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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Employing published methods for isolation of cardiac myocyte nuclei from adult rat ventricular myocardium with the use of mechanical disruption without digestive enzymes, we obtained transcriptionally active cardiac myocyte nuclei with sufficient yield and purity. The relative content of Na/K-ATPase subunit mRNAs (alpha 1, alpha 2, and beta 1) in ventricular myocardium of euthyroid rats closely matched the relative rates of transcription of the respective subunit genes determined by nuclear run-on assay. Treatment of hypothyroid rats with T(3)to elicit hyperthyroidism was associated with 2.9-, 7.5-, and seven-fold increases in the contents of alpha 1-, alpha 2, beta 1-mRNAs, respectively. In contrast, rates of transcription of the subunit genes were not changed significantly by T(3), while transcription of the 18 S ribosomal gene was stimulated identical with three-fold by the treatment. A quantitative reverse transcription-polymerase chain reaction assay for measurement of primary RNA transcripts of the beta 1 gene was developed employing a rat genomic DNA fragment that contains the first exon and part of the first intron of the beta 1 gene. The relative abundance of beta 1 primary transcripts did not change in RNA isolated from hypothyroid, euthyroid, and hyperthyroid rats. It is concluded that: (1) The relative contents of Na/K-ATPase subunit mRNAs in euthyroid adult myocardium is primarily controlled at the transcriptional level, and (2) T(3)-induced increases in the contents of Na/K-ATPase subunit mRNAs in the heart is not associated with increased rates of transcription of the subunit genes, and the effect is mediated at the post-transcriptional level.
J Mol Cell Cardiol 2000 Nov
PMID:Thyroid hormone regulation of myocardial Na/K-ATPase gene expression. 1104 Jan 2

Mitochondria seem to be involved in oxygen radical damage and aging. However, the possible relationships between oxygen consumption and oxygen radical production by functional mitochondria, and oxidative DNA damage, have not been studied previously. In order to analyze these relationships, male Wistar rats of 12 weeks of age were rendered hyper- and hypothyroid by chronic T(3) and 6-n-propyl-2-thiouracil treatments, respectively. Hypothyroidism decreased heart mitochondrial H(2)O(2) production in States 4 (to 51% of controls; P<0.05) and 3 (to 21% of controls; P<0.05). In agreement with this, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) decreased in the heart genomic DNA of hypothyroid animals to 40% of controls (P<0.001). Studies with respiratory inhibitors showed that the decrease in oxygen radical generation observed in hypothyroidism occurred at Complex III (mainly) and at Complex I; that decrease was due to the presence of a lower free radical leak in the respiratory chain (P<0.05). Hyperthyroidism did not significantly change heart mitochondrial H(2)O(2) production since the increase in State 4 oxygen consumption in comparison with control and hypothyroid animals (P<0.05) was compensated by a decrease in the free radical leak in relation to control animals (P<0.05). In agreement with this, heart 8-oxodG was not changed in hyperthyroid animals. The lack of increase in H(2)O(2) production per unit of mitochondrial protein will protect mitochondria themselves against self-inflicted damage during hyperthyroidism.
Mol Cell Endocrinol 2000 Oct 25
PMID:Effect of thyroid hormones on mitochondrial oxygen free radical production and DNA oxidative damage in the rat heart. 1106 59

Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone (T3) caused by mutations in the thyroid hormone receptor beta (TRbeta). The index patient of the family reported here, a 17-year-old woman, came to medical attention because of a diffuse goiter, short stature, and learning disabilities. Biochemical tests revealed an elevated free T4 of 5.2 ng/dl (0.8-2.1), a T3 of 270 ng/dl (80-220), and a nonsuppressed TSH of 1.79 mU/l (0.4-4). Administration of exogenous T4 or T3 did not result in the usual TSH suppression, prompting the clinical diagnosis of RTH. Her father and one of her brothers also had clinical and biochemical findings consistent with RTH. Direct sequence analysis of the TRbeta gene revealed a heterozygous transition 928A>G in exon 9 resulting in substitution of methionine 310 by leucine (M310L). This novel receptor mutant has a reduced affinity for T3 ( approximately 10% of normal) and dominant negative properties that are similar in comparison to other RTH mutations. The index patient had a normal pregnancy and delivery. At birth, the female neonate had no goiter, a significantly elevated T4, and increased TSH. The diagnosis of RTH was confirmed by sequencing the TRbeta gene. She was underweight at birth and her length was between the 5th and 10th percentile. At 26 months, her height remained at the 10th percentile but her bone age was 18 months, suggesting mild hypothyroidism at the level of the bone. In contrast, increased heart rate and restlessness are consistent with hyperthyroidism in other tissues, such as the heart and possibly the brain.
Mol Genet Metab 2000 Nov
PMID:A novel mutation (M310L) in the thyroid hormone receptor beta causing resistance to thyroid hormone in a Brazilian kindred and a neonate. 1107 20

The role of thyroid hormones in metabolic pathways are well known. However, their involvement in lipid peroxidation and antioxidant enzyme activities is not known. In this study, the in vivo injection of 6-propylthiouracil (6-PTU) did not alter the concentration of malondialdehyde (MDA) and conjugated dienes in liver. The administration of triiodothyronine (T3) or diiodothyronine (T2) increased the peroxidation rate in hypothyroid fish. However, in normal fish, only a high dose of T2 caused increased malondialdehyde (MDA) production, rather than T3. SOD activity was higher in T2-treated groups in both experiments. Glutathione peroxidase (GPx) activity was also high in hypothyroid fish treated with T2. In normal specimens, injections of T3 and T2 had no effect on GPx activity. Glutathione reductase (GR) activity was not altered by hypothyroidism while T3 (1 microg) and T2 (1 microg) increased it. Glutathione content was low in 6-PTU treated fish and high in both T3- and T2-treated groups. Thus it can be concluded that not only T3 but also T2, formed by sequential monodeiodination of T4, is also effective in influencing lipid peroxidation and antioxidant enzyme activities in Anabas. Furthermore, hypothyroidism as well as hyperthyroidism affects lipid peroxidation in this teleost.
Comp Biochem Physiol B Biochem Mol Biol 2001 Jan
PMID:Thyroid hormones regulate lipid peroxidation and antioxidant enzyme activities in Anabas testudineus (Bloch). 1116 15

Extracellular superoxide dismutase (EC-SOD) concentration was measured in sera from 141 patients with 20 forms of infantile diseases including IDDM, SLE and epilepsy, 31 healthy children (controls), and 21 healthy young men by an enzyme-linked immunosorbent assay using a polyclonal antibody against human lung EC-SOD. Serum from patients with IDDM and fever of unknown origin had a significantly (p<0.05) lower concentration of EC-SOD than control serum. Part of sera from patients with the seven forms of diseases (SLE, viral infections, epilepsy, nephrosis, hyperthyroidism, hepatic disease, and Reye syndrome), on the other hand, had a greatly high concentration of EC-SOD, albeit not statistically significant. This SOD isoenzyme profile appears to be specific to each pediatric disease.
Res Commun Mol Pathol Pharmacol 2000
PMID:Serum extracellular superoxide dismutase in pediatric patients with various diseases as judged by an ELISA. 1148 83

While the biochemical literature on free radical metabolism is extensive, there is little information on the endocrine control of tissue oxidative stress, and in the case of thyroid hormones it is mainly limited to liver tissue and to short-term effects on a few selected biochemical parameters. In this investigation, chronic hypothyroidism and hyperthyroidism were successfully induced in mice, and various oxidative-stress-related parameters were studied in skeletal muscle. In vivo and in vitro lipid peroxidation significantly increased in hyperthyroidism and did not change in the hypothyroid state. The fatty acid composition of the major phospholipid classes was affected by thyroid hormones, leading to a significant decrease in total fatty acid unsaturation both in hypothyroid and hyperthyroid muscle in phosphatidylcholine and phosphatidylethanolamine fractions. In cardiolipin, however, the double bond content significantly increased as a function of thyroid status, leading to a 2.7 fold increase in the peroxidizability index from euthyroid to hyperthyroid muscle. Cardiolipin content was also directly and significantly related to thyroid state across the three groups. Glutathione system was not modified by thyroid state. The oxidative damage marker 8-oxo-7,8-dihydro-2'-deoxyguanosine did not change in mitochondrial DNA, and decreased in genomic DNA both in hypothyroid and hyperthyroid muscle. The results indicate that chronic alterations in thyroid status specially affect oxidative damage to lipids in skeletal muscle, with a probably stronger effect on mitochondrial membranes, whereas the cytosolic redox potential and DNA are better protected possibly due to homeostatic compensatory reactions on the long-term.
Mol Cell Biochem 2001 May
PMID:Influence of hyper- and hypothyroidism on lipid peroxidation, unsaturation of phospholipids, glutathione system and oxidative damage to nuclear and mitochondrial DNA in mice skeletal muscle. 1150 85

The thyrotropin (TSH) receptor plays a preeminent role in thyroid physiology and disease. TSH, acting through the TSH receptor, is the major stimulator of thyroid cell growth, differentiation and function. In Graves' disease, the TSH receptor is the target of stimulating antibodies that cause hyperthyroidism. Although still a topic of debate, the TSH receptor has been implicated in the pathogenesis of the endocrine ophthalmopathy associated with Graves' disease. Blocking antibodies against the TSH receptor are involved in the development of hypothyroidism in a subset of patients with autoimmune hypothyroidism. Transplacental passage of stimulating or blocking TSH receptor antibodies from a mother with autoimmune thyroid disease may result in transient hyper- or hypothyroidism in early infancy. During pregnancy, the placental hormone human choriogonadotropin (hCG) can cause gestational hyperthyroidism through cross-reaction with the TSH receptor. Gestational hyperthyroidism may also be involved in the pathogenesis of hyperemesis gravidarum. Trophoblast tumors secreting hCG are a rare cause of hyperthyroidism. Somatic activating mutations of the TSH receptor have been identified as a molecular cause of toxic adenomas, whereas activating mutations in the germline give rise to nonautoimmune familial hyperthyroidism or sporadic congenital hyperthyroidism. These gain-of-function mutations are dominant, and one mutated allele is sufficient to result in disease. Inactivating germline mutations of both TSH receptor alleles lead to variable degrees of resistance to TSH, encompassing a spectrum ranging from euthyroid hyperthyrotropinemia to overt hypothyroidism with thyroid hypoplasia.
Cell Mol Life Sci 2001 Aug
PMID:The TSH receptor and its role in thyroid disease. 1157 86

The antithyroid drug, methimazole (MMI) is used to treat patients with Graves' hyperthyroidism. The major action of MMI is to inhibit synthesis of thyroid hormone in the thyroid gland. However, MMI also has antioxidant and immunomodulatory effects on thyrocytes and/or immune cells. This study identifies novel antioxidant and immunomodulatory effects of MMI involving the interferon-gamma (IFN-gamma) signaling pathway in thyroid cells. MMI inhibits transcription of the intercellular adhesion molecule-1 (ICAM-1) gene by modulating the function of transcription factor STAT1 (signal transducer and activator of transcription 1), which binds to the IFN-gamma activated site of the ICAM-1 promoter. Furthermore, MMI rapidly eliminates H(2)O(2) produced by IFN-gamma treatment in thyroid cells and thus inhibits the H(2)O(2)-mediated phosphorylation of tyrosine 701 in STAT1. MMI also eliminates H(2)O(2) in vitro. MMI facilitates electron transfer from NADPH to H(2)O(2) using thioredoxin or glutathione, fulfilling a role similar to peroxiredoxin or glutathione peroxidase, respectively. MMI prevents the IFN-gamma and H(2)O(2)-mediated reversible inactivation of phosphatases. These effects inhibit full activation of the IFN-gamma-induced Janus kinase(JAK)/STAT signaling pathway in FRTL-5 thyroid cells. These results may in part explain the antioxidant and immunomodulatory effects of MMI in thyroid cells of Graves' disease patients.
Mol Pharmacol 2001 Nov
PMID:Methimazole as an antioxidant and immunomodulator in thyroid cells: mechanisms involving interferon-gamma signaling and H(2)O(2) scavenging. 1164 25

Thyroid hormone governs a diverse repertoire of physiological functions through receptors encoded in the receptor genes alpha and beta, which each generate variant proteins. In mammals, the alpha gene generates, in addition to the normal receptor TRalpha1, a non-hormone-binding variant TRalpha2 whose exact function is unclear. Here, we present the phenotype associated with the targeted ablation of TRalpha2 expression. Selective ablation of TRalpha2 resulted in an inevitable, concomitant overexpression of TRalpha1. Both TRalpha2 +/- and -/- mice show a complex phenotype with low levels of free T3 and free T4, and have inappropriately normal levels of TSH. The thyroid glands exhibit mild morphological signs of dysfunction and respond poorly to TSH, suggesting that the genetic changes affect the ability of the gland to release thyroid hormones. However, the phenotype of the mutant mice also has features of hyperthyroidism, including decreased body weight, elevated heart rate, and a raised body temperature. Furthermore, TRalpha2-/- and TRalpha2+/- mice are obese and exhibit skeletal alterations, associated with a late-onset growth retardation. The results thus suggest that the overexpression of TRalpha1 and the concomitant decrease in TRalpha2 expression lead to a mixed hyper- and hypothyroid phenotype, dependent on the tissue studied. The phenotypes suggest that the balance of TRalpha1:TRalpha2 expressed from the TRalpha gene provides an additional level of tuning the control of growth and homeostasis in mammalian species.
Mol Endocrinol 2001 Dec
PMID:Ablation of TRalpha2 and a concomitant overexpression of alpha1 yields a mixed hypo- and hyperthyroid phenotype in mice. 1173 13

A large number of mutations have been identified in the thyrotropin (TSH) receptor (TSHR) gene causing human diseases. Toxic thyroid nodules are frequently associated with somatic constitutively activating TSHR mutations. Autosomal dominant non-autoimmune hyperthyroidism is caused by activating TSHR germline mutations. Inactivating germline mutations cause TSH unresponsiveness. Discovery of the different TSHR mutations in various regions of the receptor molecule has led to the identification of important domains for intramolecular TSHR signal transduction. However, despite the functional characterization of the naturally occurring mutations the precise molecular mechanisms of receptor activation including the processes of hormone binding, intramolecular signaling between the different TSHR domains and of G protein coupling are not completely understood. This review discusses the importance of the various receptor domains for TSHR activation identified on the basis of the naturally occurring gain or loss of function mutations and in vitro investigations performed with site-directed mutagenesis, synthetic peptides, or antibodies. Several in vitro studies have provided new insights into structure-function relationships by site-directed mutagenesis in combination with molecular modeling. These in vitro investigations have often been guided by naturally occurring mutations and have provided new insights into intramolecular changes during receptor activation. This has led to progress in understanding the mechanism of TSHR activation.
J Mol Med (Berl) 2001 Dec
PMID:Thyrotropin receptor mutations as a tool to understand thyrotropin receptor action. 1186 14


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