei... more Liver-specific inactivation of Trsp, the gene for selenocysteine tRNA, removes SePP (selenoprotein P) from plasma, causing serum selenium levels to fall from 298 µg/l to 50 µg/l and kidney selenium to decrease to 36 % of wild-type levels. Likewise, glutathione peroxidase activities decreased in plasma and kidney to 43 % and 18 % respectively of wild-type levels. This agrees nicely with data from SePP knockout mice, supporting a selenium transport role for hepatically expressed SePP. However, brain selenium levels remain unaffected and neurological defects do not occur in the liver-specific Trsp knockout mice, while SePP knockout mice suffer from neurological defects. This indicates that a transport function in plasma is exerted by hepatically derived SePP, while in brain SePP fulfils a second, hitherto unexpected, essential role.
The importance of autoantibodies (AABs) against adrenergic/muscarinic receptors in heart failure ... more The importance of autoantibodies (AABs) against adrenergic/muscarinic receptors in heart failure (HF) is not well-understood. We investigated the prevalence and clinical/prognostic associations of four AABs recognizing the M2-muscarinic receptor or the β1-, β2-, or β3-adrenergic receptor in a large and well-characterized cohort of patients with HF. Methods and results Serum samples from 2256 patients with HF from the BIOSTAT-CHF cohort and 299 healthy controls were analysed using newly established chemiluminescence immunoassays. The primary outcome was a composite of all-cause mortality and HF rehospitalization at 2-year follow-up, and each outcome was also separately investigated. Collectively, 382 (16.9%) patients and 37 (12.4%) controls were seropositive for ≥1 AAB (P = 0.045). Seropositivity occurred more frequently only for anti-M2 AABs (P = 0.025). Amongst patients with HF, seropositivity was associated with the presence of comorbidities (renal disease, chronic obstructive pulmonary disease, stroke, and atrial fibrillation) and with medication use. Only anti-β1 AAB seropositivity was associated with the primary outcome [hazard ratio (95% confidence interval): 1.37 (1.04-1.81), P = 0.024] and HF rehospitalization [1.57 (1.13-2.19), P = 0.010] in univariable analyses but remained associated only with HF rehospitalization after multivariable adjustment for the BIOSTAT-CHF risk model [1.47 (1.05-2.07), P = 0.030]. Principal component analyses showed considerable overlap in B-lymphocyte activity between seropositive and seronegative patients, based on 31 circulating biomarkers related to B-lymphocyte function. Conclusions AAB seropositivity was not strongly associated with adverse outcomes in HF and was mostly related to the presence of comorbidities and medication use. Only anti-β1 AABs were independently associated with HF rehospitalization. The exact clinical value of AABs remains to be elucidated.
Selenoprotein P (Sepp) is a remarkable selenoprotein. Among all mammalian selenoproteins, it is t... more Selenoprotein P (Sepp) is a remarkable selenoprotein. Among all mammalian selenoproteins, it is the only one containing more than one selenocysteine, and ten in humans. Sepp is a plasma protein mainly originating in the liver, but it is also expressed in other organs, notably the brain, placenta, and the lactating mamma. The main function of Sepp is transport of selenium (Se) to target tissues. Hepatocytes thus convert nutritional selenocompounds into Sepp for transport and distribution, and the mother’s milk contains Sepp as an essential gift to the offspring. The fact that about 25 % of all selenoprotein mRNAs in hepatocytes code for Sepp alone highlights its central position in the body’s Se homeostasis. Selenium status of an individual is thus reflected by the serum concentration of Sepp. Endocytic receptors of the lipoprotein receptor-related protein (Lrp) family participate in targeting cell-specific Sepp uptake and retention. A Sepp-cycle exists in brain, testes, and kidney and appears to preserve tissue Se during times of poor nutritional supply, explaining the long known hierarchical differences in tissue-specific Se retention in deficiency. Individual genotype differences may modulate these processes exerting an influence on the relative expression levels of selenoproteins, response to Se intake, and individual risk for Se-dependent diseases.
The essential trace element selenium, which is a crucial cofactor in the most important endogenou... more The essential trace element selenium, which is a crucial cofactor in the most important endogenous antioxidative systems of the human body, is attracting more and more the attention of both laypersons and expert groups. The interest of oncologists mainly focuses in the following clinical aspects: radioprotection of normal tissues, radiosensitizing in malignant tumors, antiedematous effect, prognostic impact of selenium, and effects in primary and secondary cancer prevention. Selenium is a constituent of the small group of selenocysteine-containing selenoproteins and elicits important structural and enzymatic functions. Selenium deficiency has been linked to increased infection risk and adverse mood states. It has been shown to possess cancer-preventive and cytoprotective activities in both animal models and humans. It is well established that Se has a key role in redox regulation and antioxidant function, and hence in membrane integrity, energy metabolism and protection against DNA damage. Recent clinical trials have shown the importance of
Journal of Trace Elements in Medicine and Biology, Oct 1, 2015
The German, Austrian and Swiss nutrition societies are the joint editors of the 'reference values... more The German, Austrian and Swiss nutrition societies are the joint editors of the 'reference values for nutrient intake'. They have revised the reference values for the intake of selenium and published them in February 2015. The saturation of selenoprotein P (SePP) in plasma is used as a criterion for the derivation of reference values for selenium intake in adults. For persons from selenium-deficient regions (China) SePP saturation was achieved with a daily intake of 49 g of selenium. When using the reference body weights the D-A-CH reference values are based upon, the resulting estimated value for selenium intake is 70 g/day for men and 60 g/day for women. The estimated value for selenium intake for children and adolescents is extrapolated using the estimated value for adults in relation to body weight. For infants aged 0 to under 4 months the estimated value of 10 g/day was derived from the basis of selenium intake via breast milk. For infants aged 4 to under 12 months this estimated value was used and taking into account the differences regarding body weight an estimated value of 15 g/day was derived. For lactating women compared to non-lactating women a higher reference value of 75 g/day is indicated due to the release of selenium with breast milk. The additional selenium requirement for pregnant women is negligible, so that no increased reference value is indicated.
Selenoprotein P (SePP) is a unique selenoprotein in many respects. It carries up to ten selenocys... more Selenoprotein P (SePP) is a unique selenoprotein in many respects. It carries up to ten selenocysteine moieties, which have been inserted cotranslationally with the help of two separate SECIS elements in its mRNA. The majority of serum SePP is secreted by the liver where hepatocytes convert nutritional selenocompounds into SePP for transport and distribution. Therefore, serum concentration of SePP is a useful biomarker for the selenium status of an individual. Recently, two endocytic receptors, i.e., Lrp2/megalin and Lrp8/ApoE receptor 2, have been identified which participate in target cell-specific SePP uptake and retention. A SePP-cycle has been proposed based on a tissue-specific sequence of reversible biosynthesis, secretion, and reuptake. Brain, testes, and kidney appear to use the SePP-cycle in order to preserve tissue selenium in times of poor nutritional supply. In how far individual genotype differences and common disease signals impair this pathway and disturb normal selenium metabolism and its hierarchical distribution by affecting SePP biosynthesis, secretion of isoforms and reuptake is a central research issue in basic science and biomedicine.
International Journal of Radiation Oncology Biology Physics, Nov 1, 2010
Purpose: We assessed whether adjuvant supplementation with selenium improves the selenium status ... more Purpose: We assessed whether adjuvant supplementation with selenium improves the selenium status and reduces side effects of patients treated by radiotherapy (RT) for cervical and uterine cancer. Methods and Materials: Whole-blood selenium concentrations were measured in patients with cervical cancer (n = 11) and uterine cancer (n = 70) after surgical treatment, during RT, at the end of RT, and 6 weeks after RT. Patients with initial selenium concentrations of less than 84mg/L were randomized before RT either to receive 500 mg of selenium (in the form of sodium selenite [selenaseÒ, biosyn Arzneimittel GmbH, Fellbach, Germany]) by mouth on the days of RTand 300 mg of selenium on the days without RT or to receive no supplement during RT. The primary endpoint of this multicenter Phase 3 study was to assess the efficiency of selenium supplementation during RT; the secondary endpoint was to decrease radiation-induced diarrhea and other RT-dependent side effects. Results: A total of 81 patients were randomized. We enrolled 39 in the selenium group (SG) and 42 in the control group (CG). Selenium levels did not differ between the SG and CG upon study initiation but were significantly higher in the SG at the end of RT. The actuarial incidence of diarrhea of Grade 2 or higher according to Common Toxicity Criteria (version 2) in the SG was 20.5% compared with 44.5% in the CG (p = 0.04). Other blood parameters, Eastern Cooperative Oncology Group performance status, and self-reported quality of life were not different between the groups. Conclusions: Selenium supplementation during RT is effective in improving blood selenium status in seleniumdeficient cervical and uterine cancer patients and reduces the number of episodes and severity of RT-induced diarrhea.
SARS-CoV-2 infections cause the current coronavirus disease (COVID-19) pandemic and challenge the... more SARS-CoV-2 infections cause the current coronavirus disease (COVID-19) pandemic and challenge the immune system with ongoing inflammation. Several redox-relevant micronutrients are known to contribute to an adequate immune response, including the essential trace elements zinc (Zn) and selenium (Se). In this study, we tested the hypothesis that COVID-19 patients are characterised by Zn deficiency and that Zn status provides prognostic information. Serum Zn was determined in serum samples (n = 171) collected consecutively from patients surviving COVID-19 (n = 29) or non-survivors (n = 6). Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study were used for comparison. Zn concentrations in patient samples were low as compared to healthy subjects (mean ± SD; 717.4 ± 246.2 vs 975.7 ± 294.0 μg/L, P < 0.0001). The majority of serum samples collected at different time points from the non-survivors (25/34, i.e., 73.5%) and almost half of the samples collected from the survivors (56/137, i.e., 40.9%) were below the threshold for Zn deficiency, i.e., below 638.7 μg/L (the 2.5th percentile in the EPIC cohort). In view that the Se status biomarker and Se transporter selenoprotein P (SELENOP) is also particularly low in COVID-19, we tested the prevalence of a combined deficit, i.e., serum Zn below 638.7 μg/L and serum SELENOP below 2.56 mg/L. This combined deficit was observed in 0.15% of samples in the EPIC cohort of healthy subjects, in 19.7% of the samples collected from the surviving COVID-19 patients and in 50.0% of samples from the non-survivors. Accordingly, the composite biomarker (SELENOP and Zn with age) proved as a reliable indicator of survival in COVID-19 by receiver operating characteristic (ROC) curve analysis, yielding an area under the curve (AUC) of 94.42%. We conclude that Zn and SELENOP status within the reference ranges indicate high survival odds in COVID-19, and assume that correcting a diagnostically proven deficit in Se and/or Zn by a personalised supplementation may support convalescence.
The essential trace element selenium (Se) is of central importance for human health and particula... more The essential trace element selenium (Se) is of central importance for human health and particularly for a regular functioning of the immune system. In the context of the current pandemic, Se deficiency in patients with COVID-19 correlated with disease severity and mortality risk. Selenium has been reported to be associated with the immune response following vaccination, but it is unknown whether this also applies to SARS-CoV-2 vaccines. In this observational study, adult health care workers (n = 126) who received two consecutive anti-SARS-CoV-2 vaccinations by BNT162b2 were followed for up to 24 weeks, with blood samples collected at the first and second dose and at three and 21 weeks after the second dose. Serum SARS-CoV-2 IgG titres, neutralising antibody potency, total Se and selenoprotein P concentrations, and glutathione peroxidase 3 activity were quantified. All three biomarkers of Se status were significantly correlated at all the time points, and participants who reported supplemental Se intake displayed higher Se concentrations. SARS-CoV-2 IgG titres and neutralising potency were highest three weeks after the second dose and decreased towards the last sampling point. The humoral immune response was not related to any of the three Se status biomarkers. Supplemental Se intake had no effect at any time point on the vaccination response as measured by serum SARS-CoV-2 IgG levels or neutralising potency. Overall, no association was found between Se status or supplemental Se intake and humoral immune response to COVID-19 mRNA vaccination.
Purpose We aimed to examine the prospective association between manganese, iron, copper, zinc, io... more Purpose We aimed to examine the prospective association between manganese, iron, copper, zinc, iodine, selenium, selenoprotein P, free zinc, and their interplay, with incident type 2 diabetes (T2D), cardiovascular disease (CVD) and colorectal cancer (CRC). Methods Serum trace element (TE) concentrations were measured in a case-cohort study embedded within the EPIC-Potsdam cohort, consisting of a random sub-cohort (n = 2500) and incident cases of T2D (n = 705), CVD (n = 414), and CRC (n = 219). TE patterns were investigated using principal component analysis. Cox proportional hazard models were fitted to examine the association between TEs with T2D, CVD and CRC incidence. Results Higher manganese, zinc, iodine and selenium were associated with an increased risk of developing T2D (HR Q5 vs Q1: 1.56, 1.09–2.22; HR per SD, 95% CI 1.18, 1.05–1.33; 1.09, 1.01–1.17; 1.19, 1.06–1.34, respectively). Regarding CVD, manganese, copper and copper-to-zinc ratio were associated with an increased r...
Selenium and copper are essential trace elements for humans, needed for the biosynthesis of enzym... more Selenium and copper are essential trace elements for humans, needed for the biosynthesis of enzymes contributing to redox homeostasis and redox-dependent signaling pathways. Selenium is incorporated as selenocysteine into the active site of redox-relevant selenoproteins including glutathione peroxidases (GPX) and thioredoxin reductases (TXNRD). Copper-dependent enzymes mediate electron transfer and other redox reactions. As selenoprotein expression can be modulated e.g. by H 2 O 2 , we tested the hypothesis that copper status affects selenoprotein expression. To this end, hepatocarcinoma HepG2 cells and mice were exposed to a variable copper and selenium supply in a physiologically relevant concentration range, and transcript and protein expression as well as GPX and TXNRD activities were compared. Copper suppressed selenoprotein mRNA levels of GPX1 and SELENOW, downregulated GPX and TXNRD activities and decreased UGA recoding efficiency in reporter cells. The interfering effects were successfully suppressed by applying the copper chelators bathocuproinedisulfonic acid or tetrathiomolybdate. In mice, a decreased copper supply moderately decreased the copper status and negatively affected hepatic TXNRD activity. We conclude that there is a hitherto unknown interrelationship between copper and selenium status, and that copper negatively affects selenoprotein expression and activity most probably via limiting UGA recoding. This interference may be of physiological relevance during aging, where a particular shift in the selenium to copper ratio has been reported. An increased concentration of copper in face of a downregulated selenoprotein expression may synergize and negatively affect the cellular redox homeostasis contributing to disease processes.
A decline of immune responses and dynamic modulation of the redox status are observed during agin... more A decline of immune responses and dynamic modulation of the redox status are observed during aging and are influenced by trace elements such as copper, iodine, iron, manganese, selenium, and zinc. So far, analytical studies have focused mainly on single trace elements. Therefore, we aimed to characterize age-specific profiles of several trace elements simultaneously in serum and organs of adult and old mice. This allows for correlating multiple trace element levels and to identify potential patterns of age-dependent alterations. In serum, copper and iodine concentrations were increased and zinc concentration was decreased in old as compared to adult mice. In parallel, decreased copper and elevated iron concentrations were observed in liver. The age-related reduction of hepatic copper levels was associated with reduced expression of copper transporters, whereas the increased hepatic iron concentrations correlated positively with proinflammatory mediators and Nrf2-induced ferritin H levels. Interestingly, the age-dependent inverse regulation of copper and iron was unique for the liver and not observed in any other organ. The physiological importance of alterations in the iron/copper ratio for liver function and the aging process needs to be addressed in further studies.
BACKGROUND Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed usi... more BACKGROUND Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed using serum concentrations of thyroid-stimulating hormone (TSH), which is sufficient in most cases. However, in certain conditions, such as resistance to TH due to mutations in THRB (RTHb) or TSH-releasing pituitary adenoma (TSHoma), TSH may be insufficient for a correct diagnosis, even in combination with serum TH concentrations. Likewise, under TH replacement therapy, these parameters can be misleading and do not always allow optimal treatment. Hence, additional biomarkers to assess challenging clinical conditions would be highly beneficial. METHODS Data from untargeted multi-omics analyses of plasma samples from experimental thyrotoxicosis in human and mouse were exploited to identify proteins that might represent possible biomarkers of TH function. Subsequent mouse studies were used to identify the tissue of origin and the involvement of the two different TH receptors (TR). For in depth characterisation of the underlying cellular mechanisms, primary mouse cells were used. RESULTS The analysis of the plasma proteome data sets revealed 16 plasma proteins that were concordantly differentially abundant under thyroxine treatment compared to euthyroid controls across the two species. These originated predominantly from liver, spleen and bone. Independent studies in a clinical cohort and different mouse models identified CD5L as the most robust putative biomarker under different serum TH states and treatment periods. In vitro studies revealed that CD5L originates from pro-inflammatory M1 macrophages, which are similar to liver residing Kupffer cells, and is regulated by an indirect mechanism requiring the secretion of a yet unknown factor from hepatocytes. In agreement with the role of TRα1 in immune cells and the TRβ dependent hepatocyte-derived signalling, the in vivo regulation of Cd5l expression depended on both TR isoforms. CONCLUSION Our results identify several novel targets of TH action in serum with CD5L as the most robust marker. Although further studies will be needed to validate the specificity of these targets, CD5L seems to be a promising candidate to assess TH action in hepatocyte-macrophage crosstalk.
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Papers by Lutz Schomburg