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[PMID]: 29107601
[Au] Autor:Campbell DEK; Langlois VS
[Ad] Address:Biology Department, Queen's University, Kingston, ON Canada.
[Ti] Title:Expression of sf1 and dax-1 are regulated by thyroid hormones and androgens during Silurana tropicalis early development.
[So] Source:Gen Comp Endocrinol;, 2017 Oct 28.
[Is] ISSN:1095-6840
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Thyroid hormones (THs) and androgens have been shown to be extensively involved in sexual development; however, relatively little is known with regard to TH-related and androgenic actions in sex determination. We first established expression profiles of three sex-determining genes (sf1, dax-1, and sox9) during the embryonic development of Western clawed frogs (Silurana tropicalis). Transcripts of sf1 and sox9 were detected in embryos before the period in which embryonic transcription commences indicating maternal transfer, whereas dax-1 transcripts were not detected until later in development. To examine whether TH status affects sex-determining gene expression in embryonic S. tropicalis, embryos were exposed to co-treatments of iopanoic acid (IOP), thyroxine (T4), or triiodothyronine (T3) for 96 h. Expression profiles of TH receptors and deiodinases reflect inhibition of peripheral deiodinase activity by IOP and recovery by T3. Relevantly, elevated TH levels significantly increased the expression of sf1 and dax-1 in embryonic S. tropicalis. Further supporting TH-mediated regulation, examination of the presence and frequency of transcription factor binding sites in the putative promoter regions of sex-determining genes in S. tropicalis and rodent and fish models using in silico analysis also identified TH motifs in the putative promoter regions of sf1 and dax-1. Together these findings advocate that TH actions as early as the period of embryogenesis may affect gonadal fate in frogs. Mechanisms of TH and androgenic crosstalk in relation to the regulation of steroid-related gene expression were also investigated.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1711
[Cu] Class update date: 171113
[Lr] Last revision date:171113
[St] Status:Publisher

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[PMID]: 28488362
[Au] Autor:Cavallin JE; Ankley GT; Blackwell BR; Blanksma CA; Fay KA; Jensen KM; Kahl MD; Knapen D; Kosian PA; Poole ST; Randolph EC; Schroeder AL; Vergauwen L; Villeneuve DL
[Ad] Address:Badger Technical Services, Mid-Continent Ecology Division, US Environmental Protection Agency, Duluth, Minnesota, USA.
[Ti] Title:Impaired swim bladder inflation in early life stage fathead minnows exposed to a deiodinase inhibitor, iopanoic acid.
[So] Source:Environ Toxicol Chem;36(11):2942-2952, 2017 Nov.
[Is] ISSN:1552-8618
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Inflation of the posterior and/or anterior swim bladder is a process previously demonstrated to be regulated by thyroid hormones. We investigated whether inhibition of deiodinases, which convert thyroxine (T4) to the more biologically active form, 3,5,3'-triiodothyronine (T3), would impact swim bladder inflation. Two experiments were conducted using a model deiodinase inhibitor, iopanoic acid (IOP). First, fathead minnow embryos were exposed to 0.6, 1.9, or 6.0 mg/L or control water until 6 d postfertilization (dpf), at which time posterior swim bladder inflation was assessed. To examine anterior swim bladder inflation, a second study was conducted with 6-dpf larvae exposed to the same IOP concentrations until 21 dpf. Fish from both studies were sampled for T4/T3 measurements and gene transcription analyses. Incidence and length of inflated posterior swim bladders were significantly reduced in the 6.0 mg/L treatment at 6 dpf. Incidence of inflation and length of anterior swim bladder were significantly reduced in all IOP treatments at 14 dpf, but inflation recovered by 18 dpf. Throughout the larval study, whole-body T4 concentrations increased and T3 concentrations decreased in all IOP treatments. Consistent with hypothesized compensatory responses, deiodinase-2 messenger ribonucleic acid (mRNA) was up-regulated in the larval study, and thyroperoxidase mRNA was down-regulated in all IOP treatments in both studies. These results support the hypothesized adverse outcome pathways linking inhibition of deiodinase activity to impaired swim bladder inflation. Environ Toxicol Chem 2017;36:2942-2952. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1705
[Cu] Class update date: 171027
[Lr] Last revision date:171027
[St] Status:In-Process
[do] DOI:10.1002/etc.3855

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[PMID]: 27623928
[Au] Autor:Yang F; Ma H; Belcher J; Butler MR; Redmond TM; Boye SL; Hauswirth WW; Ding XQ
[Ad] Address:Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
[Ti] Title:Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.
[So] Source:FASEB J;30(12):4313-4325, 2016 Dec.
[Is] ISSN:1530-6860
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65 mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.-Yang, F., Ma, H., Belcher, J., Butler, M. R., Redmond, T. M., Boye, S. L., Hauswirth, W. W., Ding, X.-Q. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.
[Mh] MeSH terms primary: Iodide Peroxidase/metabolism
Retina/metabolism
Retinal Degeneration/metabolism
[Mh] MeSH terms secundary: Animals
Cells, Cultured
Mice, Knockout
Retinal Cone Photoreceptor Cells/metabolism
Retinal Degeneration/genetics
Signal Transduction/physiology
Thyroid Hormones/metabolism
Triiodothyronine/metabolism
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Thyroid Hormones); 06LU7C9H1V (Triiodothyronine); EC 1.11.1.8 (Iodide Peroxidase)
[Em] Entry month:1709
[Cu] Class update date: 170921
[Lr] Last revision date:170921
[Js] Journal subset:IM
[Da] Date of entry for processing:160915
[St] Status:MEDLINE

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[PMID]: 27404574
[Au] Autor:Fernández M; Baldassarro VA; Sivilia S; Giardino L; Calzà L
[Ad] Address:Health Science and Technology Interdepartmental Center for Industrial Research, University of Bologna, Bologna, Italy.
[Ti] Title:Inflammation severely alters thyroid hormone signaling in the central nervous system during experimental allergic encephalomyelitis in rat: Direct impact on OPCs differentiation failure.
[So] Source:Glia;64(9):1573-89, 2016 Sep.
[Is] ISSN:1098-1136
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes is severely impaired by inflammatory cytokines and this could lead to remyelination failure in inflammatory/demyelinating diseases. Due to the role of thyroid hormone in the maturation of OPCs and developmental myelination, in this study we investigated (i) the possible occurrence of dysregulation of thyroid hormone signaling in the CNS tissue during experimental neuroinflammation; (ii) the possible impact of inflammatory cytokines on thyroid hormone signaling and OPCs differentiation in vitro. The disease model is the experimental allergic encephalomyelitis in female Dark-Agouti rats, whereas in vitro experiments were carried out in OPCs derived from neural stem cells. The main results are the following: (i) a strong upregulation of cytokine mRNA expression level was found in the spinal cord during experimental allergic encephalomyelitis; (ii) thyroid hormone signaling in the spinal cord (thyroid hormone receptors; deiodinase; thyroid hormone membrane transporter) is substantially downregulated, due to the upregulation of the thyroid hormone inactivating enzyme deiodinase 3 and the downregulation of thyroid hormone receptors, as investigated at mRNA expression level; (iii) when exposed to inflammatory cytokines, deiodinase 3 is upregulated in OPCs as well, and OPCs differentiation is blocked; (iv) deiodinase 3 inhibition by iopanoic acid recovers OPCs differentiation in the presence on inflammatory cytokines. These data suggest that cellular hypothyroidism occurs during experimental allergic encephalomyelitis, possibly impacting on thyroid hormone-dependent cellular processes, including maturation of OPCs into myelinating oligodendrocytes. GLIA 2016;64:1573-1589.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1607
[Cu] Class update date: 160724
[Lr] Last revision date:160724
[Js] Journal subset:IM
[St] Status:In-Process
[do] DOI:10.1002/glia.23025

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Carvalho, Denise P
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[PMID]: 27302464
[Au] Autor:Bocco BM; Louzada RA; Silvestre DH; Santos MC; Anne-Palmer E; Rangel IF; Abdalla S; Ferreira AC; Ribeiro MO; Gereben B; Carvalho DP; Bianco AC; Werneck-de-Castro JP
[Ad] Address:Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL, USA.
[Ti] Title:Thyroid hormone activation by type 2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-γ coactivator-1α expression in skeletal muscle.
[So] Source:J Physiol;594(18):5255-69, 2016 Sep 15.
[Is] ISSN:1469-7793
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:KEY POINTS: In skeletal muscle, physical exercise and thyroid hormone mediate the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a) expression that is crucial to skeletal muscle mitochondrial function. The expression of type 2 deiodinase (D2), which activates thyroid hormone in skeletal muscle is upregulated by acute treadmill exercise through a ß-adrenergic receptor-dependent mechanism. Pharmacological block of D2 or disruption of the Dio2 gene in skeletal muscle fibres impaired acute exercise-induced PGC-1a expression. Dio2 disruption also impaired muscle PGC-1a expression and mitochondrial citrate synthase activity in chronically exercised mice. ABSTRACT: Thyroid hormone promotes expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a), which mediates mitochondrial biogenesis and oxidative capacity in skeletal muscle (SKM). Skeletal myocytes express the type 2 deiodinase (D2), which generates 3,5,3'-triiodothyronine (T3 ), the active thyroid hormone. To test whether D2-generated T3 plays a role in exercise-induced PGC-1a expression, male rats and mice with SKM-specific Dio2 inactivation (SKM-D2KO or MYF5-D2KO) were studied. An acute treadmill exercise session (20 min at 70-75% of maximal aerobic capacity) increased D2 expression/activity (1.5- to 2.7-fold) as well as PGC-1a mRNA levels (1.5- to 5-fold) in rat soleus muscle and white gastrocnemius muscle and in mouse soleus muscle, which was prevented by pretreatment with 1 mg (100 g body weight)(-1) propranolol or 6 mg (100 g body weight)(-1) iopanoic acid (5.9- vs. 2.8-fold; P < 0.05), which blocks D2 activity . In the SKM-D2KO mice, acute treadmill exercise failed to induce PGC-1a fully in soleus muscle (1.9- vs. 2.8-fold; P < 0.05), and in primary SKM-D2KO myocytes there was only a limited PGC-1a response to 1 µm forskolin (2.2- vs. 1.3-fold; P < 0.05). Chronic exercise training (6 weeks) increased soleus muscle PGC-1a mRNA levels (∼25%) and the mitochondrial enzyme citrate synthase (∼20%). In contrast, PGC-1a expression did not change and citrate synthase decreased by ∼30% in SKM-D2KO mice. The soleus muscle PGC-1a response to chronic exercise was also blunted in MYF5-D2KO mice. In conclusion, acute treadmill exercise increases SKM D2 expression through a ß-adrenergic receptor-dependent mechanism. The accelerated conversion of T4 to T3 within myocytes mediates part of the PGC-1a induction by treadmill exercise and its downstream effects on mitochondrial function.
[Mh] MeSH terms primary: Iodide Peroxidase/metabolism
Muscle, Skeletal/metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics
Physical Conditioning, Animal/physiology
Thyroxine/metabolism
Triiodothyronine/metabolism
[Mh] MeSH terms secundary: Animals
Blood Glucose/analysis
Cells, Cultured
Citrate (si)-Synthase/metabolism
Gene Expression
Iodide Peroxidase/genetics
Lactic Acid/blood
Male
Mice, Inbred C57BL
Mice, Knockout
RNA, Messenger/metabolism
Rats, Wistar
Thyroxine/blood
Triiodothyronine/blood
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Blood Glucose); 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha); 0 (Ppargc1a protein, mouse); 0 (RNA, Messenger); 06LU7C9H1V (Triiodothyronine); 33X04XA5AT (Lactic Acid); EC 1.11.1.- (iodothyronine deiodinase type II); EC 1.11.1.8 (Iodide Peroxidase); EC 2.3.3.1 (Citrate (si)-Synthase); Q51BO43MG4 (Thyroxine)
[Em] Entry month:1709
[Cu] Class update date: 170915
[Lr] Last revision date:170915
[Js] Journal subset:IM
[Da] Date of entry for processing:160616
[St] Status:MEDLINE
[do] DOI:10.1113/JP272440

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[PMID]: 26474011
[Au] Autor:Way JS; Shen Y; Martinez DS
[Ad] Address:Department of Medicine, University of California, Los Angeles, Los Angeles, CA jway@mednet.ucla.edu Department of Medicine, University of California, Los Angeles, Los Angeles, CA.
[Ti] Title:Iopanoic Acid to Treat Acute Psychiatric Crisis Associated With Thyrotoxicosis: Three Case Reports and Review of the Literature.
[So] Source:J Clin Psychopharmacol;35(6):743-5, 2015 Dec.
[Is] ISSN:1533-712X
[Cp] Country of publication:United States
[La] Language:eng
[Mh] MeSH terms primary: Iopanoic Acid/pharmacology
Mental Disorders/etiology
Thyrotoxicosis/complications
Thyrotoxicosis/drug therapy
[Mh] MeSH terms secundary: Adult
Female
Humans
Iopanoic Acid/administration & dosage
Male
Young Adult
[Pt] Publication type:CASE REPORTS; LETTER; REVIEW
[Nm] Name of substance:FE9794P71J (Iopanoic Acid)
[Em] Entry month:1608
[Cu] Class update date: 151103
[Lr] Last revision date:151103
[Js] Journal subset:IM
[Da] Date of entry for processing:151017
[St] Status:MEDLINE
[do] DOI:10.1097/JCP.0000000000000418

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[PMID]: 26433919
[Au] Autor:Macaulay LJ; Chen A; Rock KD; Dishaw LV; Dong W; Hinton DE; Stapleton HM
[Ad] Address:Nicholas School of the Environment, Duke University, Durham, NC 27708, USA.
[Ti] Title:Developmental toxicity of the PBDE metabolite 6-OH-BDE-47 in zebrafish and the potential role of thyroid receptor ß.
[So] Source:Aquat Toxicol;168:38-47, 2015 Nov.
[Is] ISSN:1879-1514
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE-47) is both a polybrominated diphenyl ether (PBDE) flame retardant metabolite and a marine natural product. It has been identified both as a neurotoxicant in cell-based studies and as a developmental toxicant in zebrafish. However, hydroxylated PBDE metabolites are also considered thyroid hormone disruptors due to their structural similarity to endogenous thyroid hormones. The purpose of this study was to evaluate the effects of 6-OH-BDE-47 on a developmental pathway regulated by thyroid hormones in zebrafish. Morphological measurements of development (head trunk angle, otic vesicle length, and eye pigmentation) were recorded in embryos at 30h post fertilization (hpf) and detailed craniofacial morphology was examined in 4 day old larvae using cartilage staining. Exposure to 6-OH-BDE-47 resulted in severe developmental delays. A 100nM concentration resulted in a 26% decrease in head trunk angle, a 54% increase in otic vesicle length, and a 42% decrease in eye pigmentation. Similarly, altered developmental morphology was observed following thyroid receptor ß morpholino knockdown, exposure to the thyroid hormone triiodothyronine (T3) or to thyroid disrupting chemicals (TDC; iopanoic acid and propylthiouracil). The threshold for lower jaw deformities and craniofacial cartilage malformations was at doses greater than 50nM. Of interest, these developmental delays and effects were rescued by microinjection of TRß mRNA during the 1-2 cell stage. These data indicate that OH-BDEs can adversely affect early life development of zebrafish and suggest they may be impacting thyroid hormone regulation in vivo through downregulation of the thyroid hormone receptor.
[Mh] MeSH terms primary: Embryo, Nonmammalian/drug effects
Polybrominated Biphenyls/toxicity
Thyroid Hormone Receptors beta/metabolism
Zebrafish/physiology
[Mh] MeSH terms secundary: Animals
Thyroid Gland/drug effects
Thyroid Hormones/metabolism
Triiodothyronine/metabolism
Water Pollutants, Chemical/toxicity
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Name of substance:0 (6-OH-BDE-47); 0 (Polybrominated Biphenyls); 0 (Thyroid Hormone Receptors beta); 0 (Thyroid Hormones); 0 (Water Pollutants, Chemical); 06LU7C9H1V (Triiodothyronine)
[Em] Entry month:1603
[Cu] Class update date: 170220
[Lr] Last revision date:170220
[Js] Journal subset:IM
[Da] Date of entry for processing:151005
[St] Status:MEDLINE

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[PMID]: 26329282
[Au] Autor:Nguyen TT; Østergaard J; Gammelgaard B
[Ad] Address:Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
[Ti] Title:A method for studies on interactions between a gold-based drug and plasma proteins based on capillary electrophoresis with inductively coupled plasma mass spectrometry detection.
[So] Source:Anal Bioanal Chem;407(28):8497-503, 2015 Nov.
[Is] ISSN:1618-2650
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:An analytical method based on capillary electrophoresis (CE) and inductively coupled plasma mass spectrometry (ICP-MS) detection was developed for studies on the interaction of gold-containing drugs and plasma proteins using auranofin as example. A detection limit of 18 ng/mL of auranofin corresponding to 5.2 ng/mL Au and a precision of 1.5 % were obtained. Kinetic studies of the interaction between auranofin and protein were performed by incubation in aqueous solutions as well as 20 % human plasma at 37 °C. The reaction of auranofin with human serum albumin (HSA) and plasma proceeded fast; 50 % of un-bound auranofin disappeared within 2 and 3 min, respectively. By blocking the free cysteine (Cys-34) by iodoacetamide on HSA, it was shown that Cys-34 was the main reaction site for auranofin. By selective labeling of HSA present in 20 % human plasma with iophenoxate, it was demonstrated that HSA was the major auranofin-interacting protein in plasma. The CE-ICP-MS method is proposed as a novel approach for kinetic studies of the interactions between gold-based drugs and plasma proteins. Graphical Abstract Development of a CE-ICP-MS based method allows for studies on interaction of the gold containing drug auranofin with plasma proteins.
[Mh] MeSH terms primary: Antirheumatic Agents/blood
Auranofin/blood
Electrophoresis, Capillary/methods
Gold/chemistry
Serum Albumin/chemistry
Spectrophotometry, Atomic/methods
[Mh] MeSH terms secundary: Antirheumatic Agents/chemistry
Auranofin/chemistry
Cysteine/chemistry
Humans
Iodoacetamide/chemistry
Iopanoic Acid/chemistry
Kinetics
Limit of Detection
Serum Albumin/antagonists & inhibitors
Serum Albumin/metabolism
Staining and Labeling/methods
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Antirheumatic Agents); 0 (Serum Albumin); 3H04W2810V (Auranofin); 73TJC7JGUY (iophenoxic acid); 7440-57-5 (Gold); FE9794P71J (Iopanoic Acid); K848JZ4886 (Cysteine); ZRH8M27S79 (Iodoacetamide)
[Em] Entry month:1608
[Cu] Class update date: 151106
[Lr] Last revision date:151106
[Js] Journal subset:IM
[Da] Date of entry for processing:150903
[St] Status:MEDLINE
[do] DOI:10.1007/s00216-015-8997-3

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[PMID]: 26284425
[Au] Autor:Aoki T; Tsunekawa K; Araki O; Ogiwara T; Nara M; Sumino H; Kimura T; Murakami M
[Ad] Address:Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
[Ti] Title:Type 2 Iodothyronine Deiodinase Activity Is Required for Rapid Stimulation of PI3K by Thyroxine in Human Umbilical Vein Endothelial Cells.
[So] Source:Endocrinology;156(11):4312-24, 2015 Nov.
[Is] ISSN:1945-7170
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Thyroid hormones (THs) exert a number of physiological effects on the cardiovascular system. Some of the nongenomic actions of T3 are achieved by cross coupling the TH receptor (TR) with the phosphatidylinositol 3-kinase (PI3K)/protein kinase Akt (Akt) pathway. We observed that both T3 and T4 rapidly stimulated Akt phosphorylation and Ras-related C3 botulinum toxin substrate 1 (Rac1) activation, which resulted in cell migration, in a PI3K-dependent manner in human umbilical vein endothelial cells (HUVECs). We identified the expression of type 2 iodothyronine deiodinase (D2), which converts T4 to T3, and TRα1 in HUVECs. D2 activity was significantly stimulated by (Bu)2cAMP in HUVECs. The blockade of D2 activity through transfection of small interfering RNA (siRNA) specific to D2 as well as by addition of iopanoic acid, a potent D2 inhibitor, abolished Akt phosphorylation, Rac activation, and cell migration induced by T4 but not by T3. The inhibition of TRα1 expression by the transfection of siRNA for TRα1 canceled Akt phosphorylation, Rac activation, and cell migration induced by T3 and T4. These findings suggest that conversion of T4 to T3 by D2 is required for TRα1/PI3K-mediated nongenomic actions of T4 in HUVECs, including stimulation of Akt phosphorylation and Rac activation, which result in cell migration.
[Mh] MeSH terms primary: Human Umbilical Vein Endothelial Cells/metabolism
Iodide Peroxidase/metabolism
Phosphatidylinositol 3-Kinases/metabolism
Thyroxine/pharmacology
[Mh] MeSH terms secundary: Cell Movement/drug effects
Cells, Cultured
Human Umbilical Vein Endothelial Cells/drug effects
Humans
Phosphorylation/drug effects
Proto-Oncogene Proteins c-akt/metabolism
RNA, Small Interfering
Signal Transduction/drug effects
Thyroid Hormone Receptors alpha/genetics
Thyroid Hormone Receptors alpha/metabolism
Triiodothyronine/pharmacology
rac1 GTP-Binding Protein/metabolism
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (RNA, Small Interfering); 0 (Thyroid Hormone Receptors alpha); 06LU7C9H1V (Triiodothyronine); EC 1.11.1.- (iodothyronine deiodinase type II); EC 1.11.1.8 (Iodide Peroxidase); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.6.5.2 (rac1 GTP-Binding Protein); Q51BO43MG4 (Thyroxine)
[Em] Entry month:1602
[Cu] Class update date: 151021
[Lr] Last revision date:151021
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:150819
[St] Status:MEDLINE
[do] DOI:10.1210/en.2014-1988

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[PMID]: 25962824
[Au] Autor:Renko K; Schäche S; Hoefig CS; Welsink T; Schwiebert C; Braun D; Becker NP; Köhrle J; Schomburg L
[Ad] Address:1 Institut für Experimentelle Endokrinologie, Charité - Universitätsmedizin Berlin , Berlin, Germany .
[Ti] Title:An Improved Nonradioactive Screening Method Identifies Genistein and Xanthohumol as Potent Inhibitors of Iodothyronine Deiodinases.
[So] Source:Thyroid;25(8):962-8, 2015 Aug.
[Is] ISSN:1557-9077
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: Deiodinases (DIO1, 2, and 3) are key enzymes in thyroid hormone (TH) activation and inactivation with impact on energy metabolism, development, cell differentiation, and a number of other physiological processes. The three DIO isoenzymes thus constitute sensitive rate-limiting components within the TH axis, prone to dysregulation by endocrine disruptive compounds or disease state. In animal models and cell culture experiments, they serve as readout for local TH status and disarrangement of the hormonal axis. Furthermore, some human diseases are characterized by apparent deiodinase dysregulation (e.g., the low triiodothyronine syndrome in critical illness). Consequently, these enzymes are targets of interest for the development of pharmacological compounds with modulatory activities. Until now, the portfolio of inhibitors for these enzymes is limited. In the clinics, the DIO1-specific inhibitor propylthiouracil is in use for treatment of severe hyperthyroidism. Other well-known inhibitors (e.g., iopanoic acid or aurothioglucose) are nonselective and block all three isoenzymes. Furthermore, DIO3 was shown to be a potential oncogenic gene, which is strongly expressed in some tumors and might, in consequence, protect tumor tissue form differentiation by TH. With respect to its role in tumorigenesis, specific inhibitors of DIO3 as a potential target for anticancer drugs would be highly desirable. To this end, a flexible and convenient assay for high-throughput screening is needed. We recently described a nonradioactive screening assay, utilizing the classic Sandell-Kolthoff reaction as readout for iodide release from the substrate molecules. While we used murine liver as enzyme source, the assay was limited to murine DIO1 activity testing. Here, we describe the use of recombinant proteins as enzyme sources within the assay, expanding its suitability from murine Dio1 to human DIO1, DIO2, and DIO3. METHODS: As proof-of-concept, deiodination reactions catalyzed by these recombinant enzymes were monitored with various nonradioactive substrates and confirmed by liquid chromatography-tandem mass spectrometry. RESULTS: The contrast agent and known DIO inhibitor iopanoic acid was characterized as readily accepted substrate by DIO2 and Dio3. In a screening approach using established endocrine disrupting compounds, the natural food ingredient genistein was identified as a further DIO1-specific inhibitor, while xanthohumol turned out to potently block the activity of all three isoenzymes. CONCLUSIONS: A rapid nonradioactive screening method based on the Sandell-Kolthoff reaction is suitable for identification of environmental, nutritive and pharmacological compounds modulating activities of human deiodinase enzymes.
[Mh] MeSH terms primary: Flavonoids/therapeutic use
Genistein/therapeutic use
Iodide Peroxidase/antagonists & inhibitors
Propiophenones/therapeutic use
[Mh] MeSH terms secundary: Animals
Catalysis
Cell Differentiation
Chromatography, Liquid
DNA-Binding Proteins/chemistry
Drug Evaluation, Preclinical
Enzymes/chemistry
HEK293 Cells
Humans
Inhibitory Concentration 50
Iodide Peroxidase/chemistry
Iopanoic Acid/chemistry
Isoenzymes/chemistry
Mass Spectrometry
Mice
Open Reading Frames
Recombinant Proteins/chemistry
Thyroid Hormones/chemistry
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (DIDO1 protein, human); 0 (DNA-Binding Proteins); 0 (Enzymes); 0 (Flavonoids); 0 (Isoenzymes); 0 (Propiophenones); 0 (Recombinant Proteins); 0 (Thyroid Hormones); DH2M523P0H (Genistein); EC 1.11.1.- (iodothyronine deiodinase type II); EC 1.11.1.- (iodothyronine deiodinase type III); EC 1.11.1.8 (Iodide Peroxidase); EC 1.11.1.8 (selenodeiodinase type 1, mouse); FE9794P71J (Iopanoic Acid); T4467YT1NT (xanthohumol)
[Em] Entry month:1606
[Cu] Class update date: 150806
[Lr] Last revision date:150806
[Js] Journal subset:IM
[Da] Date of entry for processing:150513
[St] Status:MEDLINE
[do] DOI:10.1089/thy.2015.0058


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