RESUMEN
Thyroid hormones play an important role in body homeostasis by facilitating metabolism of lipids and glucose, regulating metabolic adaptations, responding to changes in energy intake, and controlling thermogenesis. Proper metabolism and action of these hormones requires the participation of various nutrients. Among them is zinc, whose interaction with thyroid hormones is complex. It is known to regulate both the synthesis and mechanism of action of these hormones. In the present review, we aim to shed light on the regulatory effects of zinc on thyroid hormones. Scientific evidence shows that zinc plays a key role in the metabolism of thyroid hormones, specifically by regulating deiodinases enzymes activity, thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) synthesis, as well as by modulating the structures of essential transcription factors involved in the synthesis of thyroid hormones. Serum concentrations of zinc also appear to influence the levels of serum T3, T4 and TSH. In addition, studies have shown that Zinc transporters (ZnTs) are present in the hypothalamus, pituitary and thyroid, but their functions remain unknown. Therefore, it is important to further investigate the roles of zinc in regulation of thyroid hormones metabolism, and their importance in the treatment of several diseases associated with thyroid gland dysfunction.
Asunto(s)
Glándula Tiroides/fisiología , Hormonas Tiroideas/metabolismo , Hormona Liberadora de Tirotropina/fisiología , Tirotropina , Zinc , Hormonas Tiroideas/química , Hormona Liberadora de Tirotropina/químicaRESUMEN
The purpose of this research was to evaluate the effects of evaporative cooling in freestall on mastitis occurrence, milk production, and composition, as well as cortisol, T3 (triiodothyronine), and T4 (thyroxin) levels in lactating dairy cows. Twenty-eight multiparous cows averaging 70 ± 10 day postpartum were used in four treatments from January to March 2003. The treatments were: Day (cooling from 7:00 a.m. to 7:00 p.m.); Night (cooling from 7:00 p.m. to 7:00 a.m.); 24-hour (cooling 24-hour); and Control (no cooling). Wired cup test was used for clinical mastitis diagnosis, and the California Mastitis Test (CMT) was used to identify subclinical mastitis. Blood and milk samples were taken weekly for microbiological and hormonal analyses. The cortisol levels were higher than normal values in all treatment groups, suggesting stress conditions, but T3 and T4 levels remained normal in all groups. The occurrence of subclinical mastitis was lower in Day and Night groups than in Control and 24-hour groups. Regarding the microbiological analyses, in all groups the isolation of Corynebacterium sp. from milk samples increased while negative coagulase staphylococci (CNS) declined as etiological agents of subclinical mastitis. However, in Day and 24-hour groups, coagulase positive staphylococci (CPS) increased mainly Staphylococcus aureus (49.8% and 47.7% respectively). The Night group showed a decrease in subclinical mastitis occurrences. Our data indicate that all animals subjected to treatments presented high levels of cortisol, indicating a stress condition. The Night treatment presented a reduction in microbial isolation, suggesting a reduced susceptibility to mastitis.
O trabalho teve como objetivo avaliar a eficiência do sistema de resfriamento adiabático evaporativo, acionado em diferentes horários, em instalação do tipo freestall e seus reflexos sobre a ocorrência de mastite, produção e composição do leite e respostas hormonais de vacas em lactação. Foram utilizadas 28 vacas em lactação (70±10 dias), multíparas, das raças Holandesa Preta e Branca e Pardo Suíça, com produção média diária de 23±2,3 kg leite/dia. O período experimental de 56 dias teve início em 20 de janeiro de 2003. Os tratamentos foram: Controle (sem resfriamento); Dia (resfriamento 7 as 19 h); Noite (resfriamento 19 às 7 h) e 24 horas (resfriamento durante 24 h). A temperatura de bulbo seco (TBS), umidade relativa do ar (UR) e a temperatura de globo negro (TGN) foram mensuradas ao longo das 24 horas. A ordenha foi realizada às 7 h e 19 h. Amostragens semanais de leite e sangue foram realizadas para análise da composição do leite (gordura, proteína, lactose e contagem de células somáticas) e determinações hormonais de cortisol, tiroxina (T4) e triiodotironina (T3). Para avaliação da ocorrência de mastite clínica e subclínica foram feitos exames semanais de TAMIS (caneca de fundo preto) e California Mastitis Test (CMT). Foram colhidas amostras de leite de todos os quartos para identificação microbiológica dos agentes causais da mastite. O tratamento Dia diminuiu (P<0,05) a temperatura do freestall em 5,3°C às 12h e em 3,5°C às 14h em relação ao grupo Controle. A umidade relativa esteve elevada (P<0,05) às 7h no tratamento Noite e às 12h, 14h e 21h no tratamento Dia. Os maiores valores de ITU foram registrados no tratamento Noite às 12h, 14h e 21h. Não foram observadas diferenças entre os tratamentos (P>0,05) para a produção e composição do leite. Nos animais do tratamento Os níveis de cortisol mostraram-se acima (P<0,05) dos níveis normais em todos os tratamentos. Já os teores de T3 e T4 estiveram dentro da faixa de normalidade. Na fase pré-experimental a maior frequência de isolamento bacteriano foi para Staphylococcus coagulase negativa. No tratamento noite e dia, houve uma diminuição na proporção de casos positivos de mastite subclínica da fase pré-experimental em relação à última semana da fase experimental. Na última semana da fase experimental houve uma diminuição de Staphylococcus coagulase negativa e aumento da ocorrência de Corynebacterium sp.
Asunto(s)
Animales , Femenino , Bovinos , Infecciones/veterinaria , Leche/química , Leche , Mastitis Bovina/diagnóstico , Mastitis Bovina/patología , Corynebacterium/virología , Cambio Ambiental , Hormonas Tiroideas/química , Staphylococcus/virologíaRESUMEN
The purpose of this research was to evaluate the effects of evaporative cooling in freestall on mastitis occurrence, milk production, and composition, as well as cortisol, T3 (triiodothyronine), and T4 (thyroxin) levels in lactating dairy cows. Twenty-eight multiparous cows averaging 70 ± 10 day postpartum were used in four treatments from January to March 2003. The treatments were: Day (cooling from 7:00 a.m. to 7:00 p.m.); Night (cooling from 7:00 p.m. to 7:00 a.m.); 24-hour (cooling 24-hour); and Control (no cooling). Wired cup test was used for clinical mastitis diagnosis, and the California Mastitis Test (CMT) was used to identify subclinical mastitis. Blood and milk samples were taken weekly for microbiological and hormonal analyses. The cortisol levels were higher than normal values in all treatment groups, suggesting stress conditions, but T3 and T4 levels remained normal in all groups. The occurrence of subclinical mastitis was lower in Day and Night groups than in Control and 24-hour groups. Regarding the microbiological analyses, in all groups the isolation of Corynebacterium sp. from milk samples increased while negative coagulase staphylococci (CNS) declined as etiological agents of subclinical mastitis. However, in Day and 24-hour groups, coagulase positive staphylococci (CPS) increased mainly Staphylococcus aureus (49.8% and 47.7% respectively). The Night group showed a decrease in subclinical mastitis occurrences. Our data indicate that all animals subjected to treatments presented high levels of cortisol, indicating a stress condition. The Night treatment presented a reduction in microbial isolation, suggesting a reduced susceptibility to mastitis.(AU)
O trabalho teve como objetivo avaliar a eficiência do sistema de resfriamento adiabático evaporativo, acionado em diferentes horários, em instalação do tipo freestall e seus reflexos sobre a ocorrência de mastite, produção e composição do leite e respostas hormonais de vacas em lactação. Foram utilizadas 28 vacas em lactação (70±10 dias), multíparas, das raças Holandesa Preta e Branca e Pardo Suíça, com produção média diária de 23±2,3 kg leite/dia. O período experimental de 56 dias teve início em 20 de janeiro de 2003. Os tratamentos foram: Controle (sem resfriamento); Dia (resfriamento 7 as 19 h); Noite (resfriamento 19 às 7 h) e 24 horas (resfriamento durante 24 h). A temperatura de bulbo seco (TBS), umidade relativa do ar (UR) e a temperatura de globo negro (TGN) foram mensuradas ao longo das 24 horas. A ordenha foi realizada às 7 h e 19 h. Amostragens semanais de leite e sangue foram realizadas para análise da composição do leite (gordura, proteína, lactose e contagem de células somáticas) e determinações hormonais de cortisol, tiroxina (T4) e triiodotironina (T3). Para avaliação da ocorrência de mastite clínica e subclínica foram feitos exames semanais de TAMIS (caneca de fundo preto) e California Mastitis Test (CMT). Foram colhidas amostras de leite de todos os quartos para identificação microbiológica dos agentes causais da mastite. O tratamento Dia diminuiu (P<0,05) a temperatura do freestall em 5,3°C às 12h e em 3,5°C às 14h em relação ao grupo Controle. A umidade relativa esteve elevada (P<0,05) às 7h no tratamento Noite e às 12h, 14h e 21h no tratamento Dia. Os maiores valores de ITU foram registrados no tratamento Noite às 12h, 14h e 21h. Não foram observadas diferenças entre os tratamentos (P>0,05) para a produção e composição do leite. Nos animais do tratamento Os níveis de cortisol mostraram-se acima (P<0,05) dos níveis normais em todos os tratamentos. Já os teores de T3 e T4 estiveram dentro da faixa de normalidade. Na fase pré-experimental a maior frequência de isolamento bacteriano foi para Staphylococcus coagulase negativa. No tratamento noite e dia, houve uma diminuição na proporção de casos positivos de mastite subclínica da fase pré-experimental em relação à última semana da fase experimental. Na última semana da fase experimental houve uma diminuição de Staphylococcus coagulase negativa e aumento da ocorrência de Corynebacterium sp.(AU)
Asunto(s)
Animales , Femenino , Bovinos , Mastitis Bovina/diagnóstico , Mastitis Bovina/patología , Infecciones/veterinaria , Leche/química , Leche , Staphylococcus/virología , Corynebacterium/virología , Hormonas Tiroideas/química , Cambio AmbientalRESUMEN
The study of the different factors regulating the bioactivity of thyroid hormones is of utmost relevance for an adequate understanding of the glandular pathophysiology. These factors must be considered by the clinician in order to achieve a successful diagnosis and treatment of glandular diseases. Among the factors regulating bioactivity of thyroid hormones are the following: A) Plasmatic membrane hormone transporters, which tissue-specific expression is responsible for the cellular uptake of hormones, B) A set of deiodinating enzymes which activate or inactivate intracellular thyroid hormone, and C) Nuclear receptors which are responsible for the different cellular responses at the transcriptional level. This review compiles analysis and discusses the most recent findings regarding the regulation of thyroid hormone bioactivity, as well as the clinical relevance of different polymorphisms and mutations currently described for membrane transporters and deiodinases. In addition, the main issues and present and future study areas are identified.
Asunto(s)
Hormonas Tiroideas/fisiología , Animales , Transporte Biológico/genética , Transporte Biológico/fisiología , Metabolismo Energético/fisiología , Regulación de la Expresión Génica/fisiología , Homeostasis/fisiología , Humanos , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/fisiología , Yodo/deficiencia , Yodo/metabolismo , Isoenzimas/genética , Isoenzimas/fisiología , Proteínas de la Membrana/genética , Proteínas de la Membrana/fisiología , Estructura Molecular , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/fisiología , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/fisiología , Polimorfismo Genético , Receptores de Hormona Tiroidea/genética , Receptores de Hormona Tiroidea/fisiología , Elementos de Respuesta/genética , Enfermedades de la Tiroides/epidemiología , Enfermedades de la Tiroides/etiología , Enfermedades de la Tiroides/genética , Enfermedades de la Tiroides/metabolismo , Hormonas Tiroideas/química , Hormonas Tiroideas/metabolismoRESUMEN
The regulation of energy homeostasis by thyroid hormones is unquestionable, and iodothyronine deiodinases are enzymes involved in the metabolic activation or inactivation of these hormones at the cellular level. T3 is produced through the outer ring deiodination of the prohormone T4, which is catalyzed by types 1 and 2 iodothyronine deiodinases, D1 and D2. Conversely, type 3 iodothyronine deiodinase (D3) catalyzes the inner ring deiodination, leading to the inactivation of T4 into reverse triiodothyronine (rT3). Leptin acts as an important modulator of central and peripheral iodothyronine deiodinases, thus regulating cellular availability of T3. Decreased serum leptin during negative energy balance is involved in the down regulation of liver and kidney D1 and BAT D2 activities. Moreover, in high fat diet induced obesity, instead of increased serum T(3) and T(4) secondary to higher circulating leptin and thyrotropin levels, elevated serum rT3 is found, a mechanism that might impair the further increase in oxygen consumption.
Asunto(s)
Metabolismo Energético/fisiología , Homeostasis/fisiología , Yoduro Peroxidasa/metabolismo , Trastornos Nutricionales/metabolismo , Obesidad/metabolismo , Hormonas Tiroideas/metabolismo , Humanos , Riñón/metabolismo , Leptina/sangre , Leptina/metabolismo , Hígado/metabolismo , Estructura Molecular , Consumo de Oxígeno/fisiología , Hormonas Tiroideas/sangre , Hormonas Tiroideas/químicaRESUMEN
Most physiological effects of thyroid hormones are mediated by the two thyroid hormone receptor subtypes, TRalpha and TRbeta. Several pharmacological effects mediated by TRbeta might be beneficial in important medical conditions such as obesity, hypercholesterolemia and diabetes, and selective TRbeta activation may elicit these effects while maintaining an acceptable safety profile. To understand the molecular determinants of affinity and subtype selectivity of TR ligands, we have successfully employed a ligand- and structure-guided pharmacophore-based approach to obtain the molecular alignment of a large series of thyromimetics. Statistically reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models were obtained using the comparative molecular field analysis (CoMFA) method, and the visual analyses of the contour maps drew attention to a number of possible opportunities for the development of analogs with improved affinity and selectivity. Furthermore, the 3D-QSSR analysis allowed the identification of a novel and previously unmentioned halogen bond, bringing new insights to the mechanism of activity and selectivity of thyromimetics.
Asunto(s)
Halógenos/química , Hormonas Tiroideas/metabolismo , Cristalografía por Rayos X , Ligandos , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Hormonas Tiroideas/químicaRESUMEN
Thyroid hormone receptors (TR) are hormone-dependent transcription regulators that play a major role in human health, development, and metabolic functions. The thyroid hormone resistance syndrome, diabetes, obesity, and some types of cancer are just a few examples of important diseases that are related to TR malfunctioning, particularly impaired hormone binding. Ligand binding to and dissociation from the receptor ultimately control gene transcription and, thus, detailed knowledge of binding and release mechanisms are fundamental for the comprehension of the receptor's biological function and development of pharmaceuticals. In this work, we present the first computational study of ligand entry into the ligand binding domain (LBD) of a nuclear receptor. We report molecular dynamics simulations of ligand binding to TRs using a generalization of the steered molecular dynamics technique designed to perform single-molecule pulling simulations along arbitrarily nonlinear driving pathways. We show that only gentle protein movements and conformational adaptations are required for ligand entry into the LBDs and that the magnitude of the forces applied to assist ligand binding are of the order of the forces involved in ligand dissociation. Our simulations suggest an alternative view for the mechanisms ligand binding and dissociation of ligands from nuclear receptors in which ligands can simply diffuse through the protein surface to reach proper positioning within the binding pocket. The proposed picture indicates that the large-amplitude protein motions suggested by the apo- and holo-RXRalpha crystallographic structures are not required, reconciling conformational changes of LBDs required for ligand entry with other nuclear receptors apo-structures that resemble the ligand-bound LBDs.
Asunto(s)
Simulación por Computador , Modelos Moleculares , Receptores de Hormona Tiroidea/química , Hormonas Tiroideas/química , Algoritmos , Sitios de Unión , Humanos , Ligandos , Estructura Molecular , Conformación Proteica , Estructura Terciaria de Proteína , Receptores de Hormona Tiroidea/metabolismo , Receptores alfa de Hormona Tiroidea/química , Receptores alfa de Hormona Tiroidea/metabolismo , Receptores beta de Hormona Tiroidea/química , Receptores beta de Hormona Tiroidea/metabolismo , Hormonas Tiroideas/metabolismoRESUMEN
Thyroid hormone (T3 and T4) has many beneficial effects including enhancing cardiac function, promoting weight loss and reducing serum cholesterol. Excess thyroid hormone is, however, associated with unwanted effects on the heart, bone and skeletal muscle. We therefore need analogs that harness the beneficial effects of thyroid hormone without the untoward effects. Such work is largely based on understanding the cellular mechanisms of thyroid hormone action, specifically the crystal structure of the nuclear receptor proteins. In clinical studies, use of naturally occurring thyroid hormone analogs can suppress TSH levels in patients with thyroid cancer without producing tachycardia. Many thyromimetic compounds have been tested in animal models and shown to increase total body oxygen consumption, and to lower weight and serum cholesterol and triglyceride levels while having minor effects on heart rate. Alternatively, analogs that specifically enhance both systolic and diastolic function are potentially useful in the treatment of chronic congestive heart failure. In addition to analogs that are thyroid hormone receptor agonists, several compounds that are thyroid hormone receptor antagonists have been identified and tested. This Review discusses the potential application of thyroid hormone analogs (both agonists and antagonists) in a variety of human disease states.
Asunto(s)
Éteres Fenílicos/farmacología , Fenilacetatos/farmacología , Receptores de Hormona Tiroidea/agonistas , Receptores de Hormona Tiroidea/antagonistas & inhibidores , Diseño de Fármacos , Humanos , Imitación Molecular , Estructura Molecular , Éteres Fenílicos/química , Éteres Fenílicos/uso terapéutico , Fenilacetatos/química , Fenilacetatos/uso terapéutico , Receptores de Hormona Tiroidea/fisiología , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Hormonas Tiroideas/química , Hormonas Tiroideas/farmacología , Hormonas Tiroideas/uso terapéuticoAsunto(s)
Humanos , Masculino , Femenino , Recién Nacido , Lactante , Niño , Adolescente , Adulto , Persona de Mediana Edad , Técnicas de Laboratorio Clínico , Enfermedades de la Tiroides , Pruebas de Función de la Tiroides , Hormonas Tiroideas , Enfermedades de la Tiroides/diagnóstico , Hormonas Tiroideas/química , Hormonas Tiroideas/orinaRESUMEN
Thyronine derivatives are essential indicators of thyroid gland diseases in clinical diagnosis and are currently used as standards for developing ordinary biochemical assays. Photooxidation of gland hormones of the thyronine (TN) family and structurally related compounds (TN, 3,5-diiodothyronine,3,3',5-triiodothyronine and 3,3',5,5'-tetraiodothyronine or thyroxine) was studied using rose bengal, eosin and perinaphthenone (PN) as dye sensitizers. Tyrosine (Tyr) and two iodinated derivatives (3-iodotyrosine and 3,5-diiodotyrosine) were also included in the study for comparative purposes. Irradiation of aqueous solutions of substrates containing xanthene dyes with visible light triggers a complex series of competitive interactions, which include the triplet excited state of the dye (3Xdye*) and singlet molecular oxygen [O2(1Deltag)]-mediated and superoxide ion-mediated reactions. Rate constants for interaction with the 3Xdye*, attributed to an electron transfer process, are in the order of 10(8)-10(9) M-1 s-1 depending on the dye and the particular substrate. The photosensitization using PN follows a pure Type-II (O2(1Deltag) mediated) mechanism. The presence of the phenolic group in Tyr, TN and iodinated derivatives dominates the kinetics of photooxidation of these compounds. The reactive rate constants, k(r), and the quotient between reactive and overall rate constants (k(r)/k(t) values, in the range of 0.7-0.06) behave in an opposite fashion compared with the overall rate constants and oxidation potentials. This apparent inconsistency was interpreted on the basis of an internal heavy atom effect, favoring the intersystem-crossing deactivation route within the encounter complex with the concomitant reduction of effective photooxidation.
Asunto(s)
Oxígeno Singlete/efectos de la radiación , Hormonas Tiroideas/química , Hormonas Tiroideas/efectos de la radiación , Evolución Biológica , Colorantes/química , Colorantes/efectos de la radiación , Eosina Amarillenta-(YS)/química , Eosina Amarillenta-(YS)/efectos de la radiación , Cinética , Luz , Mediciones Luminiscentes , Estructura Molecular , Oxidación-Reducción , Fenalenos/química , Fenalenos/efectos de la radiación , Fotoquímica , Fotólisis , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/efectos de la radiación , Rosa Bengala/química , Rosa Bengala/efectos de la radiación , Sensibilidad y Especificidad , Oxígeno Singlete/química , Tirosina/química , Tirosina/efectos de la radiaciónRESUMEN
The surface balance technique was employed to study the interactions of 3,5,3',5' tetraiodo L-thyronine, 3,5,3' triiodo L-thyronine, and 3,5-diiodothyronine with monomolecular phospholipid monolayers spread at the air-water interface. With this technique the insertion of thyroid hormones into egg yolk phosphatidylcholine was investigated. An increase of surface pressure and a substantial decrement in surface potential were observed after the injection of these hormones beneath a phospholipid monolayer. The negative dipole contribution upon hormone interaction opposes the well-known positive contribution of phospholipids. These effects correlated with iodo content of the thyroid molecule analogues 3,5,3',5' tetraiodo L-thyronine >3,5,3' triiodo L-thyronine >3,5-diiodothyronine. To our knowledge, these observations suggest a new and surprising effect of thyroid hormones on the regulation of transmembrane dipolar organization.
Asunto(s)
Potenciales de la Membrana , Membranas Artificiales , Fosfatidilcolinas/química , Hormonas Tiroideas/química , Adsorción , Aire , Lípidos de la Membrana/química , Propiedades de Superficie , Agua/químicaRESUMEN
The antioxidant capacity of thyroid hormones and the antithyroid drug propylthiouracil was studied in three model systems, namely, autoxidation of rat brain homogenates and oxidation of rat erythrocyte plasma membranes (EPM) induced by either 2,2'-azobis-(2-amidinopropane) (AAP) thermolysis or by gamma irradiation. Thyroid hormones significantly inhibited the development of lipid peroxidation in these systems at micromolar concentrations, as assessed either by visible light emission, thiobarbituric acid reactive substances accumulation or oxygen uptake. This behaviour was not observed when L-3,3',5-triiodothyronine (T3) and L-thyroxine (T4) were assayed at nanomolar concentrations. In EPM exposed to AAP or gamma irradiation, propylthiouracil inhibited the induced lipid peroxidation, with Q1/2 values of 112-150 microM. It is concluded that the antioxidant capacity of thyroid hormones found in vitro may not be of relevance in physiological conditions, which exhibit variations of T3 and T4 levels in the nanomolar range. On the other hand, the behaviour of propylthiouracil as an inhibitor of EPM lipid peroxidation is observed at concentrations close to the therapeutic levels, thus representing a possible complementary action to its antithyroid activity.