Biomedical subjects

Birgit Mentrup

Publications and source records attributed to Birgit Mentrup.

7 recordsLinked to original sources

PubMed2006

Selenium-dependent pre- and posttranscriptional mechanisms are responsible for sexual dimorphic expression of selenoproteins in murine tissues.

Important enzymes for thyroid hormone metabolism, antioxidative defense, and intracellular redox control contain selenocysteine (Sec) in their active centers. Expression of these selenoproteins is tightly controlled, and a sex-specific phenotype is observed on disturbance of selenium (Se) transport in mice. Therefore, we analyzed Se concentrations and expression levels of several selenoproteins including type I iodothyronine deiodinase (Dio1) and glutathione peroxidase (GPx) isozymes in male and female mice. On regular lab chow, serum Se levels were comparable, but serum GPx3 activity was higher in females than males (1.3-fold). Selenoprotein P (SePP) mRNA levels were higher in livers (1.3-fold) and lower in kidneys (to 31%) in female compared with male mice. Orchidectomy alleviated the sex-specific differences in SePP mRNA amounts, indicating modulatory effects of androgens on SePP expression. Female mice expressed higher levels of Dio1 mRNA in kidney (2.6-fold) and liver (1.4-fold) in comparison with male mice. This sexual dimorphic expression of Dio1 mRNA was paralleled by increased Dio1 activity in female kidney (1.8-fold) but not in liver in which males expressed higher Dio1 activity (2.8-fold). Interestingly, Se deficiency decreased Dio1 activity more effectively in males than females, and resulting hepatic enzyme levels were then comparable between the sexes. At the same time, the sex-specific difference of Dio1 activity widened in kidney. Orchidectomy or estradiol treatment of ovariectomized females impacted stronger on renal than hepatic Dio1 expression. Thus, we conclude that Se-dependent posttranscriptional mechanisms are operational that affect either translational efficiency or Dio1 stability in a sex- and tissue-specific manner.

Animals↗

PubMed2006

Genistein and other soya isoflavones are potent ligands for transthyretin in serum and cerebrospinal fluid.

Consumption of soya-based nutrients is increasing in modern society because of their potentially protective effects against chronic diseases. Soya products are also heavily advertised as alternative drugs for relief from symptoms of the menopause and for hormone replacement therapy. However, because of their oestrogenic activity, negative effects of isoflavones have been postulated. Therefore, we analysed influences of soya isoflavones, major soya constituents with endocrine activity, on thyroxine (T4) binding to its distribution proteins. Serum binding of (125)I-labelled L-T4 was analysed in the absence or presence of increasing concentrations of soya isoflavones using non-denaturing PAGE for analysis. Complete displacement of [(125)I]T4 binding to transthyretin (TTR) was observed in human serum incubated with genistein at concentrations >10 microM; interference started at >0.1 microM. Glycitein showed decreased and daidzein the lowest displacement potency. [(125)I]T4 was displaced to albumin in rat and to T4-binding globulin in human serum. Soya isoflavones also obstruct [(125)I]T4 binding to TTR in human cerebrospinal fluid (CSF). The inhibitory effect was confirmed in direct binding assays using purified TTR with 50% inhibitory concentration values of 0.07 microM for genistein, 0.2 microM for glycitein and 1.8 microM for daidzein. The present study underlined a potent competition of soya isoflavones for T4 binding to TTR in serum and CSF. Isoflavones might alter free thyroid hormone concentrations resulting in altered tissue availability and metabolism. As a consequence of this interference, one could expect a disturbance in the feedback regulation of hormonal networks, including the pituitary-thyroid-periphery axis during development and in adult organisms.

Animals↗

PubMed2005

Selenoprotein expression in Hürthle cell carcinomas and in the human Hürthle cell carcinoma line XTC.UC1.

Hürthle cell carcinomas (HTC) are characterized by mitochondrial amplification and enhanced oxygen metabolism. To clarify if defects in enzymes scavenging reactive oxygen species are involved in the pathogenesis of HTC, we analyzed selenium (Se)-dependent expression of various detoxifying selenoproteins in the HTC cell line XTC.UC1. Glutathione peroxidase and thioredoxin reductase activity was found both in cell lysates and conditioned media of XTC.UC1 cells and was increased by Na(2)SeO(3). Western blot analysis demonstrated the presence of thioredoxin reductase both in cell lysates and conditioned media and of glutathione peroxidase 3 in conditioned media. Type I 5'-deiodinase, another selenoprotein that catalyzes thyroid hormone metabolism, was detectable only in cell lysates by enzyme assay and Western blot, and responded to stimulation by both Na(2)SeO(3) and retinoic acid. A selenoprotein P signal was detected in conditioned media by Western blot, but was not enhanced by Na(2)SeO(3) treatment. In situ hybridization revealed glutathione peroxidase mRNAs in HTC specimen; glutathione peroxidase 3 mRNA levels were reduced. These data suggest adequate expression and Se-dependent regulation of a couple of selenoproteins involved in antioxidant defense and thyroid hormone metabolism in XTC.UC1 cells, so far giving no evidence of a role of these proteins in the pathogenesis of HTCs.

Adenoma, Oxyphilic↗

PubMed2004

Endocrine active compounds affect thyrotropin and thyroid hormone levels in serum as well as endpoints of thyroid hormone action in liver, heart and kidney.

To assess interference with endocrine regulation of the thyroid axis, rats (female, ovariectomised) were treated for 12 weeks with the suspected endocrine active compounds (EAC) or endocrine disrupters (ED) 4-nonylphenol (NP), octyl-methoxycinnamate (OMC) and 4-methylbenzylidene-camphor (4-MBC) as well as 17beta-estradiol (E2) and 5alpha-androstane-3beta,17beta-diol (Adiol) on the background of a soy-free or soy-containing diet, and endpoints relevant for regulation via the thyroid axis were measured. Thyrotropin (TSH) and thyroid hormone (T4, T3) serum levels were altered, but not in a way consistent with known mechanisms of feedback regulation of the thyroid axis. In the liver, malic enzyme (ME) activity was significantly increased by E2 and Adiol, slightly by OMC and MBC and decreased by soy, whereas type I 5'-deiodinase (5'DI) was decreased by all treatments. This may be due rather to the estrogenic effect of the ED, as there is no obvious correlation with T4 or T3 serum levels. None of the substances inhibited thyroid peroxidase (TPO) in vitro, except for NP. In general, several endocrine active compounds disrupt the endocrine feedback regulation of the thyroid axis. However, there was no uniform, obvious pattern in the effects of those ED tested, but each compound elicited its own spectrum of alterations, arguing for multiple targets of interference with the complex network of thyroid hormone action and metabolism.

Animals↗

PubMed2004

Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis.

OBJECTIVE: Proinflammatory cytokines are involved in the pathogenesis of non-thyroidal illness (NTI), as shown by studies with IL-6-/- and IL-12-/- mice. Interleukin (IL)-6 changes peripheral thyroid hormone metabolism, and IL-12 seems to be involved in the regulation of the central part of the hypothalamic-pituitary-thyroid (HPT) axis during illness. IL-18 is a proinflammatory cytokine which shares important biological properties with IL-12, such as interferon (IFN)-gamma-inducing activity. DESIGN: By studying the changes in the HPT-axis during bacterial lipopolysaccharide (LPS)-induced illness in IL-18-/-, IFNgammaR-/- and wild-type (WT) mice, we wanted to unravel the putative role of IL-18 and IFNgamma in the pathogenesis of NTI. RESULTS: LPS induced a decrease in pituitary type 1 deiodinase (D1) activity (P<0.05, ANOVA) in WT mice, but not in IL-18-/- mice, while the decrease in D2 activity was similar in both strains. LPS decreased serum thyroid hormone levels and liver D1 mRNA within 24 h similarly in IL-18-/-, and WT mice. The expression of IL-1, IL-6 and IFNgamma mRNA expression was significantly lower in IL-18-/- mice than in WT, while IL-12 mRNA expression was similar. IFNgammaR-/- mice had higher basal D1 activity in the pituitary than WT mice (P<0.05); LPS induced a decrease of D2, but not of D1, activity in the pituitary which was similar in both strains. In the liver, the LPS-induced increase in cytokine expression was not different between IFNgammaR-/- mice and WT mice, and the decrease in serum T3 and T4 levels and hepatic D1 mRNA was also similar. CONCLUSIONS: The relative decrease in serum T3 and T4 and liver D1 mRNA in response to LPS is similar in IL-18-/-, IFNgammaR-/- and WT mice despite significant changes in hepatic cytokine induction. However, the LPS-induced decrease in D1 activity in the pituitary of WT mice is absent in IL-18-/- mice; in contrast, LPS did not decrease pituitary D1 activity in the IFNgammaR-/- mice or their WT, which might be due to the genetic background of the mice. Our results suggest that IL-18 is also involved in the regulation of the central part of the HPT axis during illness.

Animals↗

PubMed2002

A complex DNA-repeat structure within the Selenoprotein P promoter contains a functionally relevant polymorphism and is genetically unstable under conditions of mismatch repair deficiency.

Epidemiological data, animal studies and interventional studies provide evidence for a potential chemopreventive effect of selenium during development of colorectal cancer. The human glycoprotein Selenoprotein P (SeP) contains up to 50% of plasma selenium content. SeP is expressed in the gastrointestinal tract and the liver, where its expression is downregulated by various proinflammatory cytokines (Il1beta, TGFbeta, IFNgamma). Previously, we have demonstrated dramatically reduced SeP expression in human colon adenomas. Here, we have identified a complex (A)4-C-(A)4-GG-(A)8-GCT-(TC)5-(T)17 (bp -429 to bp - 477) repeat structure within the SeP promoter and we have analysed this regulatory DNA sequence with respect to polymorphisms, genomic instability and functional relevance to promoter activity. As opposed to the (TC)5 variant we identified a novel (TC)3 polymorphism within this repeat in the general population, which conferred significantly reduced basal promoter activity to reporter gene constructs in HepG2 cells. Allelic distribution of this (TC)(n) element was similar in colon carcinoma patients and healthy controls. Additionally, we observed genetic instability within the (T)17 repeat motif in colon cancers of the mutator phenotype. This instability of the (T)17 repeat had no effect on basal promoter activity in reporter gene assays. In conclusion, we characterised a complex repeat structure within the SeP promoter that may be of functional relevance to SeP gene expression. Further studies on the effect of different SeP promoter genotypes on SeP protein expression and disease susceptibility are needed.

Base Pair Mismatch↗

PubMed2002

Proinflammatory cytokines inhibit the expression and function of human type I 5'-deiodinase in HepG2 hepatocarcinoma cells.

OBJECTIVE: The sick euthyroid syndrome in critically ill patients without primary disease of the thyroid gland is characterised by low serum total triiodothyronine (T3), normal to elevated thyroxine (T4), elevated reverse T3 (rT3) and normal TSH levels. The aim of this work was to clarify if impaired T4 and rT3 5'-deiodination is an underlying mechanism. DESIGN AND METHODS: We analysed the effect of the human recombinant proinflammatory cytokines interleukin (IL)-6 and IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on human type I 5'-iodothyronine deiodinase (5'DI) enzyme activity in the human hepatocarcinoma cell line HepG2, i.e. in a homologous human system. Furthermore, we analysed transcriptional effects of the cytokines by transient transfection assays using the luciferase or chloramphenicol acetyltransferase (CAT) reporter genes under the control of 1480 nucleotides of the human 5'DI promoter. RESULTS: IL-6 at 500 pg/ml and TNF-alpha at 25 ng/ml had no significant effect, whereas 100 ng/ml IFN-gamma or 10 ng/ml IL-1beta reduced 5'DI enzyme activity to 77.9 and 59.5% of control values. IFN-gamma did not alter, IL-6 and TNF-alpha moderately decreased (in the case of IL-6 only in the CAT system), and IL-1beta (0.01-10 ng/ml) dose-dependently inhibited 5'DI promoter activity to a minimum of 38.1%. CONCLUSION: IL-1beta inhibited both 5'DI enzyme and promoter activity and, thus, may exert its effect on thyroid hormone metabolism at least partially through direct inhibition of hepatic 5'DI gene transcription.

Carcinoma, Hepatocellular↗