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1.
Biomed Res Int ; 2021: 6681491, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34195279

RESUMO

Background: Although hypothyroidism during pregnancy may develop grave outcomes for both mothers and offspring, management of which is still a challenge due to the insufficient understanding of this disease. The close correlation between hypothyroidism and preeclampsia is well documented, suggesting that preeclampsia is a potential risk factor for the development of maternal hypothyroidism. However, the exact role of preeclampsia in gestational hypothyroidism is still obscure. Objective: In this study, we explored the possible mechanisms of the effect of preeclampsia on thyroid function of maternal rats. Methods: Thirty pregnant rats were randomly divided into normal pregnancy control (NOP), preeclampsia (PE), and preeclampsia supplemented with amlodipine besylate (PEAml). NG-Nitro-L-arginine-methyl ester was used to induce preeclamptic symptoms. On gestational day 21, rats were sacrificed, and then, the ultrastructure of the thyroid gland, type 1 iodothyronine deiodinase (Dio1) expression, and serum-free thyroxine (FT4), free triiodothyronine (FT3), and thyroid stimulation hormones (TSH) were assessed. Results: Compared to NOP rats, results of PE rats showed that thyroid follicular cells' ultrastructure was damaged; both hepatic Dio1 mRNA and protein levels were decreased. Interestingly, these changes were ameliorated in PEAml rats. Additionally, FT4, FT3, and TSH levels have no significant differences among groups. Conclusion: These findings indicated that preeclampsia could disrupt synthesis, secretion, and metabolism function of thyroid hormones by damaging thyroid follicular cells and interfering Dio1 expression.


Assuntos
Hipotireoidismo/metabolismo , Iodeto Peroxidase/metabolismo , Fígado/enzimologia , Pré-Eclâmpsia/metabolismo , Glândula Tireoide/ultraestrutura , Hormônios Tireóideos/sangue , Animais , Feminino , Hipotireoidismo/complicações , NG-Nitroarginina Metil Éster/metabolismo , Gravidez , Prenhez , Ratos , Ratos Sprague-Dawley , Fatores de Risco , Tireotropina/sangue , Tiroxina/sangue , Fatores de Tempo , Tri-Iodotironina/sangue
2.
Nat Commun ; 12(1): 4446, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290257

RESUMO

The type 2 deiodinase (D2) in the neonatal liver accelerates local thyroid hormone triiodothyronine (T3) production and expression of T3-responsive genes. Here we show that this surge in T3 permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increases H3K9me3 levels during post-natal days 1-5 (P1-P5), and results in methylation of 1,508 DNA sites (H-sites) in the adult mouse liver. These sites are associated with 1,551 areas of reduced chromatin accessibility (RCA) within core promoters and 2,426 within intergenic regions, with reduction in the expression of 1,363 genes. There is strong spatial correlation between density of H-sites and RCA sites. Chromosome conformation capture (Hi-C) data reveals a set of 81 repressed genes with a promoter RCA in contact with an intergenic RCA ~300 Kbp apart, within the same topologically associating domain (χ2 = 777; p < 0.00001). These data explain how the systemic hormone T3 acts locally during development to define future expression of hepatic genes.


Assuntos
Epigênese Genética , Fígado/metabolismo , Tri-Iodotironina/metabolismo , Animais , Animais Recém-Nascidos , Cromatina/metabolismo , Metilação de DNA , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Fígado/crescimento & desenvolvimento , Camundongos , Camundongos Knockout
3.
Genes (Basel) ; 12(5)2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062726

RESUMO

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that afflicts multiple organs, especially kidneys and joints. In addition to genetic predisposition, it is now evident that DNA methylation and microRNAs (miRNAs), the two major epigenetic modifications, are critically involved in the pathogenesis of SLE. DNA methylation regulates promoter accessibility and gene expression at the transcriptional level by adding a methyl group to 5' cytosine within a CpG dinucleotide. Extensive evidence now supports the importance of DNA hypomethylation in SLE etiology. miRNAs are small, non-protein coding RNAs that play a critical role in the regulation of genome expression. Various studies have identified the signature lupus-related miRNAs and their functional contribution to lupus incidence and progression. In this review, the mutual interaction between DNA methylation and miRNAs regulation in SLE is discussed. Some lupus-associated miRNAs regulate DNA methylation status by targeting the DNA methylation enzymes or methylation pathway-related proteins. On the other hand, DNA hyper- and hypo-methylation are linked with dysregulated miRNAs expression in lupus. Further, we specifically discuss the genetic imprinting Dlk1-Dio3 miRNAs that are subjected to DNA methylation regulation and are dysregulated in several autoimmune diseases, including SLE.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Epigênese Genética , Impressão Genômica , Iodeto Peroxidase/genética , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana/genética , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Metilação de DNA , Humanos , Iodeto Peroxidase/metabolismo , Proteínas de Membrana/metabolismo , MicroRNAs/genética
4.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065957

RESUMO

The presented research concerns the triple activity of trans-cinnamic (tCA), ferulic (FA) and syringic acids (SA). They act as thyroid peroxidase (TPO) activators, lipoxygenase (LOX) inhibitors and show antiradical activity. All compounds showed a dose-dependent TPO activatory effect, thus the AC50 value (the concentration resulting in 50% activation) was determined. The tested compounds can be ranked as follows: tCA > FA > SA with AC50 = 0.10, 0.39, 0.69 mM, respectively. Strong synergism was found between FA and SA. The activatory effects of all tested compounds may result from interaction with the TPO allosteric site. It was proposed that conformational change resulting from activator binding to TPO allosteric pocket results from the flexibility of a nearby loop formed by residues Val352-Tyr363. All compounds act as uncompetitive LOX inhibitors. The most effective were tCA and SA, whereas the weakest was FA (IC50 = 0.009 mM and IC50 0.027 mM, respectively). In all cases, an interaction between the inhibitors carboxylic groups and side-chain atoms of Arg102 and Arg139 in an allosteric pocket of LOX was suggested. FA/tCA and FA/SA acted synergistically, whereas tCA/SA demonstrated antagonism. The highest antiradical activity was found in the case of SA (IC50 = 0.22 mM). FA/tCA and tCA/SA acted synergistically, whereas antagonism was found for the SA/FA mixture.


Assuntos
Autoantígenos/metabolismo , Ativadores de Enzimas/farmacologia , Iodeto Peroxidase/metabolismo , Proteínas de Ligação ao Ferro/metabolismo , Inibidores de Lipoxigenase/farmacologia , Compostos Fitoquímicos/farmacologia , Proteína-Lisina 6-Oxidase/metabolismo , Autoantígenos/química , Cinamatos/química , Cinamatos/farmacologia , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Relação Dose-Resposta a Droga , Ativadores de Enzimas/química , Ácido Gálico/análogos & derivados , Ácido Gálico/química , Ácido Gálico/farmacologia , Humanos , Concentração Inibidora 50 , Iodeto Peroxidase/química , Proteínas de Ligação ao Ferro/química , Inibidores de Lipoxigenase/química , Modelos Moleculares , Compostos Fitoquímicos/química , Proteína-Lisina 6-Oxidase/química , Relação Estrutura-Atividade
5.
Endocrinology ; 162(8)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33963379

RESUMO

Thyroid hormones exert pleiotropic, essential actions in mammalian, including human, development. These actions depend on provision of thyroid hormones in the circulation but also to a remarkable extent on deiodinase enzymes in target tissues that amplify or deplete the local concentration of the primary active form of the hormone T3 (3,5,3'-triiodothyronine), the high affinity ligand for thyroid hormone receptors. Genetic analyses in mice have revealed key roles for activating (DIO2) and inactivating (DIO3) deiodinases in cell differentiation fates and tissue maturation, ultimately promoting neonatal viability, growth, fertility, brain development, and behavior, as well as metabolic, endocrine, and sensory functions. An emerging paradigm is how the opposing activities of DIO2 and DIO3 are coordinated, providing a dynamic switch that controls the developmental timing of a tissue response, often during neonatal and maturational transitions. A second paradigm is how cell to cell communication within a tissue determines the response to T3. Deiodinases in specific cell types, often strategically located near to blood vessels that convey thyroid hormones into the tissue, can regulate neighboring cell types, suggesting a paracrine-like layer of control of T3 action. We discuss deiodinases as switches for developmental transitions and their potential to influence tissue dysfunction in human thyroid disorders.


Assuntos
Envelhecimento/metabolismo , Iodeto Peroxidase/metabolismo , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Desenvolvimento Humano , Humanos
6.
Front Endocrinol (Lausanne) ; 12: 587518, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981284

RESUMO

Thyroxine and triiodothyronine (T3) are classical thyroid hormones and with relatively well-understood actions. In contrast, the physiological role of thyroid hormone metabolites, also circulating in the blood, is less well characterized. These molecules, namely, reverse triiodothyronine, 3,5-diiodothyronine, 3-iodothyronamine, tetraiodoacetic acid and triiodoacetic acid, mediate both agonistic (thyromimetic) and antagonistic actions additional to the effects of the classical thyroid hormones. Here, we provide an overview of the main factors influencing thyroid hormone action, and then go on to describe the main effects of the metabolites and their potential use in medicine. One section addresses thyroid hormone levels in corona virus disease 19 (COVID-19). It appears that i) the more potently-acting molecules T3 and triiodoacetic acid have shorter half-lives than the less potent antagonists 3-iodothyronamine and tetraiodoacetic acid; ii) reverse T3 and 3,5-diiodothyronine may serve as indicators for metabolic dysregulation and disease, and iii) Nanotetrac may be a promising candidate for treating cancer, and resmetirom and VK2809 for steatohepatitis. Further, the use of L-T3 in the treatment of severely ill COVID-19 patients is critically discussed.


Assuntos
COVID-19/epidemiologia , SARS-CoV-2 , Doenças da Glândula Tireoide/epidemiologia , Doenças da Glândula Tireoide/metabolismo , Hormônios Tireóideos/fisiologia , COVID-19/sangue , Comorbidade , Di-Iodotironinas/fisiologia , Humanos , Iodeto Peroxidase/metabolismo , SARS-CoV-2/fisiologia , Doenças da Glândula Tireoide/virologia , Hormônios Tireóideos/sangue , Hormônios Tireóideos/uso terapêutico , Tiroxina/fisiologia , Tri-Iodotironina/fisiologia , Tri-Iodotironina Reversa/fisiologia
7.
Exp Biol Med (Maywood) ; 246(14): 1597-1606, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33882700

RESUMO

This study aimed to track and evaluate the effect of low-dose irisin on the browning of white adipose tissue (WAT) in mice using magnetic resonance imaging (MRI) noninvasively in vivo. Mature white adipocytes extracted from mice were cultured, induced and characterized before being treated by irisin. The volume and fat fraction of WAT were quantified using MRI in normal chow diet and high fat mice after injection of irisin. The browning of cultured white adipocytes and WAT in mice were validated by immunohistochemistry and western blotting for uncoupling protein 1 (UCP1) and deiodinase type II (DIO2). The serum indexes were examined with high fat diet after irisin intervention. UCP1 and DIO2 in adipocytes showed increases responding to the irisin treatment. The size of white adipocytes in mice receiving irisin intervention was reduced. MRI measured volumes and fat fraction of WAT were significantly lower after Irisin treatment. Blood glucose and cholesterol levels were reduced in high fat diet mice after irisin treatment. Irisin intervention exerted browning of WAT, resulting reduction of volume and fat fraction of WAT as measured by MRI. Furthermore, it improved the condition of mice with diet-induced obesity and related metabolic disorders.


Assuntos
Adipócitos/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Fibronectinas/farmacologia , Adipócitos/metabolismo , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Branco/diagnóstico por imagem , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Fibronectinas/metabolismo , Iodeto Peroxidase/metabolismo , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Desacopladora 1/metabolismo
8.
Development ; 148(8)2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33757992

RESUMO

The thyroid hormone T3 and its nuclear receptor TRα1 control gut development and homeostasis through the modulation of intestinal crypt cell proliferation. Despite increasing data, in-depth analysis on their specific action on intestinal stem cells is lacking. By using ex vivo 3D organoid cultures and molecular approaches, we observed early responses to T3 involving the T3-metabolizing enzyme Dio1 and the transporter Mct10, accompanied by a complex response of stem cell- and progenitor-enriched genes. Interestingly, specific TRα1 loss-of-function (inducible or constitutive) was responsible for low ex vivo organoid development and impaired stem cell activity. T3 treatment of animals in vivo not only confirmed the positive action of this hormone on crypt cell proliferation but also demonstrated its key action in modulating the number of stem cells, the expression of their specific markers and the commitment of progenitors into lineage-specific differentiation. In conclusion, T3 treatment or TRα1 modulation has a rapid and strong effect on intestinal stem cells, broadening our perspectives in the study of T3/TRα1-dependent signaling in these cells.


Assuntos
Proliferação de Células , Intestinos , Transdução de Sinais , Células-Tronco/metabolismo , Receptores alfa dos Hormônios Tireóideos/metabolismo , Tri-Iodotironina/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Feminino , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Células-Tronco/citologia , Receptores alfa dos Hormônios Tireóideos/genética , Tri-Iodotironina/genética
9.
Endocrinology ; 162(8)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33720335

RESUMO

Deiodinases modify the biological activity of thyroid hormone (TH) molecules, ie, they may activate thyroxine (T4) to 3,5,3'-triiodothyronine (T3), or they may inactivate T3 to 3,3'-diiodo-L-thyronine (T2) or T4 to reverse triiodothyronine (rT3). Although evidence of deiodination of T4 to T3 has been available since the 1950s, objective evidence of TH metabolism was not established until the 1970s. The modern paradigm considers that the deiodinases not only play a role in the homeostasis of circulating T3, but they also provide dynamic control of TH signaling: cells that express the activating type 2 deiodinase (D2) have enhanced TH signaling due to intracellular build-up of T3; the opposite is seen in cells that express type 3 deiodinase (D3), the inactivating deiodinase. D2 and D3 are expressed in metabolically relevant tissues such as brown adipose tissue, skeletal muscle and liver, and their roles have been investigated using cell, animal, and human models. During development, D2 and D3 expression customize for each tissue/organ the timing and intensity of TH signaling. In adult cells, D2 is induced by cyclic adenosine monophosphate (cAMP), and its expression is invariably associated with enhanced T3 signaling, expression of PGC1 and accelerated energy expenditure. In contrast, D3 expression is induced by hypoxia-inducible factor 1α (HIF-1a), dampening T3 signaling and the metabolic rate. The coordinated expression of these enzymes adjusts TH signaling in a time- and tissue-specific fashion, affecting metabolic pathways in health and disease states.


Assuntos
Iodeto Peroxidase/metabolismo , Hormônios Tireóideos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Jejum/metabolismo , Humanos
10.
Endocrine ; 74(1): 100-107, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33761105

RESUMO

PURPOSE: The deiodinases activate or inactivate the thyroid hormones (TH) in virtually all tissues in both physiological and pathological conditions. The three deiodinases, DIO1, DIO2, and DIO3, have different catalytic functions and regulate TH tissue distribution. The aim of the present study was to evaluate the modulation of gene expression of the deiodinases and TH transporters and protein levels of DIO1 in parietal and frontal areas of cerebral cortex of spontaneously hypertensive rats (SHRs), after two successive mandibular extensions (ME). METHODS: ME was performed on anesthetized rats by a dilatator appropriately designed and real-time PCR and western blotting techniques were employed for gene expression and protein level study. RESULTS: Mean blood pressure (MBP) significantly decreased in 2ME-treated rats when compared to sham-operated rats (p < 0.001) and this decrease lasted for the entire observation period. In gene expression analysis, in 2ME-treated rats we did not observe any significant variation of DIO1 and DIO3 with respect to the sham-operated rats. Differently, DIO2 gene expression significantly increased in frontal area of 2ME-treated rats, with respect to sham-operated rats (p < 0.01). Furthermore, in parietal area, protein levels of DIO1 in 2ME-treated rats were significantly higher than in sham-operated rats (p < 0.01). Moreover MCT8 and OATP1C1 both resulted significantly higher (p < 0.05 and p < 0.001) in sham frontal cortex. CONCLUSION: In summary, our data on SHRs, while confirming the hypotensive effect of two MEs, show that the treatment also solicits the three deiodinases production in the cerebral cortex.


Assuntos
Iodeto Peroxidase , Hormônios Tireóideos , Animais , Encéfalo/metabolismo , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Proteínas de Membrana Transportadoras , Ratos
11.
Endocrinology ; 162(6)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33606002

RESUMO

Iodothyronine deiodinases are enzymes capable of activating and inactivating thyroid hormones (THs) and have an important role in regulating TH action in tissues throughout the body. Three types of deiodinases (D1, D2, and D3) were originally defined based on their biochemical characteristics. Cloning of the first complementary DNAs in the 1990s (Dio1 in rat and dio2 and dio3 in frog) allowed to confirm the existence of 3 distinct enzymes. Over the years, increasing genomic information revealed that deiodinases are present in all chordates, vertebrates, and nonvertebrates and that they can even be found in some mollusks and annelids, pointing to an ancient origin. Research in nonmammalian models has substantially broadened our understanding of deiodinases. In relation to their structure, we discovered for instance that biochemical properties such as inhibition by 6-propyl-2-thiouracil, stimulation by dithiothreitol, and temperature optimum are subject to variation. Data from fish, amphibians, and birds were key in shifting our view on the relative importance of activating and inactivating deiodination pathways and in showing the impact of D2 and D3 not only in local but also whole body T3 availability. They also led to the discovery of new local functions such as the acute reciprocal changes in D2 and D3 in hypothalamic tanycytes upon photostimulation, involved in seasonal rhythmicity. With the present possibilities for rapid and precise gene silencing in any species of interest, comparative research will certainly further contribute to a better understanding of the importance of deiodinases for adequate TH action, also in humans.


Assuntos
Pesquisa Biomédica , Iodeto Peroxidase/fisiologia , Vertebrados , Animais , Animais de Laboratório , Anuros , Pesquisa Biomédica/história , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Aves , Peixes , História do Século XX , História do Século XXI , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Ratos , Hormônios Tireóideos/metabolismo , Vertebrados/genética , Vertebrados/fisiologia
12.
Endocrinology ; 162(4)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33539515

RESUMO

Hormones are key drivers of cancer development, and alteration of the intratumoral concentration of thyroid hormone (TH) is a common feature of many human neoplasias. Besides the systemic control of TH levels, the expression and activity of deiodinases constitute a major mechanism for the cell-autonomous, prereceptoral control of TH action. The action of deiodinases ensures tight control of TH availability at intracellular level in a time- and tissue-specific manner, and alterations in deiodinase expression are frequent in tumors. Research over the past decades has shown that in cancer cells, a complex and dynamic expression of deiodinases is orchestrated by a network of growth factors, oncogenic proteins, and miRNA. It has become increasingly evident that this fine regulation exposes cancer cells to a dynamic concentration of TH that is functional to stimulate or inhibit various cellular functions. This review summarizes recent advances in the identification of the complex interplay between deiodinases and cancer and how this family of enzymes is relevant in cancer progression. We also discuss whether deiodinase expression could represent a diagnostic tool with which to define tumor staging in cancer treatment or even a therapeutic tool against cancer.


Assuntos
Iodeto Peroxidase/metabolismo , Neoplasias/enzimologia , Animais , Humanos , Iodeto Peroxidase/genética , Neoplasias/genética , Neoplasias/metabolismo , Hormônios Tireóideos/metabolismo
14.
J Diabetes Investig ; 12(6): 931-939, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33421302

RESUMO

AIMS/INTRODUCTION: Type 2 diabetes mellitus is a group of metabolism abnormalities in carbohydrates and energy. Our aim was to investigate resting energy expenditure (REE) and blood glucose changes after biliary diversion in mice with diabetes. MATERIALS AND METHODS: Male mice with diabetes were randomly divided into biliary diversion and sham groups. REE was detected by indirect calorimetry, the levels of fasting blood glucose, total bile acids and triiodothyronine were analyzed. After mice were killed, the weight amount of brown adipose tissue (BAT) and gastrocnemius was measured, and the expression level of G protein-coupled bile acid receptor and type 2 iodothyronine deiodinase in BAT and gastrocnemius were examined. RESULTS: The two groups of mice were pair-fed, the bodyweights (P < 0.001) and the fasting blood glucose level (P < 0.001) in the biliary diversion group significantly decreased 24 weeks after surgery. The intraperitoneal glucose tolerance test (P = 0.035) and oral glucose tolerance test (P = 0.027) showed improvement in glucose tolerance after surgery. The REE level significantly increased 24 weeks after surgery (P = 0.005), the levels of total bile acids (P = 0.014) and triiodothyronine (P < 0.001) increased at the 24th postoperative week. The weight ratio of BAT (P = 0.038) and gastrocnemius (P = 0.026) in the biliary diversion group were higher than that in the sham group. The expression of G protein-coupled bile acid receptor in BAT (P < 0.001) and gastrocnemius (P = 0.003) were upregulated after surgery, and the type 2 iodothyronine deiodinase expression also increased in BAT (P = 0.015) and gastrocnemius (P = 0.015). CONCLUSIONS: The REE level increased and the glucose metabolism improved in mice with diabetes after biliary diversion.


Assuntos
Desvio Biliopancreático/métodos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirurgia , Metabolismo Energético , Tecido Adiposo Marrom/fisiopatologia , Animais , Ácidos e Sais Biliares/metabolismo , Modelos Animais de Doenças , Jejum/sangue , Teste de Tolerância a Glucose , Iodeto Peroxidase/metabolismo , Camundongos , Músculo Esquelético/fisiopatologia , Período Pós-Operatório , Receptores Acoplados a Proteínas G/metabolismo , Descanso/fisiologia
15.
Ann Clin Biochem ; 58(1): 29-37, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33040575

RESUMO

Reverse T3 (3,3',5'-triiodothyronine or rT3) is the third most abundant iodothyronine circulating in human blood and is produced by the inner ring deiodination of the pro-hormone thyroxine (T4). Unlike the more abundant and active metabolite T3, the measurement of serum rT3 is yet to find a routine clinical application. As rT3 binds weakly to the T3 thyroid nuclear hormone receptors, it is thought to represent an inactive end-product of thyroid hormone metabolism, diverting T4 away from T3 production. The analysis of serum rT3 has, up until recently, been measured by competitive radioimmunoassay, but these methods have been superseded by mass-spectrometric methods which are less susceptible to interference from other more abundant iodothyronines. Serum rT3 concentration is increased as part of the non-thyroidal illness syndrome, and by administration of common medications such as amiodarone which inhibit the metabolism of rT3. Serum rT3 concentration is also affected by genetic conditions that affect the iodothyronine deiodinases, as well as thyroid transporters and transport proteins. Analysis of rT3 can provide a useful diagnostic fingerprint for these conditions. rT3 has been shown to bind extra-nuclear iodothyronine receptors with a potential role in cell proliferation; however, the clinical relevance of these findings awaits further study.


Assuntos
Síndromes do Eutireóideo Doente/sangue , Síndromes do Eutireóideo Doente/diagnóstico , Glândula Tireoide/metabolismo , Tri-Iodotironina Reversa/sangue , Amiodarona/efeitos adversos , Amiodarona/uso terapêutico , Humanos , Iodeto Peroxidase/metabolismo , Glândula Tireoide/patologia , Tiroxina/sangue
16.
Cancer Lett ; 501: 224-233, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33221455

RESUMO

High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy with a need for better understanding the disease pathogenesis. The biologically active thyroid hormone, T3, is considered a tumor suppressor by promoting cell differentiation and mitochondrial respiration. Tumors evolved a strategy to avoid these anticancer actions by expressing the T3 catabolizing enzyme, Deiodinase type 3 (DIO3). This stimulates cancer proliferation and aerobic glycolysis (Warburg effect). We identified DIO3 expression in HGSOC cell lines, tumor tissues from mice and human patients, fallopian tube (FT) premalignant lesion and secretory cells of normal FT, considered the disease site-of-origin. Stable DIO3 knockdown (DIO3-KD) in HGSOC cells led to increased T3 bioavailability and demonstrated induced apoptosis and attenuated proliferation, migration, colony formation, oncogenic signaling, Warburg effect and tumor growth in mice. Proteomics analysis further indicated alterations in an array of cancer-relevant proteins, the majority of which are involved in tumor suppression and metabolism. Collectively this study establishes the functional role of DIO3 in facilitating tumorigenesis and metabolic reprogramming, and proposes this enzyme as a promising target for inhibition in HGSOC.


Assuntos
Cistadenocarcinoma Seroso/patologia , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Neoplasias Ovarianas/patologia , Regulação para Cima , Aerobiose , Animais , Linhagem Celular Tumoral , Proliferação de Células , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Tubas Uterinas/metabolismo , Tubas Uterinas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glicólise , Humanos , Camundongos , Gradação de Tumores , Transplante de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo
17.
Mol Cell Endocrinol ; 519: 111056, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33069856

RESUMO

Seasonal timing is important for many critical life history events of vertebrates, and photoperiod is often used as a reliable seasonal cue. In mammals and birds, it has been established that a photoperiod-driven seasonal clock resides in the brain and pituitary, and is driven by increased levels of pituitary thyroid stimulating hormone (TSH) and brain type 2 iodothyronine deiodinase (DIO2), which leads to local increases in triiodothyronine (T3). In order to determine if a similar mechanism occurs in fish, we conducted photoperiod manipulations in anadromous (migratory) Atlantic salmon (Salmo salar) that use photoperiod to time the preparatory development of salinity tolerance which accompanies downstream migration in spring. Changing daylength from short days (light:dark (LD) 10:14) to long days (LD 16:8) for 20 days increased gill Na+/K+-ATPase (NKA) activity, gill NKAα1b abundance and plasma growth hormone (GH) levels that normally accompany increased salinity tolerance of salmon in spring. Long-day exposure resulted in five-fold increases in pituitary tshßb mRNA levels after 10 days and were sustained for at least 20 days. tshßb mRNA levels in the saccus vasculosus were low and not influenced by photoperiod. Increased daylength resulted in significant increases in dio2b mRNA levels in the hypothalamus and midbrain/optic tectum regions of the brain. The results are consistent with the presence of a photoperiod-driven seasonal clock in fish which involves pituitary TSH, brain DIO2 and the subsequent production of T3, supporting the hypothesis that this is a common feature of photoperiodic regulation of seasonality in vertebrates.


Assuntos
Encéfalo/enzimologia , Iodeto Peroxidase/metabolismo , Fotoperíodo , Hipófise/metabolismo , Salmo salar/fisiologia , Tireotropina/metabolismo , Animais , Brânquias/metabolismo , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Distribuição Tecidual
18.
PLoS One ; 15(12): e0240338, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33306682

RESUMO

Thyroid hormones are important modulators of metabolic activity in mammals and alter cholesterol and fatty acid levels through activation of the nuclear thyroid hormone receptor (THR). Currently, there are several THRß agonists in clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) that have demonstrated the potential to reduce liver fat and restore liver function. In this study, we tested three THRß-agonism-based NASH treatment candidates, GC-1 (sobetirome), MGL-3196 (resmetirom), and VK2809, and compared their selectivity for THRß and their ability to modulate the expression of genes specific to cholesterol and fatty acid biosynthesis and metabolism in vitro using human hepatic cells and in vivo using a rat model. Treatment with GC-1 upregulated the transcription of CPT1A in the human hepatocyte-derived Huh-7 cell line with a dose-response comparable to that of the native THR ligand, triiodothyronine (T3). VK2809A (active parent of VK2809), MGL-3196, and VK2809 were approximately 30-fold, 1,000-fold, and 2,000-fold less potent than T3, respectively. Additionally, these relative potencies were confirmed by quantification of other direct gene targets of THR, namely, ANGPTL4 and DIO1. In primary human hepatocytes, potencies were conserved for every compound except for VK2809, which showed significantly increased potency that was comparable to that of its active counterpart, VK2809A. In high-fat diet fed rats, a single dose of T3 significantly reduced total cholesterol levels and concurrently increased liver Dio1 and Me1 RNA expression. MGL-3196 treatment resulted in concentration-dependent decreases in total and low-density lipoprotein cholesterol with corresponding increases in liver gene expression, but the compound was significantly less potent than T3. In conclusion, we have implemented a strategy to rank the efficacy of THRß agonists by quantifying changes in the transcription of genes that lead to metabolic alterations, an effect that is directly downstream of THR binding and activation.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores beta dos Hormônios Tireóideos/agonistas , Transcrição Genética/efeitos dos fármacos , Acetatos/farmacologia , Acetatos/uso terapêutico , Proteína 4 Semelhante a Angiopoietina/metabolismo , Animais , Linhagem Celular Tumoral , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Hepatócitos , Humanos , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Malato Desidrogenase/genética , Malato Desidrogenase/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Organofosfonatos/farmacologia , Organofosfonatos/uso terapêutico , Fenóis/farmacologia , Fenóis/uso terapêutico , Cultura Primária de Células , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Ratos , Uracila/análogos & derivados , Uracila/farmacologia , Uracila/uso terapêutico
19.
Sci Rep ; 10(1): 15401, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958818

RESUMO

Iodothyronine deiodinases (Dios) are important selenoproteins that control the concentration of the active thyroid hormone (TH) triiodothyronine through regioselective deiodination. The X-ray structure of a truncated monomer of Type III Dio (Dio3), which deiodinates TH inner rings through a selenocysteine (Sec) residue, revealed a thioredoxin-fold catalytic domain supplemented with an unstructured Ω-loop. Loop dynamics are driven by interactions of the conserved Trp207 with solvent in multi-microsecond molecular dynamics simulations of the Dio3 thioredoxin(Trx)-fold domain. Hydrogen bonding interactions of Glu200 with residues conserved across the Dio family anchor the loop's N-terminus to the active site Ser-Cys-Thr-Sec sequence. A key long-lived loop conformation coincides with the opening of a cryptic pocket that accommodates thyroxine (T4) through an I⋯Se halogen bond to Sec170 and the amino acid group with a polar cleft. The Dio3-T4 complex is stabilized by an I⋯O halogen bond between an outer ring iodine and Asp211, consistent with Dio3 selectivity for inner ring deiodination. Non-conservation of residues, such as Asp211, in other Dio types in the flexible portion of the loop sequence suggests a mechanism for regioselectivity through Dio type-specific loop conformations. Cys168 is proposed to attack the selenenyl iodide intermediate to regenerate Dio3 based upon structural comparison with related Trx-fold proteins.


Assuntos
Química Computacional/métodos , Iodeto Peroxidase/metabolismo , Tiroxina/química , Tiroxina/metabolismo , Halogênios/química , Ligação de Hidrogênio , Iodeto Peroxidase/química , Iodeto Peroxidase/fisiologia , Conformação Molecular , Selenocisteína , Selenoproteínas/metabolismo , Selenoproteínas/fisiologia , Transdução de Sinais , Hormônios Tireóideos , Tri-Iodotironina/metabolismo
20.
FASEB J ; 34(9): 12072-12082, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32776612

RESUMO

Mammals adapt to seasons using a neuroendocrine calendar defined by the photoperiodic change in the nighttime melatonin production. Under short photoperiod, melatonin inhibits the pars tuberalis production of TSHß, which, in turn, acts on tanycytes to regulate the deiodinase 2/3 balance resulting in a finely tuned seasonal control of the intra-hypothalamic thyroid hormone T3. Despite the pivotal role of this T3 signaling for synchronizing reproduction with the seasons, T3 cellular targets remain unknown. One candidate is a population of hypothalamic neurons expressing Rfrp, the gene encoding the RFRP-3 peptide, thought to be integral for modulating rodent's seasonal reproduction. Here we show that nighttime melatonin supplementation in the drinking water of melatonin-deficient C57BL/6J mice mimics photoperiodic variations in the expression of the genes Tshb, Dio2, Dio3, and Rfrp, as observed in melatonin-proficient mammals. Notably, we report that this melatonin regulation of Rfrp expression is no longer observed in mice carrying a global mutation of the T3 receptor, TRα, but is conserved in mice with a selective neuronal mutation of TRα. In line with this observation, we find that TRα is widely expressed in the tanycytes. Altogether, our data demonstrate that the melatonin-driven T3 signal regulates RFRP-3 neurons through non-neuronal, possibly tanycytic, TRα.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Melatonina/farmacologia , Neuropeptídeos/biossíntese , Receptores dos Hormônios Tireóideos/metabolismo , Tri-Iodotironina/metabolismo , Animais , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Camundongos , Camundongos Knockout , Neuropeptídeos/genética , Receptores dos Hormônios Tireóideos/genética , Tri-Iodotironina/genética
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