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1.
Artigo em Inglês | MEDLINE | ID: mdl-33542545

RESUMO

The current Coronavirus disease outbreak requires that physicians work in collaboration with other physicians especially in intensive care and emergency units. To fight against this new disease, whose pathogenesis, effects, and results have not been clearly demonstrated, especially in patients with the pre-existing chronic disease, requires special expertise and perspectives. Due to the need for dynamic glucocorticoid treatment at different stages of the disease in patients with adrenal insufficiency, the existence of reports indicating that "coronavirus disease 2019" also affects the adrenal reserve, and the use of glucocorticoids also in advanced stages in patients with Coronavirus disease require this issue to be emphasized with precision. Herein, treatment of the pre-existing adrenal insufficiency in patients with actual Coronavirus disease and the effects of the this critical disease on the adrenal gland have been reviewed.


Assuntos
Insuficiência Adrenal/tratamento farmacológico , Glucocorticoides/uso terapêutico , Hidrocortisona/uso terapêutico , Glândulas Suprarrenais/metabolismo , Insuficiência Adrenal/complicações , Insuficiência Adrenal/metabolismo , Gerenciamento Clínico , Progressão da Doença , Terapia de Reposição Hormonal/métodos , Hospitalização , Humanos , Inflamação , Estresse Fisiológico
2.
Cell Mol Life Sci ; 78(7): 3577-3590, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33464382

RESUMO

Endogenous steroid hormones, especially glucocorticoids and mineralocorticoids, derive from the adrenal cortex, and drastic or sustained changes in their circulatory levels affect multiple organ systems. Although hypoxia signaling in steroidogenesis has been suggested, knowledge on the true impact of the HIFs (Hypoxia-Inducible Factors) in the adrenocortical cells of vertebrates is scant. By creating a unique set of transgenic mouse lines, we reveal a prominent role for HIF1α in the synthesis of virtually all steroids in vivo. Specifically, mice deficient in HIF1α in adrenocortical cells displayed enhanced levels of enzymes responsible for steroidogenesis and a cognate increase in circulatory steroid levels. These changes resulted in cytokine alterations and changes in the profile of circulatory mature hematopoietic cells. Conversely, HIF1α overexpression resulted in the opposite phenotype of insufficient steroid production due to impaired transcription of necessary enzymes. Based on these results, we propose HIF1α to be a vital regulator of steroidogenesis as its modulation in adrenocortical cells dramatically impacts hormone synthesis with systemic consequences. In addition, these mice can have potential clinical significances as they may serve as essential tools to understand the pathophysiology of hormone modulations in a number of diseases associated with metabolic syndrome, auto-immunity or even cancer.


Assuntos
Glândulas Suprarrenais/metabolismo , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Esteroides/biossíntese , Animais , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
3.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33466491

RESUMO

Androgens represent the main hormones responsible for maintaining hormonal balance and function in the prostate and testis. As they are involved in prostate and testicular carcinogenesis, more detailed information of their active concentration at the site of action is required. Since the introduction of the term intracrinology as the local formation of active steroid hormones from inactive precursors of the adrenal gland, mainly dehydroepiandrosterone (DHEA) and DHEA-S, it is evident that blood circulating levels of sex steroid hormones need not reflect their actual concentrations in the tissue. Here, we review and critically evaluate available methods for the analysis of human intraprostatic and intratesticular steroid concentrations. Since analytical approaches have much in common in both tissues, we discuss them together. Preanalytical steps, including various techniques for separation of the analytes, are compared, followed by the end-point measurement. Advantages and disadvantages of chromatography-mass spectrometry (LC-MS, GC-MS), immunoanalytical methods (IA), and hybrid (LC-IA) are discussed. Finally, the clinical information value of the determined steroid hormones is evaluated concerning differentiating between patients with cancer or benign hyperplasia and between patients with different degrees of infertility. Adrenal-derived 11-oxygenated androgens are mentioned as perspective prognostic markers for these purposes.


Assuntos
Glândulas Suprarrenais/metabolismo , Androgênios/metabolismo , Próstata/metabolismo , Testículo/metabolismo , Animais , Hormônios Esteroides Gonadais/metabolismo , Humanos , Masculino , Esteroides/metabolismo
4.
J Steroid Biochem Mol Biol ; 208: 105821, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33465421

RESUMO

Quantitative reverse transcription polymerase chain reaction (RT-qPCR) is commonly used for gene expression analysis, and the accuracy of its results depends greatly on chosen reference genes. Adrenal gland is the core of the occurrence and development of fetal-originated adult diseases. Its dysplasia or dysfunction may increase susceptibility to adult disease, which has apparent sex differences. To explore the optimal combination of reference genes for RT-qPCR in female and male rats adrenal development, we selected seven reference genes (GAPDH, ß-actin, etc.), and use RT-qPCR to detect genes expression during different stages of rats adrenal development under physiological conditions. Then we analysed data using GeNorm, NormFinder and BestKeeper to select the optimal combination of reference genes. Further, we used the intrauterine growth retardation (IUGR) model of rat caused by prenatal caffeine exposure (PCE) to verify the stability and accuracy of the selected combination of reference genes under physiological conditions. The results showed that TBP + ß-actin could be the optimal combination of reference genes for fetal rat adrenals under physiological conditions, without obvious sex differences. In infancy and adolescence, the optimal combination of reference genes for adrenals had sex differences, and females were GAPDH + ß-actin, while males were GAPDH + SDHA. In PCE model, the optimal combination of reference genes was consistent with physiological conditions. Using combination of reference genes to analyze target genes can improve the accuracy of the results. In summary, this study provided reliable combination of reference genes for RT-qPCR and experimental supports for researches on adrenal development.


Assuntos
Glândulas Suprarrenais/crescimento & desenvolvimento , Organogênese/genética , Reação em Cadeia da Polimerase em Tempo Real , Padrões de Referência , Actinas/genética , Glândulas Suprarrenais/metabolismo , Animais , Cafeína/farmacologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Masculino , Ratos
5.
Life Sci ; 270: 119122, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33508294

RESUMO

The adrenal glands have striking morpho-biochemical features that render them vulnerable to the effects of toxins. AIMS: This study was conducted to explore the therapeutic utility of extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) against fluoride-induced adrenal toxicity. MATERIALS AND METHODS: The work included isolation and further identification of BMSC-EVs by transmission electron microscopy and flow cytometric analysis. Adrenal toxicity in rats was induced by oral administration of 300 ppm of sodium fluoride (NaF) in drinking water for 60 days followed by a single dose injection of BMSC-EVs. The effects of BMSC-EVs against NaF was evaluated by adrenal oxidant/antioxidant biomarkers, hormonal assay of plasma adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) and mRNA gene expression quantitation for adrenal cortical steroidogenic pathway-encoding genes. Histopathological examination of the adrenal tissue was performed. KEY FINDINGS: BMSC-EVs were effectively isolated and characterized. NaF exposure decreased adrenal superoxide dismutase and catalase activities, increased adrenal malondialdehyde levels, elevated plasma ACTH, diminished CORT concentrations and downregulated the adrenal cortical steroidogenic pathway-encoding genes. In addition, NaF-induced marked adrenal histopathological lesions. SIGNIFICANCE: BMSC-EVs treatment repaired damaged adrenal tissue and recovered its function greatly following NaF consumption. BMSC-EVs reversed the toxic effects of NaF and reprogramed injured adrenal cells by activating regenerative processes.


Assuntos
Glândulas Suprarrenais/metabolismo , Vesículas Extracelulares/transplante , Células-Tronco Mesenquimais/metabolismo , Animais , Células da Medula Óssea/citologia , Diferenciação Celular/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Feminino , Fluoretos/efeitos adversos , Fluoretos/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Microscopia Eletrônica de Transmissão/métodos , Ratos
6.
Methods Mol Biol ; 2233: 233-251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33222139

RESUMO

Fusion of vesicles with the plasma membrane and liberation of their contents is a multistep process involving several proteins. Correctly assigning the role of specific proteins and reactions in this cascade requires a measurement method with high temporal resolution. Patch-clamp recordings of cell membrane capacitance in combination with calcium measurements, calcium uncaging, and carbon-fiber amperometry allow for the accurate determination of vesicle pool sizes, their fusion kinetics, and their secreted oxidizable content. Here, we will describe this method in a model system for neurosecretion, the adrenal chromaffin cells, which secrete adrenaline.


Assuntos
Cálcio/metabolismo , Células Cromafins/metabolismo , Exocitose/genética , Técnicas de Patch-Clamp/métodos , Glândulas Suprarrenais/metabolismo , Animais , Sinalização do Cálcio/genética , Capacitância Elétrica , Cinética , Potenciais da Membrana/genética , Camundongos
7.
Radiol Clin North Am ; 58(6): 1099-1113, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33040851

RESUMO

Endocrine disorders associated with adrenal pathologies can be caused by insufficient adrenal gland function or excess hormone secretion. Excess hormone secretion may result from adrenal hyperplasia or hormone-secreting (ie, functioning) adrenal masses. Based on the hormone type, functioning adrenal masses can be classified as cortisol-producing tumors, aldosterone producing tumors, and androgen-producing tumors, which originate in the adrenal cortex, as well as catecholamine-producing pheochromocytomas, which originate in the medulla. Nonfunctioning lesions can cause adrenal gland enlargement without causing hormonal imbalance. Evaluation of adrenal-related endocrine disorders requires clinical and biochemical workup associated with imaging evaluation to reach a diagnosis and guide management.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Síndrome de Cushing/diagnóstico por imagem , Doenças do Sistema Endócrino/diagnóstico por imagem , Feocromocitoma/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Adrenalectomia/métodos , Aldosterona/metabolismo , Androgênios/metabolismo , Síndrome de Cushing/patologia , Doenças do Sistema Endócrino/fisiopatologia , Feminino , Humanos , Hidrocortisona/metabolismo , Masculino , Feocromocitoma/patologia , Prognóstico , Índice de Gravidade de Doença
9.
Chemosphere ; 260: 127565, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32758781

RESUMO

The effects of fluoride on endocrine tissues has not been sufficiently explored to date. The current body of knowledge suggest significant effects of that mineral on reducing sex hormone levels, which may consequently impair fertility and disrupt puberty. The majority of studies confirm that sodium fluoride increases TSH levels and decreases the concentrations of T3 and T4 produced by the thyroid. Moreover, a correlation was observed between NaF and increased secretion of PTH by the parathyroid glands, without a significant impact on body calcium levels. Probably, fluoride may exert adverse effects on insulin levels, impairing pancreatic function and resulting in abnormal glucose tolerance. Observations also include decreased levels of cortisol secreted by the adrenal glands. In light of the few existing studies, the mechanism of fluoride toxicity on the endocrine system has been described.


Assuntos
Sistema Endócrino/efeitos dos fármacos , Fluoretos/farmacologia , Glândulas Suprarrenais/metabolismo , Animais , Fluoretos/efeitos adversos , Fluoretos/toxicidade , Humanos , Hidrocortisona/metabolismo , Insulina/análise , Glândulas Paratireoides/efeitos dos fármacos , Glândulas Paratireoides/metabolismo , Fluoreto de Sódio/farmacologia , Fluoreto de Sódio/toxicidade , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo
10.
Eur J Endocrinol ; 183(4): 399-409, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698132

RESUMO

Context: Unilateral aldosteronomas should suppress renin and contralateral aldosterone secretion. Complete aldosterone suppression in contralateral adrenal vein sample (AVS) could predict surgical outcomes. Objectives: To retrospectively evaluate the prevalence of basal contralateral suppression using Aldosterone (A)contralateral(CL)/Aperipheral(P) as compared to (A/Cortisol(C)CL)/(A/C)P ratio in primary aldosteronism (PA) patients studied in two Canadian centers. To determine the best cut-off to predict clinical and biochemical surgical cure. To compare the accuracy of ACL/AP to the basal and post-ACTH lateralization index (LI) in predicting surgical cure. Methods: In total, 330 patients with PA and successful AVS were included; 124 lateralizing patients underwent surgery. Clinical and biochemical cure at 3 and 12 months were evaluated using the PASO criteria. Results: Using ACL/AP and (A/C)CL/(A/C)P at the cut-off of 1, the prevalence of contralateral suppression was 6 and 45%, respectively. Using ROC curves, the ACL/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)CL/(A/C)P is associated with biochemical cure only. The cut-offs for ACL/AP offering the best sensitivity (Se) and specificity (Sp) for clinical and biochemical cures at 12 months are 2.15 (Se: 63% and Sp: 71%) and 6.15 (Se: 84% and Sp: 77%), respectively. Basal LI and post-ACTH LI are associated with clinical cure but only the post-ACTH LI is associated with biochemical cure. Conclusions: In lateralized PA, basal contralateral suppression defined by ACL/AP is rare and incomplete compared to the (A/C)CL/(A/C)P ratio and is associated with clinical and biochemical postoperative outcome, but with modest accuracy.


Assuntos
Neoplasias das Glândulas Suprarrenais/sangue , Glândulas Suprarrenais/metabolismo , Adenoma Adrenocortical/sangue , Aldosterona/sangue , Coleta de Amostras Sanguíneas/métodos , Hiperaldosteronismo/sangue , Hiperaldosteronismo/epidemiologia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Glândulas Suprarrenais/patologia , Adrenalectomia/estatística & dados numéricos , Adenoma Adrenocortical/diagnóstico , Adenoma Adrenocortical/epidemiologia , Adenoma Adrenocortical/cirurgia , Adulto , Aldosterona/análise , Canadá/epidemiologia , Estudos de Coortes , Técnicas de Diagnóstico Endócrino , Regulação para Baixo , Feminino , Humanos , Hidrocortisona , Hiperaldosteronismo/patologia , Hiperaldosteronismo/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
11.
Nat Commun ; 11(1): 2673, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471973

RESUMO

Aldosterone, produced by the adrenals and under the control of plasma angiotensin and potassium levels, regulates hydromineral homeostasis and blood pressure. Here we report that the neuropeptide substance P (SP) released by intraadrenal nerve fibres, stimulates aldosterone secretion via binding to neurokinin type 1 receptors (NK1R) expressed by aldosterone-producing adrenocortical cells. The action of SP is mediated by the extracellular signal-regulated kinase pathway and involves upregulation of steroidogenic enzymes. We also conducted a prospective proof-of-concept, double blind, placebo-controlled clinical trial aimed to investigate the impact of the NK1R antagonist aprepitant on aldosterone secretion in healthy male volunteers (EudraCT: 2008-003367-40, ClinicalTrial.gov: NCT00977223). Participants received during two 7-day treatment periods aprepitant (125 mg on the 1st day and 80 mg during the following days) or placebo in a random order at a 2-week interval. The primary endpoint was plasma aldosterone levels during posture test. Secondary endpoints included basal aldosterone alterations, plasma aldosterone variation during metoclopramide and hypoglycaemia tests, and basal and stimulated alterations of renin, cortisol and ACTH during the three different stimulatory tests. The safety of the treatment was assessed on the basis of serum transaminase measurements on days 4 and 7. All pre-specified endpoints were achieved. Aprepitant decreases aldosterone production by around 30% but does not influence the aldosterone response to upright posture. These results indicate that the autonomic nervous system exerts a direct stimulatory tone on mineralocorticoid synthesis through SP, and thus plays a role in the maintenance of hydromineral homeostasis. This regulatory mechanism may be involved in aldosterone excess syndromes.


Assuntos
Aldosterona/sangue , Aprepitanto/farmacologia , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Adolescente , Córtex Suprarrenal/metabolismo , Glândulas Suprarrenais/metabolismo , Adulto , Aldosterona/metabolismo , Células Cultivadas , Humanos , Hipoglicemia/sangue , Masculino , Metoclopramida , Mineralocorticoides/biossíntese , Placebos/administração & dosagem , Estudo de Prova de Conceito , Estudos Prospectivos , Transaminases/sangue , Adulto Jovem
12.
PLoS One ; 15(5): e0233386, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437460

RESUMO

Salt is an essential nutrient; however, excessive salt intake is a prominent public health concern worldwide. Various physiological functions are associated with circadian rhythms, and disruption of circadian rhythms is a prominent risk factor for cardiovascular diseases, cancer, and immune disease. Certain nutrients are vital regulators of peripheral circadian clocks. However, the role of a high-fat and high-salt (HFS) diet in the regulation of circadian gene expression is unclear. This study aimed to investigate the effect of an HFS diet on rhythms of locomotor activity, caecum glucocorticoid secretion, and clock gene expression in mice. Mice administered an HFS diet displayed reduced locomotor activity under normal light/dark and constant dark conditions in comparison with those administered a normal diet. The diurnal rhythm of caecum glucocorticoid secretion and the expression levels of glucocorticoid-related genes and clock genes in the adrenal gland were disrupted with an HFS diet. These results suggest that an HFS diet alters locomotor activity, disrupts circadian rhythms of glucocorticoid secretion, and downregulates peripheral adrenal gland circadian clock genes.


Assuntos
Ritmo Circadiano/fisiologia , Dieta Hiperlipídica , Glucocorticoides/biossíntese , Atividade Motora/fisiologia , Cloreto de Sódio na Dieta , Glândulas Suprarrenais/metabolismo , Animais , Relógios Circadianos/fisiologia , Masculino , Camundongos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo
13.
Rev. esp. med. nucl. imagen mol. (Ed. impr.) ; 39(2): 84-91, mar.-abr. 2020. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-196348

RESUMO

OBJETIVO: Determinar las razones de los diferentes patrones de captación suprarrenal de la colina radiomarcada en pacientes con cáncer de próstata o renal sometidos a una tomografía por emisión de positrones/tomografía computarizada con 18F-Fluoroetilcolina (18F-Colina). MÉTODOS: Se analizaron 49 estudios de tomografía por emisión de positrones/tomografía computarizada con colina radiomarcada (96 glándulas suprarrenales), determinándose su morfología, el patrón de captación y el valor de captación máximo estandarizado. Se registraron, evaluaron o contabilizaron otros 15 parámetros más, se calcularon los índices de parámetros escogidos y se comprobó su correlación con la captación de las glándulas suprarrenales. RESULTADOS: Las glándulas suprarrenales presentaron un amplio abanico de intensidades de captación de la colina radiomarcada (rango: 2-7,9), así como diferentes patrones de captación (difuso, focal o mixto). La captación máxima en la glándula suprarrenal derecha (4,3+/-1,2) se correlacionó positivamente con el grosor del parénquima en su punto de captación máxima (5,3mm +/-1,5; p = 0,000). La captación máxima en las glándulas derecha e izquierda, así como la captación suprarrenal media se correlacionaron con la captación máxima en la hipófisis (p = 0,000, p = 0,000 y p=0001, respectivamente), así como con la captación máxima en hígado (p = 0,008, p = 0,000 y p = 0,011, respectivamente). En el grupo estudiado no hubo correlación significativa entre los valores de captación estandarizada de las glándulas suprarrenales y el tratamiento hormonal ni con la edad de los pacientes. CONCLUSIONES: La variabilidad de la captación del radiotrazador de la colina en las glándulas suprarrenales depende probablemente del metabolismo corporal global y de la función hipofisaria expresada a través de correlaciones estadísticamente significativas con la captación hepática e hipofisaria. En la tomografía por emisión de positrones de las glándulas suprarrenales normales, debe evaluarse con precaución aquellos patrones de captación predominantemente focales o mixtos con áreas de captación focal, con el fin de evitar errores diagnósticos


PURPOSE: To find reasons of different radioactive choline adrenal uptake in prostate or renal cancer patients who underwent 18F-fluoroethylcholine positron emission tomography/computed tomography. METHODS: Forty-nine positron emission tomography/computed tomography studies with radioactive choline (96 adrenal glands) were analysed with respect to the adrenal glands shape, uptake pattern and maximum standardised uptake value. Fifteen other parameters were recorded, assessed or counted, ratios of chosen parameters were calculated, and checked for correlation with adrenal glands uptake. RESULTS: Adrenal glands presented a wide range of radioactive choline uptake intensities (range 2-7.9) and different uptake patterns (diffuse, focal or mixed). Maximum uptake in the right (4.3+/-1.2) adrenal gland positively correlated with the thickness of the parenchyma at the point of maximal uptake (5.3mm+/-1.5) (p = 0.000). Maximum uptake in the right and left adrenal gland, as well as mean adrenal gland uptake, correlated with maximum uptake in the pituitary gland (p = 0.000, p = 0.000 and p = 0.001, respectively) and with maximum uptake in liver (p = 0.008, p = 0.000 and p = 0.011, respectively). Neither hormonal treatment nor patients' age significantly correlated with standardised uptake values of adrenal glands in the studied group. CONCLUSIONS: The variability of radiocholine uptake in adrenal glands depends probably on overall body metabolism and hypophyseal function expressed by statistically significant correlation with liver and pituitary gland uptake. Predominant focal or mixed with focal areas uptake patterns on positron emission tomography in normal in computed tomography adrenal glands should be assessed with caution to avoid a diagnostic mistake


Assuntos
Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Glândulas Suprarrenais/diagnóstico por imagem , Colina/análogos & derivados , Radioisótopos de Flúor/farmacocinética , Tomografia Computadorizada por Raios X , Glândulas Suprarrenais/anatomia & histologia , Glândulas Suprarrenais/metabolismo , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/metabolismo , Colina/farmacocinética , Fígado/diagnóstico por imagem , Fígado/metabolismo , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X/métodos , Estudos Retrospectivos
14.
Am J Physiol Regul Integr Comp Physiol ; 318(5): R855-R869, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32186897

RESUMO

Angiotensin II (ANG II) Agtr1a receptor (AT1A) is expressed in cells of the arcuate nucleus of the hypothalamus that express the leptin receptor (Lepr) and agouti-related peptide (Agrp). Agtr1a expression in these cells is required to stimulate resting energy expenditure in response to leptin and high-fat diets (HFDs), but the mechanism activating AT1A signaling by leptin remains unclear. To probe the role of local paracrine/autocrine ANG II generation and signaling in this mechanism, we bred mice harboring a conditional allele for angiotensinogen (Agt, encoding AGT) with mice expressing Cre-recombinase via the Lepr or Agrp promoters to cause cell-specific deletions of Agt (AgtLepr-KO and AgtAgrp-KO mice, respectively). AgtLepr-KO mice were phenotypically normal, arguing against a paracrine/autocrine AGT signaling mechanism for metabolic control. In contrast, AgtAgrp-KO mice exhibited reduced preweaning survival, and surviving adults exhibited altered renal structure and steroid flux, paralleling previous reports of animals with whole body Agt deficiency or Agt disruption in albumin (Alb)-expressing cells (thought to cause liver-specific disruption). Surprisingly, adult AgtAgrp-KO mice exhibited normal circulating AGT protein and hepatic Agt mRNA expression but reduced Agt mRNA expression in adrenal glands. Reanalysis of RNA-sequencing data sets describing transcriptomes of normal adrenal glands suggests that Agrp and Alb are both expressed in this tissue, and fluorescent reporter gene expression confirms Cre activity in adrenal gland of both Agrp-Cre and Alb-Cre mice. These findings lead to the iconoclastic conclusion that extrahepatic (i.e., adrenal) expression of Agt is critically required for normal renal development and survival.


Assuntos
Glândulas Suprarrenais/metabolismo , Proteína Relacionada com Agouti/metabolismo , Angiotensinogênio/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Metabolismo Energético , Rim/metabolismo , Receptores para Leptina/metabolismo , Glândulas Suprarrenais/crescimento & desenvolvimento , Proteína Relacionada com Agouti/deficiência , Proteína Relacionada com Agouti/genética , Angiotensinogênio/deficiência , Angiotensinogênio/genética , Animais , Núcleo Arqueado do Hipotálamo/crescimento & desenvolvimento , Comunicação Autócrina , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Rim/crescimento & desenvolvimento , Masculino , Camundongos Knockout , Miocárdio/metabolismo , Comunicação Parácrina , Receptores para Leptina/deficiência , Receptores para Leptina/genética , Albumina Sérica/genética , Albumina Sérica/metabolismo , Transdução de Sinais
15.
J Virol ; 94(11)2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32213610

RESUMO

Ebola virus (EBOV) continues to pose a significant threat to human health, as evidenced by the 2013-2016 epidemic in West Africa and the ongoing outbreak in the Democratic Republic of the Congo. EBOV causes hemorrhagic fever, organ damage, and shock culminating in death, with case fatality rates as high as 90%. This high lethality combined with the paucity of licensed medical countermeasures makes EBOV a critical human pathogen. Although EBOV infection results in significant damage to the liver and the adrenal glands, little is known about the molecular signatures of injury in these organs. Moreover, while changes in peripheral blood cells are becoming increasingly understood, the host responses within organs and lymphoid tissues remain poorly characterized. To address this knowledge gap, we tracked longitudinal transcriptional changes in tissues collected from EBOV-Makona-infected cynomolgus macaques. Following infection, both liver and adrenal glands exhibited significant and early downregulation of genes involved in metabolism, coagulation, hormone synthesis, and angiogenesis; upregulated genes were associated with inflammation. Analysis of lymphoid tissues showed early upregulation of genes that play a role in innate immunity and inflammation and downregulation of genes associated with cell cycle and adaptive immunity. Moreover, transient activation of innate immune responses and downregulation of humoral immune responses in lymphoid tissues were confirmed with flow cytometry. Together, these data suggest that the liver, adrenal gland, and lymphatic organs are important sites of EBOV infection and that dysregulating the function of these vital organs contributes to the development of Ebola virus disease.IMPORTANCE Ebola virus (EBOV) remains a high-priority pathogen since it continues to cause outbreaks with high case fatality rates. Although it is well established that EBOV results in severe organ damage, our understanding of tissue injury in the liver, adrenal glands, and lymphoid tissues remains limited. We begin to address this knowledge gap by conducting longitudinal gene expression studies in these tissues, which were collected from EBOV-infected cynomolgus macaques. We report robust and early gene expression changes within these tissues, indicating they are primary sites of EBOV infection. Furthermore, genes involved in metabolism, coagulation, and adaptive immunity were downregulated, while inflammation-related genes were upregulated. These results indicate significant tissue damage consistent with the development of hemorrhagic fever and lymphopenia. Our study provides novel insight into EBOV-host interactions and elucidates how host responses within the liver, adrenal glands, and lymphoid tissues contribute to EBOV pathogenesis.


Assuntos
Glândulas Suprarrenais , Ebolavirus , Regulação Viral da Expressão Gênica/imunologia , Doença pelo Vírus Ebola , Fígado , Tecido Linfoide , Doenças dos Macacos , Transcrição Genética/imunologia , Glândulas Suprarrenais/imunologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/virologia , Animais , Ebolavirus/imunologia , Ebolavirus/metabolismo , Feminino , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/metabolismo , Doença pelo Vírus Ebola/patologia , Doença pelo Vírus Ebola/veterinária , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Tecido Linfoide/virologia , Macaca fascicularis , Masculino , Doenças dos Macacos/imunologia , Doenças dos Macacos/metabolismo , Doenças dos Macacos/patologia , Doenças dos Macacos/virologia
16.
Nat Rev Endocrinol ; 16(5): 284-296, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32203405

RESUMO

The adrenal gland is a source of sex steroid precursors, and its activity is particularly relevant during fetal development and adrenarche. Following puberty, the synthesis of androgens by the adrenal gland has been considered of little physiologic importance. Dehydroepiandrosterone (DHEA) and its sulfate, DHEAS, are the major adrenal androgen precursors, but they are biologically inactive. The second most abundant unconjugated androgen produced by the human adrenals is 11ß-hydroxyandrostenedione (11OHA4). 11-Ketotestosterone, a downstream metabolite of 11OHA4 (which is mostly produced in peripheral tissues), and its 5α-reduced product, 11-ketodihydrotestosterone, are bioactive androgens, with potencies equivalent to those of testosterone and dihydrotestosterone. These adrenal-derived androgens all share an oxygen atom on carbon 11, so we have collectively termed them 11-oxyandrogens. Over the past decade, these androgens have emerged as major components of several disorders of androgen excess, such as congenital adrenal hyperplasia, premature adrenarche and polycystic ovary syndrome, as well as in androgen-dependent tumours, such as castration-resistant prostate cancer. Moreover, in contrast to the more extensively studied, traditional androgens, circulating concentrations of 11-oxyandrogens do not demonstrate an age-dependent decline. This Review focuses on the rapidly expanding knowledge regarding the implications of 11-oxyandrogens in human physiology and disease.


Assuntos
Glândulas Suprarrenais/metabolismo , Androgênios/metabolismo , Doenças do Sistema Endócrino/metabolismo , Hiperplasia Suprarrenal Congênita/metabolismo , Androgênios/química , Feminino , Humanos , Masculino , Oxigênio/química , Síndrome do Ovário Policístico/metabolismo , Neoplasias da Próstata/metabolismo , Puberdade Precoce/metabolismo
17.
J Vis Exp ; (156)2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32150172

RESUMO

Immunostaining is widely used in biomedical research to show the cellular expression pattern of a given protein. Multiplex immunostaining allows labeling using multiple primary antibodies. To minimize antibody cross-reactivity, multiplex immunostaining using indirect staining requires unlabeled primary antibodies from different host species. However, the appropriate combination of different species antibodies is not always available. Here, we describe a method of using unlabeled primary antibodies from the same host species (e.g., in this case both antibodies are from rabbit) for multiplex immunofluorescence on formalin-fixed paraffin-embedded (FFPE) mouse adrenal sections. This method uses the same procedure and reagents used in the antigen retrieval step to strip the activity of the previously stained primary antibody complex. Slides were stained with the first primary antibody using a general immunostaining protocol followed by a binding step with a biotinylated secondary antibody. Then, an avidin-biotin-peroxidase signal development method was used with fluorophore-tyramide as the substrate. The immunoactivity of the first primary antibody complex was stripped through immersion in a microwaved boiling sodium citrate solution for 8 min. The insoluble fluorophore-tyramide deposition remained on the sample, which allowed the slide to be stained with other primary antibodies. Although this method eliminates most false positive signals, some background from antibody cross-reactivity may remain. If the samples are enriched with endogenous biotin, a peroxidase-conjugated secondary antibody may be used to replace the biotinylated secondary antibody to avoid the false positive from recovered endogenous biotin.


Assuntos
Glândulas Suprarrenais/metabolismo , Anticorpos Monoclonais/imunologia , Corantes Fluorescentes/química , Técnicas Imunoenzimáticas/métodos , Micro-Ondas , Tiramina/análogos & derivados , 3-Hidroxiesteroide Desidrogenases/imunologia , Glândulas Suprarrenais/imunologia , Animais , Biotinilação , Sistema Enzimático do Citocromo P-450/imunologia , Imunofluorescência , Humanos , Camundongos , Peroxidase/metabolismo , Coelhos , Coloração e Rotulagem , Tiramina/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-32169652

RESUMO

The contribution of individual lipoprotein species to the generation of the adrenal cholesterol pool used for the synthesis of anti-inflammatory glucocorticoid species remains unknown. Here we examined the impact of specific lowering of very low-density lipoprotein (VLDL) and low-density (LDL) levels on adrenal cholesterol and glucocorticoid homeostasis. Hereto, lethally-irradiated hypercholesterolemic apolipoprotein E (APOE) knockout mice received APOE-containing bone marrow from wild-type mice (n = 6) or APOE knockout control bone marrow (n = 10) and were subsequently fed a regular chow diet. Transplantation with wild-type bone marrow was associated with a 10-fold decrease in VLDL/LDL-cholesterol levels. No changes were observed in adrenal weights, adrenal cholesterol content, or basal plasma corticosterone levels. However, food deprivation-induced corticosterone secretion was 64% lower (P < 0.05) in wild-type bone marrow recipients as compared to APOE knockout bone marrow recipients, in the context of similar plasma adrenocorticotropic hormone (ACTH) levels. A parallel 19-29% decrease in adrenal relative mRNA expression levels of ACTH-responsive genes SR-BI (P < 0.01), STAR (P < 0.05), and CYP11A1 (P < 0.05) was detected. In support of relative glucocorticoid insufficiency, blood lymphocyte and eosinophil concentrations were respectively 2.4-fold (P < 0.01) and 8-fold (P < 0.001) higher in wild-type bone marrow recipients under food deprivation stress conditions. In conclusion, we have shown that a selective lowering of VLDL/LDL levels in APOE knockout mice through a transplantation with APOE-containing wild-type bone marrow is associated with a decreased maximal adrenal glucocorticoid output. Our studies provide experimental support for the hypothesis that, in vivo, VLDL/LDL serves as the primary source of cholesterol used for glucocorticoid synthesis during food deprivation stress.


Assuntos
Glândulas Suprarrenais/metabolismo , Colesterol/metabolismo , Privação de Alimentos , Glucocorticoides/metabolismo , Hipercolesterolemia/metabolismo , Lipoproteínas VLDL/metabolismo , Animais , Apolipoproteínas E/genética , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Eur J Endocrinol ; 182(3): 265-273, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32038030

RESUMO

Objectives: We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA). Design: Multicenter retrospective study by Japan PA study. Method: We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI <2 with ACTH-stimulated LI ≥4 (Bilateral (B) to U group, n = 15); and basal LI ≥2 with ACTH-stimulated LI <4 (U to B group, n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria. Results: Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI. Conclusions: Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group.


Assuntos
Glândulas Suprarrenais/metabolismo , Cosintropina/farmacologia , Hiperaldosteronismo/cirurgia , Adenoma/patologia , Neoplasias das Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/efeitos dos fármacos , Adrenalectomia , Adenoma Adrenocortical/patologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Sensibilidade e Especificidade , Resultado do Tratamento
20.
PLoS One ; 15(2): e0218910, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32069307

RESUMO

We previously showed that postmortem serum levels of adrenocorticotropic hormone (ACTH) were significantly higher in cases of hypothermia (cold exposure) than other causes of death. This study examined how the human hypothalamic-pituitary-adrenal axis, and specifically cortisol, responds to hypothermia. Human samples: Autopsies on 205 subjects (147 men and 58 women; age 15-98 years, median 60 years) were performed within 3 days of death. Cause of death was classified as either hypothermia (cold exposure, n = 14) or non-cold exposure (controls; n = 191). Cortisol levels were determined in blood samples obtained from the left and right cardiac chambers and common iliac veins using a chemiluminescent enzyme immunoassay. Adrenal gland tissues samples were stained for cortisol using a rabbit anti-human polyclonal antibody. Cell culture: AtT20, a mouse ACTH secretory cell line, and Y-1, a corticosterone secretory cell line derived from a mouse adrenal tumor, were analyzed in mono-and co-culture, and times courses of ACTH (in AtT20) and corticosterone (in Y-1) secretion were assessed after low temperature exposure mimicking hypothermia and compared with data for samples collected postmortem for other cases of death. However, no correlation between ACTH concentration and cortisol levels was observed in hypothermia cases. Immunohistologic analyses of samples from hypothermia cases showed that cortisol staining was localized primarily to the nucleus rather than the cytoplasm of cells in the zona fasciculata of the adrenal gland. During both mono-culture and co-culture, AtT20 cells secreted high levels of ACTH after 10-15 minutes of cold exposure, whereas corticosterone secretion by Y-1 cells increased slowly during the first 15-20 minutes of cold exposure. Similar to autopsy results, no correlation was detected between ACTH levels and corticosterone secretion, either in mono-culture or co-culture experiments. These results suggested that ACTH-independent cortisol secretion may function as a stress response during cold exposure.


Assuntos
Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Hidrocortisona/metabolismo , Hipotermia/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade
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