The hypothyroid brain

  The thyroid gland is controlled by a feedback system, the hypothalamus-pituitary-thyroid axis, and produces thyroid hormone (TH), which plays a critical role in growth, development and cellular metabolism. Diseases of the thyroid are well defined clinically and biochemically and diseases affecting thyroid function can cause both clinical hypothyroidisms, the most common cause of thyroid dysfunction, occurs when there is a decrease in the production of thyroid hormones, and hyperthyroidism, when there is an increase in hormone production. Common systemic manifestations of hypothyroidism include fatigue, dry skin, weight gain, hair loss, cold intolerance, hoarseness and constipation. Patients affected by this condition present a number of central and peripheral signs in the nervous system that may be neurological manifestations that occur along with the systemic disease. The conversion of thyroid hormone in the target tissue is done by three distinct deiodinases: type I, type II and type III. Each deiodinase has a different function in order to maintain thyroid hormone homeostasis in the tissues. Other proteins important for thyroid state are the TH transporters. MCT8, OATP1C1 and LAT1 and 2 transporters regulate T4 and T3 flow in the cells. The action of THs depends on the interaction of several proteins that are specialized in the control of thyroid hormone homeostasis not only in the brain but also in various tissues. THs are important for the maturation of the brain from the intrauterine period and remain important to adulthood. When there is some disturbance in the control mechanisms for the state of thyroid hormone, the consequences to the tissues, especially the CNS, can range from mild damage to severe impairment in neuronal development

Estudo da homeostase do hormônio tiroidiano durante a diferenciação de células pluripotentes em neurônios humanos com síndrome de rett e controle

Rett syndrome (RTT; MIM 312750) is a severe neurodegenerative disease that mainly affects girls, and its principal cause is the mutation in the methyl CpG binding protein 2 gene (MECP2), this gene is present in the X chromosome, and is related to epigenetic regulation, metilation. Studies have shown that the insulin-like growth factor 1 (IGF1) can rescue the characteristics of neurons derived of patients with RTT to levels similar to control neurons. The thyroid hormones (TH: T3 and T4) are extremely important hormones for the development and maintenance of the central nervous system, and the control of their production and action should be well regulated. This hormone is produced in the thyroid gland and acts virtually in all tissues. To the entrance of the hormone into the target cells it is necessary that there are specialized transporters, such as MCT8 and MCT10. Inside the cell the main thyroid hormone is T3, but the thyroid gland produces mainly T4 (80%), so there must be a mechanism that converts T4 to T3. The desiodases (DIO 1, 2 and 3) are specialized enzymes that can activate or inactivate the THs to have cellular action. TH genomic action occurs through nuclear receptors that bind to DNA. These receptors, TRalpha 1, TRbeta 1 and TRbeta 2, are central to this genomic action of thyroid hormone. Several studies have shown that a dysregulated TH homeostasis can lead to severe neurodevelopmental problems. Taking into account the importance of THs to neuronal formation, our study aims were to correlate the homeostasis of this hormone with Rett syndrome and tried to verify whether treatment with the hormone can rescue the neurons derived from patients with RTT. We showed that genes related to TH homeostasis are altered not only in neuronal cell stage of development but also during the preceding stages, as pluripotent stem cell and neural progenitor cell. Furthermore, we showed that the action of IGF-1 in RTT neuronal rescue is related to the increased expression of IGF1 receptor in this syndrome and that the neurons respond to IGF1 action due to the presence of TRalpha 3.A Síndrome de Rett (RTT; OMIM 312750) é uma doença neurodegenerativa grave que afeta principalmente meninas, que tem como sua principal causa mutações no gene do fator de transcrição ligador de proteína metil-CpG 2 (MECP2), um gene presente no cromossomo X, relacionado com a metilação. Alguns estudos já mostraram que o fator de crescimento semelhante a insulina 1 (IGF1) pode recuperar as características de neurônios derivados de pacientes com RTT à níveis semelhantes a neurônios controles. Os hormônios tiroidiano (HTs, T3 e T4) são extremamente importantes para o desenvolvimento e manutenção do sistema nervoso central, e o controle de sua produção e ação devem estar bem regulados. Estes hormônios são produzidos na glândula tiroide e atuam virtualmente em todos os tecidos. Para entrar na célula alvo é preciso que haja transportadores especializados, tais quais MCT8 e MCT10. Dentro da célula o principal agente tiroidia é o T3. No entanto a glândula tiroidiana produz principalmente T4 (80%). Portanto, é preciso que haja um mecanismo que converta o T4 em T3. As desiodases (DIO 1, 2 e 3) são enzimas especializadas, que podem ativar ou inativar os HTs para que haja ação celular. A ação genômica do HT, quando o hormônio atua em seus receptores nucleares, ocorre através de receptores nucleares que se ligam ao DNA. Estes receptores, TRalpha 1, TRbeta 1 e TRbeta 2, são fundamentais para a ação do hormônio tiroidiano. Diversos estudos já mostraram que uma homeostase do HT desregulada pode levar a severos problemas do neurodesenvolvimento. Considerando a importância dos HTs para a formação neuronal, o nosso trabalho teve como objetivo relacionar a homeostase dos HTs com a síndrome de Rett e ainda tentou verificar se o tratamento com o hormônio pode recuperar os neurônios derivados de paciente com RTT. Mostramos que a homeostase do HT está alterada não só na fase neuronal do desenvolvimento celular, mas também nas fases anteriores, como célula tronco pluripotente e célula progenitora neuronal. Ainda, nós mostramos neste trabalho que a ação do IGF1 na recuperação neuronal em RTT está relacionada com o aumento da expressão do receptor de IGF1 nesta síndrome e que os neurônios respondem à ação do IGF1 devido a presença do TRalpha 3.Dados abertos - Sucupira - Teses e dissertações (2013 a 2016

Effect of iron supplementation and restriction on the regulation of myoglobin (Mb) gene and protein expression in skeletal and cardiac muscles of rats

O ferro (Fe) é um oligoelemento capaz de aceitar e doar elétrons. Tal propriedade o torna extremamente útil em diversos componentes importantes ao bom funcionamento do organismo e da célula. O Fe está associado a algumas proteínas, está presente em citocromos, em moléculas que se ligam ao oxigênio (hemoglobina e mioglobina) e em uma grande variedade de enzimas. O aumento e a diminuição da sua oferta levam a alterações na expressão de RNAs mensageiros e proteínas responsáveis pela sua própria homeostase. Sabe-se que a expressão de vários genes envolvidos no metabolismo do Fe é regulada pós-transcricionalmente, por meio de mecanismo que é desencadeado por sua ligação em regiões não traduzíveis presentes em mRNAs específicos, o que interfere no seu grau de poliadenilação, e por conseguinte, na estabilidade e na tradução do transcrito. A Mb é uma heme-proteína de 18,8 kDa, altamente expressa no tecido muscular esquelético e cardíaco, e que pertence a mesma família da hemoglobina. Sabendo-se que cerca de 15% do Fe existente no organismo está presente nos músculos, no presente trabalho avaliamos se a suplementação e restrição de Fe, a curto e longo prazo, alteram a expressão gênica da Mb no músculo oxidativo Soleus (S), glicolítico Extensor Digital Longo (EDL) e no cardíaco. Observamos que a restrição de Fe, a longo prazo, provocou um aumento na expressão gênica e protéica da Mb, apenas no músculo Soleus, sem alterar o grau de poliadenilação do transcrito, enquanto a suplementação não alterou os parâmetros avaliados em nenhum dos tecidos. A administração aguda de Fe não alterou a expressão gênica e protéica da Mb, nem o grau de poliadenilação do transcrito em nenhum dos tecidos estudados. Estes resultados sugerem que a regulação da expressão da Mb pelo Fe se dá apenas transcricionalmente, e de maneira tecido específica.Iron is a trace element that can accept and donate electrons. This property makes iron extremely important to several components involved with the proper functioning of the organism and cells. Iron is associated with some proteins, is present in cytochromes, molecules that bind to oxygen (hemoglobin and myoglobin) and a variety of enzymes. The increase and decrease of its offer lead to changes in the expression of mRNAs and proteins responsible for their own homeostasis. It is known that the expression of several genes involved in the metabolism of iron is regulated post-transcriptionally through a mechanism that is triggered by its binding in non-translatable regions of specific mRNAs, which interferes with their polyadenylation, and as a consequence, with the stability and translation of the transcripts. Mb is a heme-protein with 18,8 kDa, highly expressed in skeletal and cardiac muscle, and it belongs to the same family of hemoglobin. About 15% of iron in the body is present in muscle tissue. Thus, this study aimed to investigate if long- and short-term Fe supplementation and restriction affect Mb gene expression in the oxidative Soleus (S), glycolitic Extensorum Digitalis Longus (EDL), and cardiac muscles. It was shown that long- term Fe restriction increased Mb mRNA and protein expression only in S muscle, without interfering in the transcript polyadenylation, whereas Fe supplementation did not alter any parameter evaluated in the three tissues. The short-term iron administration did not change the Mb mRNA, polyadenylation and protein expression in any of the tissues studied. The present results indicate that the regulation of Mb gene expression by iron occurs only at transcriptional level and in a tissue specific manner

The hypothyroid brain

  The thyroid gland is controlled by a feedback system, the hypothalamus-pituitary-thyroid axis, and produces thyroid hormone (TH), which plays a critical role in growth, development and cellular metabolism. Diseases of the thyroid are well defined clinically and biochemically and diseases affecting thyroid function can cause both clinical hypothyroidisms, the most common cause of thyroid dysfunction, occurs when there is a decrease in the production of thyroid hormones, and hyperthyroidism, when there is an increase in hormone production. Common systemic manifestations of hypothyroidism include fatigue, dry skin, weight gain, hair loss, cold intolerance, hoarseness and constipation. Patients affected by this condition present a number of central and peripheral signs in the nervous system that may be neurological manifestations that occur along with the systemic disease. The conversion of thyroid hormone in the target tissue is done by three distinct deiodinases: type I, type II and type III. Each deiodinase has a different function in order to maintain thyroid hormone homeostasis in the tissues. Other proteins important for thyroid state are the TH transporters. MCT8, OATP1C1 and LAT1 and 2 transporters regulate T4 and T3 flow in the cells. The action of THs depends on the interaction of several proteins that are specialized in the control of thyroid hormone homeostasis not only in the brain but also in various tissues. THs are important for the maturation of the brain from the intrauterine period and remain important to adulthood. When there is some disturbance in the control mechanisms for the state of thyroid hormone, the consequences to the tissues, especially the CNS, can range from mild damage to severe impairment in neuronal development