Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The direct relaxant effects of thyroid hormones on mesenteric resistance vessels were investigated using an isometric wire myograph. Both the L- and the D-isomers of thyroxine (T4) and triiodothyronine (T3) were studied. In contrast with the long-term effects of thyroid hormones, both T4 enantiomers proved more potent in inducing vascular relaxation than the two T3 enantiomers. The interaction between thyroid hormones and calcium-induced contractions was studied. T4 concentration dependently inhibited the Ca2+ induced contractions, showing noncompetitive interaction. Furthermore, we investigated whether the endothelium was involved in the relaxant effect to L-T4. The T4 induced relaxation proved impaired by prior incubation with the nitric oxide (NO) inhibitor N-omega-nitro-L-arginine methylester HCl (L-NAME, 0.1 microM), indicating that T4 is able to stimulate the production of endothelium-derived NO. L-T4-induced relaxation was enhanced by prior incubation with indomethacin (10 microM), whereas in endothelium-denuded preparations an unaltered response was found. The present results indicate that L-T4-induced relaxation is established by an indirect effect via the endothelium and by a direct effect on vascular smooth muscle cells, possibly by influencing calcium fluxes. Because vascular relaxation is established at supraphysiologic concentrations (approximately 100 times the basal level) of thyroid hormone, it is concluded that the direct effect of thyroid hormone on mesenteric vascular smooth muscle cells are not relevant for the in vivo situation.
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PMID:The direct effects of thyroid hormones on rat mesenteric resistance arteries. 918 75

TRH has been reported to possess several neurophysiological actions in the brain. To gain insights into the molecular mechanisms underlying these effects, particularly in the cerebellum, we attempted to clone a cDNA that was regulated by TRH using TRH knockout mice and subtractive cDNA analysis. Over 100 clones obtained by subtractive hybridization analysis between the wild-type and TRH-1-cerebellum were analyzed. Four clones among them were identical and cdc2-related kinase (PFTAIRE protein kinase 1 (PFTK1)) cDNA, which was previously reported to be expressed only in the brain and testis. PFTK1 mRNA levels in the euthyroid TRH-1- cerebellum supplemented with thyroid hormone were significantly decreased compared with those in the wild-type. Induction of PFTK1 mRNA by TRH was also observed in a time- and dose-dependent manner in human medulloblastoma-derived HTB-185 cells that expressed TRH receptor subtype I mRNA. In addition, treatment of 8-Br-cGMP significantly increased PFTK1 mRNA levels, and a specific inhibitor of cGMP production, ODQ, completely blocked TRH-induced expression of PFTK1 mRNA. Furthermore, induction of PFrK1 mRNA by TRH was significantly inhibited by a NOS specific inhibitor, L-NAME, but not by a MEK inhibitor, PD98059 or a calcium channel inhibitor, nimodipine. These findings demonstrated, for the first time, a novel pathway between a neuropeptide and a cell cycle related peptide in the brain, and PFTK1 may be a key regulator for TRH action in t he cerebellum through t he NO-cGMP pathway.
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PMID:A novel TRH-PFTAIRE protein kinase 1 pathway in the cerebellum: subtractive hybridization analysis of TRH-deficient mice. 1207 16

We studied the effects of a possible interaction between partial nitric oxide deficiency and thyroid hormone excess on the long-term control of blood pressure (BP) and morphological and renal variables and examined the role of the renin-angiotensin system in the increased BP of this interaction. Eight groups (n=8 each) of male Wistar rats were used: a control group; 3 groups that were treated with thyroxine (50 microg/d), Nw-nitro-L-arginine methyl ester (L-NAME; subpressor dose, 1.5 mg x kg(-1) d(-1)), or thyroxine plus L-NAME; and another 4 similarly treated groups that received losartan (20 mg x kg(-1) x d(-1)) in their drinking fluid. All treatments were maintained for 3 weeks. The time course of tail systolic BP was recorded once a week. At the end of the experimental period, we measured mean arterial pressure in conscious rats and assessed the morphological, metabolic, plasma, and renal variables. Thyroxine produced a mild BP increase from the second week of treatment and an increase in plasma angiotensin II and plasma nitrates/nitrites by the end of the study. Simultaneous administration of thyroxine and a subpressor dose of L-NAME produced a marked BP increase that reached significance from the first week of treatment. Losartan produced normotension in thyroxine-treated rats and attenuated the BP elevation in thyroxine+L-NAME-treated rats. Hyperthyroid rats showed relative renal and ventricular hypertrophy, absence of absolute left ventricular hypertrophy, and proteinuria. These alterations were not changed by losartan. We conclude that an impaired nitric oxide system might have a counterregulatory homeostatic role against the prohypertensive effects of thyroid hormone and that the renin-angiotensin system plays an important role in thyroxine+L-NAME hypertension.
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PMID:Increased pressor sensitivity to chronic nitric oxide deficiency in hyperthyroid rats. 1282 1

The orphan nuclear receptor CAR (NR1I3) has been characterized as a central component in the coordinate response to xenobiotic and endobiotic stress. In this study, we demonstrate that CAR plays a pivotal function in energy homeostasis and establish an unanticipated metabolic role for this nuclear receptor. Wild-type mice treated with the synthetic CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) exhibited decreased serum concentration of the thyroid hormone (TH) thyroxine (T(4)). However, treatment of Car(-/-) mice with TCPOBOP failed to elicit these changes. To examine whether CAR played a role in the regulation of TH levels under physiological conditions, wild-type and Car(-/-) mice were fasted for 24 h, a process known to alter TH metabolism in mammals. As expected, the serum triiodothyronine and T(4) concentrations decreased in wild-type mice. However, triiodothyronine and T(4) levels in fasted Car(-/-) mice remained significantly higher than those in fasted wild-type animals. Concomitant with the changes in serum TH levels, both CAR agonist treatment and fasting induced the expression of CAR target genes (notably, Cyp2b10, Ugt1a1, Sultn, Sult1a1, and Sult2a1) in a receptor-dependent manner. Importantly, the Ugt1a1, Sultn, Sult1a1, and Sult2a1 genes encode enzymes that are capable of metabolizing TH. An attenuated reduction in TH levels during fasting, as observed in Car(-/-) mice, would be predicted to increase weight loss during caloric restriction. Indeed, when Car(-/-) animals were placed on a 40% caloric restriction diet for 12 weeks, Car(-/-) animals lost over twice as much weight as their wild-type littermates. Thus, CAR participates in the molecular mechanisms contributing to homeostatic resistance to weight loss. These data imply that CAR represents a novel therapeutic target to uncouple metabolic rate from food intake and has implications in obesity and its associated disorders.
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PMID:The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. 1500 31

This study was designed to determine if the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA), now in clinical trials for heart failure, alters endothelial function after myocardial infarction (MI). Three weeks after MI, adult Sprague-Dawley rats were randomly assigned to DITPA (375 microg/100 g subcutaneous) or no treatment of 3 weeks. In MI rats, left ventricular (LV) end-diastolic pressure and LV dP/dt decreased (P < 0.05). DITPA did not change MAP (87 +/- 10 versus 90 +/- 7 mm Hg) or LV end-diastolic pressure (23 +/- 3 versus 19 +/- 9 mm Hg) but did lower (P < 0.05) LV dP/dt (4,633 +/- 797 versus 3,650 +/- 1,236 mm Hg/s). In aortic segments from MI rats, DITPA enhanced the acetylcholine dependent vasorelaxation (59 +/- 11% at 10(-4) M, P < 0.05) and isoproterenol induced vasorelaxation (57 +/- 13% at 10(-4) M, P < 0.05). The increases in vasorelaxation were blocked with l-NAME and restored with L-arginine. Treatment with DITPA increased (P < 0.05) eNOS protein content in aortic tissue from sham rats (3.8 +/- 2.8 to 44.5 +/- 7.1 integrated intensity units (II)/microg) and in MI rats (5.3 +/- 3.4 to 28.3 +/- 8.9 II/microg). In endothelial cells, 24 hours' treatment with DITPA (10 microM) increased (P < 0.01) eNOS protein expression from 22.1 +/- 4.8 to 52.7 +/- 16.8 II/microg protein and DITPA (20 microM) increased eNOS to 49.1+/- 15.2 II/microg protein. The thyroid analog DITPA enhances endothelial nitric oxide and beta-adrenergic-mediated vasorelaxation by increasing nitric oxide in the vasculature.
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PMID:Thyroid hormone analog, DITPA, improves endothelial nitric oxide and beta-adrenergic mediated vasorelaxation after myocardial infarction. 1545 53

The detoxification and elimination of potentially toxic foreign and endogenous compounds depends on the concerted action of xenobiotic metabolizing enzymes. Nuclear hormone receptors (NHRs) have emerged as key regulators of the expression of these enzymes and his review focuses on the xenosenor CAR (Constitutive Androstane Receptor, NR1I3). CAR is highly expressed in the liver and the small intestine, two key tissues expressing xenobiotic metabolizing enzymes, and mediates the induction of their expression by the widely used antiepileptic drug, phenobarbital (PB) and the potent synthetic inducer 1, 4-bis-(2-(3, 5, -dichloropyridyloxy)) benzene (TCPOBOP). TCPOBOP is an agonist ligand for CAR. PB induces its nuclear translocation, which results in increased expression of CAR target genes since, unlike the classical, ligand-dependent nuclear receptors, CAR is an apparently constitutive transactivator. This constitutive activity is inhibited by the inverse agonist ligands androstanol and androstenol. The CAR mediated induction of the expression of xenobiotic metabolizing enzymes is generally protective, but can be deleterious if toxic metabolites are produced. CAR also has a protective role in the stress response elicited by hyperbilirubinemia, as well as lithocholic acid induced cholestasis. In addition, recent studies show that CAR activation disrupts thyroid hormone homeostasis. Finally, CAR activation promotes hepatocyte proliferation and blocks apoptosis, and is essential for the tumorigenesis induced by its activators PB and TCPOBOP. The role of CAR in endobiotic and xenobiotics metabolism has clinical implications in disease prevention, drug-drug interactions, and the development of better drug treatments.
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PMID:CAR, the continuously advancing receptor, in drug metabolism and disease. 1610 72

Morphological and functional alterations in Hashimoto's thyroiditis (HT) are predominantly mediated by Th1 cytokines through apoptotic cell death. This ultimate step could be preceded by functional injuries in thyroid hormone synthesis. The action of two Th1 cytokines (IL-1alpha/IFN-gamma) on thyroperoxidase (TPO) and thyroid oxidase (ThOXs) expression was tested in human thyrocytes isolated from normal tissues, Graves' disease (GD) tissues, and autonomous toxic nodules. There was no evidence of cell death. Nitric oxide (NO) release was induced by cytokines but was absent when NG-nitro-L-arginine methyl ester (L-NAME) was coincubated. When thyrotropin (TSH)-incubated normal and GD thyrocytes were treated with IL-1alpha/IFN-gamma, TPO and ThOXs protein and mRNA expression dropped, a decrease partially prevented by L-NAME, suggesting that NO acts as a mediator of Th1 effects. In thyrocytes from autonomous toxic nodules, the high level of TPO and ThOXs protein expression was not influenced by TSH or by cytokines, a finding partially reproduced when normal thyrocytes were treated with increasing concentrations of TSH. In conclusion, incubation of normal or GD thyrocytes with Th1 cytokines induces a significant reduction in TSH-increased expression of both TPO and ThOXs, an effect partially mediated by NO. The thyroid cell function can therefore be severely affected in HT, even when cells remain viable. In autonomous toxic nodules, cells become partially insensitive to exogenous Th1 cytokines.
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PMID:Expression of TPO and ThOXs in human thyrocytes is downregulated by IL-1alpha/IFN-gamma, an effect partially mediated by nitric oxide. 1647 76

In the early 1960s, phenobarbital (PB) was shown to induce hepatic drug metabolism and the induction was implicated in the molecular mechanism of drug tolerance development. Since then, it has become evident that PB not only induces drug metabolism, but also triggers pleiotropic effects on liver function, such as cell growth and communication, proliferation of the endoplasmic reticulum, tumor promotion, glucose metabolism, steroid/thyroid hormone metabolism, and bile acid synthesis. Upon activation by PB and numerous PB-type inducers, the nuclear receptor CAR mediates those pleiotropic actions by regulating various hepatic genes, utilizing multiple regulatory mechanisms.
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PMID:Phenobarbital confers its diverse effects by activating the orphan nuclear receptor car. 1668 49

Disruption of the genes encoding for the transcription coactivators, peroxisome proliferator-activated receptor (PPAR)-interacting protein (PRIP/ASC-2/RAP250/TRBP/NRC) and PPAR-binding protein (PBP/TRAP220/DRIP205/MED1), results in embryonic lethality by affecting placental and multiorgan development. Targeted deletion of coactivator PBP gene in liver parenchymal cells (PBP(LIV-/-)) results in the near abrogation of the induction of PPARalpha and CAR (constitutive androstane receptor)-regulated genes in liver. Here, we show that targeted deletion of coactivator PRIP gene in liver (PRIP(LIV-/-)) does not affect the induction of PPARalpha-regulated pleiotropic responses, including hepatomegaly, hepatic peroxisome proliferation, and induction of mRNAs of genes involved in fatty acid oxidation system, indicating that PRIP is not essential for PPARalpha-mediated transcriptional activity. We also provide additional data to show that liver-specific deletion of PRIP gene does not interfere with the induction of genes regulated by nuclear receptor CAR. Furthermore, disruption of PRIP gene in liver did not alter zoxazolamine-induced paralysis, and acetaminophen-induced hepatotoxicity. Studies with adenovirally driven EGFP-CAR expression in liver demonstrated that, unlike PBP, the absence of PRIP does not prevent phenobarbital-mediated nuclear translocation/retention of the receptor CAR in liver in vivo and cultured hepatocytes in vitro. These results show that PRIP deficiency in liver does not interfere with the function of nuclear receptors PPARalpha and CAR. The dependence of PPARalpha- and CAR-regulated gene transcription on coactivator PBP but not on PRIP attests to the existence of coactivator selectivity in nuclear receptor function.
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PMID:Transcription coactivator PRIP, the peroxisome proliferator-activated receptor (PPAR)-interacting protein, is redundant for the function of nuclear receptors PParalpha and CAR, the constitutive androstane receptor, in mouse liver. 1760 99

Polybrominated diphenyl ethers (PBDEs) are a class of polyhalogenated aromatic compounds commercially used as fire retardants in consumer products. These compounds have been shown to decrease thyroid hormone concentrations in rodents after acute exposures. This study examines the ability of 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) to decrease circulating thyroid hormone concentrations and pairs this with BDE 47-induced effects on genes involved in thyroid hormone homeostasis. Female C57BL/6 mice (9 weeks old) were orally administered 3, 10, or 100 mg/kg/day of BDE 47 for 4 days. Animals were euthanized 24 h after the final dose (day 5) and liver, kidney, and serum were collected for analysis. BDE 47 caused a significant 43% decrease at 100 mg/kg/day in serum total thyroxine (T(4)) concentrations. There was no increase in hepatic T(4)-glucuronidation activity, but significant increases in hepatic Ugt1a1, Ugt1a7, and Ugt2b5 mRNA expression accompany significant decreases in T(4) concentrations at 100 mg/kg/day of BDE 47. Induction of PROD activity occurred at the lowest dose (3 mg/kg/day). Cyp2b10 mRNA expression also increased significantly at 10 and 100 mg/kg/day. These key findings show that BDE activates the nuclear receptor, CAR. Decreases in Mdr1a mRNA expression also occurred at the lowest dose administered (3 mg/kg/day BDE 47). BDE 47 exposure also decreased hepatic transthyretin and monocarboxylate transporter 8 (Mct8) mRNA expression, suggesting that while induction of UGTs may be partly responsible for T(4) decreases, other mechanisms are also involved. No effects were seen in the kidney. We conclude that changes in hepatic UGTs and transporters may be involved in decreases in circulating T(4) following BDE 47 exposure.
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PMID:Possible mechanisms of thyroid hormone disruption in mice by BDE 47, a major polybrominated diphenyl ether congener. 1796 24


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