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Pharmacogenetics of glucocorticoid replacement could optimize the treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

MOREIRA, Ricardo P. P.; JORGE, Alexander A. L.; GOMES, Larissa G.; KAUPERT, Laura C.; MASSUD FILHO, João; MENDONCA, Berenice B.; BACHEGA, Tânia A. S. S.
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.01%
INTRODUCTION: 21-hydroxylase deficiency is an autosomal recessive disorder that causes glucocorticoid deficiency and increased androgen production. Treatment is based on glucocorticoid replacement; however, interindividual variability in the glucocorticoid dose required to achieve adequate hormonal control has been observed. OBJECTIVE: The present study aimed to evaluate the association between polymorphic variants involved inglucocorticoid action and/or metabolism and the mean daily glucocorticoid dose in 21-hydroxylase deficiency patients. METHODS: We evaluated 53 patients with classical forms of 21-hydroxylase deficiency who were receiving cortisone acetate. All patients were between four and six years of age and had normal androgen levels. RESULTS: The P450 oxidoreductase A503V, HSD11B1 rs12086634, and CYP3A7*1C variants were found in 19%, 11.3% and 3.8% of the patients, respectively. The mean ± SD glucocorticoid dose in patients with the CYP3A7*1C and wild-type alleles was 13.9 ± 0.8 and 19.5 ± 3.2 mg/m²/d, respectively. We did not identify an association between the P450 oxidoreductase or HSD11B1 allelic variants and the mean glucocorticoid dose. CONCLUSION: Patients carrying the CYP3A7*1C variant required a significantly lower mean glucocorticoid dose. Indeed...

Differential immunoreactivity of glucocorticoid receptors and vasopressin in neurons of the anterior and medial parvocellular subdvisions of the hypothalamic paraventricular nucleus

SOUZA, Leandro Marques de; FRANCI, Celso Rodrigues
Fonte: PERGAMON-ELSEVIER SCIENCE LTD Publicador: PERGAMON-ELSEVIER SCIENCE LTD
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.96%
arginine-vasopressin in the parvocellular neurons of the hypothalamic paraventricular nucleus is known to play an important role in the control of the hypothalamo-pituitary-adrenal axis. In the present study, we verify plasma corticosterone levels, the distribution of glucocorticoid receptor- and arginine-vasopressin-positive neurons, and the co-localization of both glucocorticoid receptors and arginine-vasopressin in neurons in the anterior and medial parvocellular subdivisions of the paraventricular nucleus after manipulations of the hypothalamus-pituitary-adrenal axis. Normal, sham surgery, and adrenalectomized male rats were subjected to intraperitoneal injections of saline or dexamethasone to measure plasma corticosterone levels by a radioimmunoassay. We also examined arginine-vasopressin and glucocorticoid receptor immunofluorescence in sections from the paraventricular nucleus. Our results showed that the immunoreactivity of arginine-vasopressin neurons increased in the anterior parvocellular subdivision and decreased in the medial parvocellular subdivision from adrenalectomized rats treated with dexamethasone. On the other hand, we showed that the immunoreactivity of glucocorticoid receptors increased in the anterior and medial parvocellular subdivisions of these same animals. However...

Prolonged Physical Training Decreases mRNA Levels of Glucocorticoid Receptor and Inflammatory Genes

SILVA, Tatiane Sousa e; LONGUI, Carlos Alberto; ROCHA, Mylene Neves; FARIA, Claudia Dutra Costantin; MELO, Murilo Rezende; FARIA, Thelma Gomes; SOUZA, Julio Antonio de; RIZZO, Luiz Vicente
Fonte: KARGER Publicador: KARGER
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.93%
Background/Aims: Prolonged physical exercise induces adaptive alterations in the hypothalamic-pituitary axis, increasing cortisol metabolism, and reducing cortisol synthesis and glucocorticoid sensitivity. The mechanisms responsible for this relative glucocorticoid resistance remain unknown but may involve expression of genes encoding glucocorticoid receptor (GR) and/or inflammatory molecules of nuclear factor kappa B1 (NFkB1) signaling pathway and cytokines. This study aimed to determine the impact of prolonged physical training on the expression of genes involved in glucocorticoid action and inflammatory response. Methods: Normal sedentary male cadets of the Brazilian Air Force Academy were submitted to 6 weeks of standardized physical training. Eighteen of 29 initially selected cadets were able to fully complete the training program. Fasting glucose, insulin and cortisol levels, cytokine concentration and the expression of genes encoding GR, NFkB1, inhibitor of NFkB1 and IkB kinase A were determined before and after the training period. Results: Prolonged physical exercise reduced the basal cortisol levels and the percent cortisol reduction after dexamethasone. These findings were associated with a significant reduction in the mRNA levels of GR (6.3%)...

Caracterização funcional de genes diferencialmente regulados por glicocorticóides e análise do proteoma em linhagem de glioma sensível à hormônios anti-tumorais glicocorticóides; Functional characterization of glucocorticoid differentially regulated genes and proteomic analysis of the anti-tumoral effect of glucocorticoid in a glucocorticoid-sensitive rat glioma cell line

Demasi, Marcos Angelo Almeida
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 13/05/2005 Português
Relevância na Pesquisa
36.82%
O efeito dos hormônios glicocorticóides (GC) de suprimir o crescimento celular é exercido através de cascatas celulares nas quais a transcrição de genes de resposta primária, mediada direta ou indiretamente pelo receptor de GC, regulam a transcrição e a atividade de um conjunto de genes, incluindo fatores importantes para a progressão no ciclo celular. Entretanto, a conexão funcional entre diversos dos genes ativados ou inibidos por GC e a inibição da proliferação de determinados tipos celulares ainda não é completamente conhecida. Nosso laboratório isolou a variante ST1, a partir da linhagem C6 de glioma de rato, utilizando-a como modelo de estudo do mecanismo de ação de GC como agentes anti-tumorais. O tratamento com GC confere, às células ST1, um crescimento totalmente dependente de soro e ancoragem, morfologia em cultura semelhante à de fibroblastos normais e incapacidade de gerar tumor em camundongos da linhagem "nude", caracterizando uma completa reversão fenotípica tanto in vitro como in vivo. Como abordagens para o entendimento do mecanismo molecular da ação de GCs, o laboratório vem buscando a clonagem de produtos gênicos diferencialmente expressos através do uso de técnicas que permitam a análise da abundância relativa dos mRNAs...

Mecanismos moleculares envolvidos na redução da proliferação de células beta pancreáticas induzida por glicocorticóides.; Underlying molecular mechanisms in the glucocorticoid-induced inhibition of pancreatic beta cell proliferation.

Carvalho, José Edgar Nicoletti
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 21/06/2010 Português
Relevância na Pesquisa
36.82%
Durante a gravidez, o pâncreas endócrino materno sofre alterações morfológicas e funcionais que resultam no aumento da massa de células beta e da secreção de insulina. Nos estágios finais da gestação ocorre aumento dos níveis plasmáticos de glicocorticóides que resulta na diminuição da secreção e da proliferação das células beta. Este fenômeno, que ocorre no período compreendido entre o final da gravidez e o inicio da lactação, promove a reversão fisiológica da adaptação funcional que se fez necessária durante a gravidez. Assim, estudamos mecanismos moleculares envolvidos na redução de proliferação destas células. As proteínas cinases reguladas por sinais extracelulares (ERK) estão envolvidas no crescimento e sobrevida celular. Os resultados mostram que o glicocorticóide sintético, dexametasona, diminui a proliferação de células beta e, para isto, induz diminuição da fosforilação das ERK-1/2 por meio do aumento da expressão de uma fosfatase de MAPK (MKP-1). Este mecanismo deve estar envolvido no remodelamento pancreático pós-natal induzido pelos glicocorticóides.; During pregnancy, maternal pancreatic islets undergo morphofunctional changes that increase beta cell mass and insulin secretion. At late stages of pregnancy there is an increase in plasma glucocorticoid levels that inhibit beta cell proliferation and beta cell function. This situation...

Avaliação dos perfis de metabólitos de glicocorticóides fecais em cachorros-vinagre (Speothos venaticus) mantidos em cativeiro e suas possíveis implicações na função reprodutiva; Evaluation of fecal glucocorticoid metabolite profiles in captive bush dog (Speothos venaticus) and its possible role in the reproductive function

Hirata, Suzana Bezzegh
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 07/10/2009 Português
Relevância na Pesquisa
36.88%
O objetivo do presente estudo foi avaliar os perfis de metabólitos de glicocorticóides fecais através de radioimunoensaio em cachorros-vinagre (Speothos venaticus) mantidos em cativeiro e suas possíveis implicações na função reprodutiva. Duas fêmeas e quatro machos adultos, após período de condicionamento, foram marcados e tiveram suas fezes recolhidas durante 45 dias. Estes animais recebiam diariamente marcadores (corantes e miçangas) para a devida identificação das amostras fecais. O desafio com ACTH foi realizado em uma das fêmeas e mostrou o perfil reativo esperado, validando a técnica do ponto de vista fisiológico. As concentrações de metabólitos de glicocorticóides fecais para o grupo em geral variaram de 2,32 a 65,09 μ/g de fezes secas, com média e desvio-padrão de 18,11±11,33 μ/g de fezes secas, respectivamente. Quatro animais apresentaram um pico cada um, porém aparentemente, sem relação com qualquer evento estressante em particular. Não se verificou diferença significativa nos perfis de glicocorticóides fecais entre machos e fêmeas, nem entre a fêmea dominante e os outros indivíduos. Tais resultados sugerem que os animais estão bem adaptados à condição do cativeiro e provavelmente isentos ou minimamente afetados pelo estresse. A dosagem dos glicocorticóides fecais é uma ferramenta útil no monitoramento não-invasivo para avaliar a condição de estresse do cachorrovinagre...

Glucocorticoid-induced osteoporosis

Gregório,Luiz Henrique de; Lacativa,Paulo G. Sampaio; Melazzi,Ana Cláudia C.; Russo,Luis Augusto Tavares
Fonte: Sociedade Brasileira de Endocrinologia e Metabologia Publicador: Sociedade Brasileira de Endocrinologia e Metabologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/08/2006 Português
Relevância na Pesquisa
36.88%
Glucocorticoid-induced osteoporosis is the most frequent cause of secondary osteoporosis. Glucocorticoids cause a rapid bone loss in the first few months of use, but the most important effect of the drug is suppression of bone formation. The administration of oral glucocorticoid is associated with an increased risk of fractures at the spine and hip. The risk is related to the dose, but even small doses can increase the risk. Patients on glucocorticoid therapy lose more trabecular than cortical bone and the fractures are more frequent at the spine than at the hip. Calcium, vitamin D and activated forms of vitamin D can prevent bone loss and antiresorptive agents are effective for prevention and treatment of bone loss and to decrease fracture risk. Despite the known effects of glucocorticoids on bone, only a few patients are advised to take preventive measures and treat glucocorticoid-induced osteoporosis.

Simultaneous evaluation of in vivo glucocorticoid sensitivity and expression of glucocorticoid receptor alpha-isoform in rheumatoid arthritis patients

Cobra,Jayme F.; Melo,Murilo R.; Faria,Claudia D. C.; Longui,Carlos Alberto; Monte,Osmar
Fonte: Sociedade Brasileira de Endocrinologia e Metabologia Publicador: Sociedade Brasileira de Endocrinologia e Metabologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/02/2009 Português
Relevância na Pesquisa
36.82%
OBJECTIVES: To analyze glucocorticoid (GC) sensitivity using intravenous very low dose dexamethasone suppression test (IV-VLD-DST) in patients with rheumatoid arthritis (RA) and its correlation with glucocorticoid receptor alpha-isoform (GRα) gene expression. METHODS: We evaluated 20 healthy controls and 32 RA patients with Health Assessment Questionnaire (HAQ) and Disease Activity Score 28 joints (DAS) scores and IV-VLD-DST and GRα expression in mononuclear cells. RESULTS: Basal cortisol and the percentage of cortisol reduction after IV-VLD-DST were lower in RA patients than in controls, whereas GRα expression was similar among groups. In the RA group there was an inverse correlation between GRα expression and the percentage of cortisol suppression that was not observed in controls. There was a direct relationship between DAS and GRα expression. CONCLUSIONS: Mechanisms involved in GC resistance observed in patients with RA are possibly not at the level of GRα gene expression, since it was similar among groups and GRα increased with disease activity.

Comparison of two commercial kits and two extraction methods for fecal glucocorticoid analysis in ocelots (Leopardus pardalis) submitted to ACTH challenge

Dias,Eduardo Antunes; Nichi,Marcilio; Guimarães,Marcelo A.B.V.
Fonte: Colégio Brasileiro de Patologia Animal - CBPA; Empresa Brasileira de Pesquisa Agropecuária (EMBRAPA) Publicador: Colégio Brasileiro de Patologia Animal - CBPA; Empresa Brasileira de Pesquisa Agropecuária (EMBRAPA)
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/07/2008 Português
Relevância na Pesquisa
36.82%
The ocelot (Leopardus pardalis) is included in list of wild felid species protected by CITES and is part of conservation strategies that necessarily involve the use of assisted reproduction techniques, which requires practical and minimally invasive techniques of high reproducibility that permit the study of animal reproductive physiology. The objective of this study was to compare and validate two commercial assays: ImmuChem Double Antibody Corticosterone 125I RIA from ICN Biomedicals, Costa Mesa, CA, USA; and Coat-a-Count Cortisol 125I RIA from DPC, Los Angeles, CA, USA, for assessment of fecal glucocorticoid metabolites in ocelots submitted to ACTH (adrenocorticotropic hormone) challenge. Fecal samples were collected from five ocelots kept at the Brazilian Center of Neotropical Felines, Associação Mata Ciliar, São Paulo, Brazil, and one of the animals was chosen as a negative control. The experiment was conducted over a period of 9 days. On day 0, a total dose of 100 IU ACTH was administered intramuscularly. Immediately after collection the samples were stored at 20C in labeled plastic bags. The hormone metabolites were subsequently extracted and assayed using the two commercial kits. Previously it was performed a trial with the DPC kit to check the best extraction method for hormones metabolites. Data were analyzed with the SAS program for Windows V8 and reported as means ± SEM. The Schwarzenberger extraction method was slightly better when compared with the Wasser extraction method (103...

Pharmacogenetics of glucocorticoid replacement could optimize the treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Moreira,Ricardo P. P.; Jorge,Alexander A. L.; Gomes,Larissa G.; Kaupert,Laura C.; Massud Filho,João; Mendonca,Berenice B.; Bachega,Tânia A. S. S.
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2011 Português
Relevância na Pesquisa
37.01%
INTRODUCTION: 21-hydroxylase deficiency is an autosomal recessive disorder that causes glucocorticoid deficiency and increased androgen production. Treatment is based on glucocorticoid replacement; however, interindividual variability in the glucocorticoid dose required to achieve adequate hormonal control has been observed. OBJECTIVE: The present study aimed to evaluate the association between polymorphic variants involved inglucocorticoid action and/or metabolism and the mean daily glucocorticoid dose in 21-hydroxylase deficiency patients. METHODS: We evaluated 53 patients with classical forms of 21-hydroxylase deficiency who were receiving cortisone acetate. All patients were between four and six years of age and had normal androgen levels. RESULTS: The P450 oxidoreductase A503V, HSD11B1 rs12086634, and CYP3A7*1C variants were found in 19%, 11.3% and 3.8% of the patients, respectively. The mean ± SD glucocorticoid dose in patients with the CYP3A7*1C and wild-type alleles was 13.9 ± 0.8 and 19.5 ± 3.2 mg/m²/d, respectively. We did not identify an association between the P450 oxidoreductase or HSD11B1 allelic variants and the mean glucocorticoid dose. CONCLUSION: Patients carrying the CYP3A7*1C variant required a significantly lower mean glucocorticoid dose. Indeed...

Association of glucocorticoid receptor polymorphisms with clinical and metabolic profiles in polycystic ovary syndrome

Maciel,Gustavo A.Rosa; Moreira,Ricardo P.P.; Bugano,Diogo D.G.; Hayashida,Sylvia A.Y.; Marcondes,Jose A.M.; Gomes,Larissa G.; Mendonca,Berenice B.; Bachega,Tania A.S.S.; Baracat,Edmund C.
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/03/2014 Português
Relevância na Pesquisa
36.93%
OBJECTIVES: We aimed to investigate whether glucocorticoid receptor gene polymorphisms are associated with clinical and metabolic profiles in patients with polycystic ovary syndrome. Polycystic ovary syndrome is a complex endocrine disease that affects 5-8% of women and may be associated with metabolic syndrome, which is a risk factor for cardiovascular disease. Cortisol action and dysregulation account for metabolic syndrome development in the general population. As glucocorticoid receptor gene (NR3C1) polymorphisms regulate cortisol sensitivity, we hypothesized that variants of this gene may be involved in the adverse metabolic profiles of patients with polycystic ovary syndrome. METHOD: Clinical, metabolic and hormonal profiles were evaluated in 97 patients with polycystic ovary syndrome who were diagnosed according to the Rotterdam criteria. The alleles of the glucocorticoid gene were genotyped. Association analyses were performed using the appropriate statistical tests. RESULTS: Obesity and metabolic syndrome were observed in 42.3% and 26.8% of patients, respectively. Body mass index was positively correlated with blood pressure, triglyceride, LDL-c, total cholesterol, glucose and insulin levels as well as HOMA-IR values and inversely correlated with HDL-c and SHBG levels. The BclI and A3669G variants were found in 24.7% and 13.4% of alleles...

Sexually dimorphic effects of maternal asthma during pregnancy on placental glucocorticoid metabolism and fetal growth

Clifton, V.
Fonte: Springer Publicador: Springer
Tipo: Artigo de Revista Científica
Publicado em //2005 Português
Relevância na Pesquisa
36.82%
Human pregnancy is associated with sexually dimorphic differences in mortality and morbidity of the fetus with the male fetus experiencing the poorest outcome following complications such as pre-eclampsia, pre-term delivery and infection. The physiological mechanisms that confer these differences have not been well characterised in the human. Work conducted on the effect of maternal asthma during pregnancy, combining data collected from the mother, placenta and fetus has found some significant sex-related mechanistic differences associated with fetal growth in both normal pregnancies and pregnancies complicated by asthma. Specifically, sexually dimorphic differences have been found in placental glucocorticoid metabolism in male and female fetuses of normal pregnancies. In response to the presence of maternal asthma, only the female fetus alters placental glucocorticoid metabolism resulting in decreased growth. The male fetus does not alter placental function or growth in response to maternal asthma. As a result of the alterations in glucocorticoid metabolism in the female, downstream changes occur in pathways regulated by glucocorticoids. These data suggest that the female fetus adjusts placental function and reduces growth to compensate for maternal disease. However...

Glucocorticoid Mechanisms Of Neonatal Separation Effects On Adult Learning And Memory

Wilber, Aaron Albert
Fonte: [Bloomington, Ind.] : Indiana University Publicador: [Bloomington, Ind.] : Indiana University
Tipo: Doctoral Dissertation
Português
Relevância na Pesquisa
37.03%
Thesis (Ph.D.) - Indiana University, Psychology, 2010; Many studies have documented the relationship between adverse early experience and the development of psychiatric disorders. Understanding the mental health consequences of perinatal stressors is crucial to preventative treatment. Neonatal maternal separation in the rat is a good model system for assessing the effects of adverse early experience, and eyeblink conditioning is a good model for studying the relationship between neonatal stress and adult learning and memory. Previously, I showed that daily neonatal maternal separation (1h/day on postnatal days 2-14) increases plasma corticosterone levels during the first and second postnatal week. Further, I showed that neonatal maternal separation impairs adult eyeblink conditioning and produces a correlated increase in glucocorticoid receptor expression in the posterior interpositus nucleus of the cerebellum. My dissertation research is focused on characterizing the role of glucocorticoids in this effect. I measured cerebellar glucocorticoid receptor expression on postnatal day 15 and 21, and found that maternal separation (1h/day on postnatal days 2-14) prevented a normal decrease in glucocorticorticoid receptor expression in the interpositus from postnatal day 15 to 21. Further...

Mecanismos moleculares de regulación de la sensibilidad a glucocorticoides por las citoquinas; Molecular mechanisms of glucocorticoid sensetivity regulation by cytokines

Costas, Mónica Alejandra
Fonte: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires Publicador: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires
Tipo: info:eu-repo/semantics/doctoralThesis; tesis doctoral; info:eu-repo/semantics/publishedVersion Formato: application/pdf
Publicado em //1996 Português
Relevância na Pesquisa
37.07%
Las citoquinas inducen la producción de glucocorticoides (GC), los cuales inhiben la producción de citoquinas y sus acciones biológicas, protegiendo al organismo de una respuesta inmune exacerbada. Se observó que el factor de necrosis tumoral-a (TNF-a) aumentó la actividad transcripcional inducida por GC vía elementos respondedores a GC (GRE) en fibroblastos de ratón L-929 transfectadas con un plásmido reporter inducible por GC. Además, TNF-a aumentó el número de receptores para GC (GR) y la actividad transcripcional en el promotor de GR (HGRP) en células L-929 transfectadas con un plásmido reporter HGRP. TNF-a no tuvo efecto en células que no expresan GR pero que sí expresan receptores para TNF-a, aunque, el efecto fue evidente cuando estas células fueron cotransfectadas con un vector de expresión para GR. Estas acciones ponen de manifiesto, que TNF-a puede aumentar la actividad transcripcional de GR en respuesta a GC independientemente del aumento en el número de GR. Más aún, TNF-a aumentó la unión de GR a GRE. Como correlato biológico de estos efectos, un priming (preincubación) de TNF-a (dosis baja, no citotóxica) aumentó significativamente la sensibilidad a la acción inhibitoria de los GC sobre la citotoxicidad/apoptosis inducida por TNF-a en las células L-929. TNF-a e IL-1b tuvieron el mismo efecto estimulatorio sobre la actividad transcripcional de GR en distintos tipos celulares (glioma...

Mecanismos moleculares involucrados en la modulación de la actividad del receptor de glucocorticoides; Molecular mechanism underlying glucocorticoid receptor´s activity modulation

Presman, Diego Martín
Fonte: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires Publicador: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires
Tipo: info:eu-repo/semantics/doctoralThesis; tesis doctoral; info:eu-repo/semantics/publishedVersion Formato: application/pdf
Publicado em //2010 Português
Relevância na Pesquisa
37.01%
A lo largo de esta tesis se investigaron algunos de los mecanismos moleculares que modulan la actividad del receptor de glucocorticoides (GR), un factor de transcripción regulado por ligando. En primer lugar, utilizando cuatro esteroides con diferentes actividades se estudió cómo la estructura del ligando afecta la actividad transcripcional del GR. Además, mediante la técnica de Número y Brillo se demostró por primera vez, en forma directa, que el receptor es capaz de homodimerizar in vivo. Los resultados sugieren que este proceso sería independiente de la unión al ADN y a coactivadores como TIF2. En segundo lugar, se investigaron los mecanismos responsables de la inducción dependiente de glucocorticoides del gen pro‐apoptótico Bax, en células derivadas de timoma de ratón S49. Los resultados indican que el aumento transcripcional de bax no es causado por la estabilización de su ARNm, y que las primeras 6.5 kb del promotor del gen no estarían involucradas en el efecto inductor mediado por el GR. A través del uso de un glucocorticoide disociado, sugerimos que el GR induce la expresión de Bax mediante un mecanismo de transactivación. Más aún, no se descarta la posibilidad que el efecto del GR sea indirecto, es decir...

Nongenomic glucocorticoid inhibition via endocannabinoid Release in the hypothalamus: a fast feedback mechanism

Shi Di; Malcher-Lopes, Renato; Halmos, Katalin Cs.; Tasker, Jeffrey G.
Fonte: Universidade Católica de Brasília Publicador: Universidade Católica de Brasília
Tipo: Artigo de Revista Científica Formato: Texto
Português
Relevância na Pesquisa
36.93%
Glucocorticoid negative feedback in the brain controls stress, feeding, and neural-immune interactions by regulating the hypothalamic– pituitary–adrenal axis, but the mechanisms of inhibition of hypothalamic neurosecretory cells have never been elucidated. Using wholecell patch-clamp recordings in an acute hypothalamic slice preparation, we demonstrate a rapid suppression of excitatory glutamatergic synaptic inputs to parvocellular neurosecretory neurons of the hypothalamic paraventricular nucleus (PVN) by the glucocorticoids dexamethasone and corticosterone. The effect was maintained with dexamethasone conjugated to bovine serum albumin and was not seen with direct intracellular glucocorticoid perfusion via the patch pipette, suggesting actions at a membrane receptor. The presynaptic inhibition of glutamate release by glucocorticoids was blocked by postsynaptic inhibition of G-protein activity with intracellularGDP- -S application, implicating a postsynaptic G-protein-coupled receptor and the release of a retrograde messenger. The glucocorticoid effect was not blocked by the nitric oxide synthesis antagonist NG-nitro-L-arginine methyl ester hydrochloride or by hemoglobin but was blocked completely by the CB1 cannabinoid receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2...

Pharmacogenetics of glucocorticoid replacement could optimize the treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Moreira, Ricardo P. P.; Jorge, Alexander A. L.; Gomes, Larissa G.; Kaupert, Laura C.; Massud Filho, João; Mendonca, Berenice B.; Bachega, Tânia A. S. S.
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; ; Formato: application/pdf
Publicado em 01/01/2011 Português
Relevância na Pesquisa
37.01%
INTRODUCTION: 21-hydroxylase deficiency is an autosomal recessive disorder that causes glucocorticoid deficiency and increased androgen production. Treatment is based on glucocorticoid replacement; however, interindividual variability in the glucocorticoid dose required to achieve adequate hormonal control has been observed. OBJECTIVE: The present study aimed to evaluate the association between polymorphic variants involved inglucocorticoid action and/or metabolism and the mean daily glucocorticoid dose in 21-hydroxylase deficiency patients. METHODS: We evaluated 53 patients with classical forms of 21-hydroxylase deficiency who were receiving cortisone acetate. All patients were between four and six years of age and had normal androgen levels. RESULTS: The P450 oxidoreductase A503V, HSD11B1 rs12086634, and CYP3A7*1C variants were found in 19%, 11.3% and 3.8% of the patients, respectively. The mean ± SD glucocorticoid dose in patients with the CYP3A7*1C and wild-type alleles was 13.9 ± 0.8 and 19.5 ± 3.2 mg/m²/d, respectively. We did not identify an association between the P450 oxidoreductase or HSD11B1 allelic variants and the mean glucocorticoid dose. CONCLUSION: Patients carrying the CYP3A7*1C variant required a significantly lower mean glucocorticoid dose. Indeed...

Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and the protein kinase B

Boehmer, C; Henke, Guido; Schniepp, Roman; Palmada, Monica; Rothstein, Jeffrey; Broer, Stefan; Lang, Florian
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.88%
Surface expression of the glial glutamate transporter EAAT1 is stimulated by insulin-like growth factor 1 through activation of phosphatidylinositol-3-kinase. Downstream targets include serum and glucocorticoid-sensitive kinase isoforms SGK1, SGK2 and SGK3, and protein kinase B. SGK1 regulates Nedd4-2, a ubiquitin ligase that prepares cell membrane proteins for degradation. To test whether Nedd4-2, SGK1, SGK3 and protein kinase B regulate EAAT1, cRNA encoding EAAT1 was injected into Xenopus oocytes with or without additional injection of wild-type Nedd4-2, constitutively active S422DSGK1, inactive K127NSGK1, wild-type SGK3 and/or constitutively active T308D,S473DPKB. Glutamate induces a current in Xenopus oocytes expressing EAAT1, but not in water-injected oocytes, which is decreased by co-expression of Nedd4-2, an effect reversed by additional co-expression of S422DSGK1, SGK3 and T308D,S473DPKB, but not K127NSGK1. Site-directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4-2 protein ( S382A,S468ANedd4-2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Moreover, the current is significantly larger in T482DEAAT1- than in T482AEAAT1-expressing oocytes, indicating that a negative charge mimicking phosphorylation at T482 increases transport. The experiments reveal a powerful novel mechanism that regulates the activity of EAAT1. This mechanism might participate in the regulation of neuronal excitability and glutamate transport in other tissues.

Glucocorticoid-induced hypertension: from mouse to man

Whitworth, Judith; Schyvens, Chris; Zhang, Yafei; Mangos, George; Kelly, John
Fonte: Blackwell Science Asia Publicador: Blackwell Science Asia
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.93%
1. Adrenocorticotrophic hormone (ACTH) raises blood pressure in humans, sheep, rat and mouse. In rat and humans, but not sheep, the hypertension can be explained by glucocorticoid excess. 2. In both rat and humans, the hypertension is associated with a rise in cardiac output and renal vascular resistance. 3. In both rat and humans, the nitric oxide system is implicated in glucocorticoid hypertension. 4. In both rat and humans, hypertension due to naturally occurring glucocorticoids is not prevented by drugs that block classical glucocorticoid or mineralocorticoid receptors. 5. Abnormalities in glucocorticoid metabolism may contribute to some forms of 'essential' hypertension.

Molecular mechanisms of glucocorticoid receptor signaling

Labeur,Marta; Holsboer,Florian
Fonte: Medicina (Buenos Aires) Publicador: Medicina (Buenos Aires)
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/10/2010 Português
Relevância na Pesquisa
36.88%
This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR). Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glucocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress.