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Biomedical subjects

George P Chrousos

Publications and source records attributed to George P Chrousos.

At least 19 recordsLinked to original sources
PubMed2006

Adrenal function improves in asthmatic children on inhaled steroids: a longitudinal study.

BACKGROUND/AIMS: Asthmatic children on long-term treatment with inhaled corticosteroids (ICS) may exhibit mild adrenal suppression. We aimed to test the hypothesis that baseline adrenal function of some asthmatic children might be lower than that of others and that this difference might be accentuated by ICS therapy. METHODS: A low-dose Synacthen test was performed in 41 prepubertal asthmatic children placed on long-term inhaled budesonide (400 microg/day) prior to the onset of ICS treatment, 6 and 12 months later. Five children withdrew before the 6- and another 2 before the 12-month follow-up. RESULTS: Low adrenal function was demonstrated in 4 children (9.8%) upon recruitment and in another 8 at the 6-month evaluation (22.2%). Adrenal function normalized in the aforementioned 4 children at the 6-month evaluation, while 6 (17.6%) exhibited suppressed adrenal function at the 12-month evaluation. Three of these patients had also exhibited adrenal suppression at the 6-month visit. A significant improvement in peak cortisol values from baseline to the 6- and 12-month evaluation (95% confidence intervals: -283.9 to -69.0 and -239.8 to -50.8, respectively) was evident when children with suppressed adrenal response at the second or third evaluation were excluded. CONCLUSIONS: In many asthmatic children, adrenal response improves on long-term ICS. The expected adrenal suppression of certain patients on maintenance ICS appears to constitute a separate phenomenon.

Administration, Inhalation↗
PubMed2006

Puberty-related influences on brain development.

Puberty is a time of striking changes in cognition and behavior. To indirectly assess the effects of puberty-related influences on the underlying neuroanatomy of these behavioral changes we will review and synthesize neuroimaging data from typically developing children and adolescents and from those with anomalous hormone or sex chromosome profiles. The trajectories (size by age) of brain morphometry differ between boys and girls, with girls generally reaching peak gray matter thickness 1-2 years earlier than boys. Both boys and girls with congenital adrenal hyperplasia (characterized by high levels of intrauterine testosterone), have smaller amygdala volume but the brain morphometry of girls with CAH did not otherwise significantly differ from controls. Subjects with XXY have gray matter reductions in the insula, temporal gyri, amygdala, hippocampus, and cingulate-areas consistent with the language-based learning difficulties common in this group.

Adolescent↗
PubMed2006

Hormonal and cytokine regulation of early implantation.

Implantation of the blastocyst into the endometrium is a delicately controlled process and a prerequisite for the furtherance of the mammalian species. A complex network of molecules is involved in preparing both the endometrium and blastocyst for a successful interaction. However, the exact molecular steps are poorly understood. Studies so far have shown that disruption of certain pathways results in fertility defects. Impaired implantation is currently considered to be the most important limiting factor for the establishment of viable pregnancies in assisted reproduction. It is expected that elucidating the molecular background of the process will enable accurate diagnosis and effective treatment of infertility.

Animals↗
PubMed2006

Morphological and binding properties of interleukin-6 on thin ZnO films grown on (100) silicon substrates for biosensor applications.

To develop effective protein immobilization technology with minimal amounts of protein for high sensitivity surface acoustic wave biosensors, we determined the binding properties, and morphological characteristics of human interleukin-6 (IL-6), a pro-inflammatory cytokine, on the surface of ZnO, and SiO(2) films grown onto (100) Si substrates, for the first time. Interleukin-6 was immobilized in the range of 0.276-10 pg/ml on the surface of ZnO and SiO(2), and visualized at each stage, while protein-protein interactions were measured with the antigen/antibody immunoassay of solid-phase ELISA, which we modified for these types of substrates. A relative mass value was determined in each case. ELISA detected upward of 1 and 6 ng/ml of protein applied on ZnO and SiO(2), respectively. It is concluded that the more reactive ZnO surface is a new and more effective template for protein immobilization.

Binding Sites↗
PubMed2006

Premature ovarian failure, endothelial dysfunction and estrogen-progestogen replacement.

Cardiovascular disease, including coronary artery disease, stroke and peripheral vascular disease, is the leading cause of death among women. Vascular endothelial dysfunction is an early marker of atherosclerosis. Women with premature ovarian failure (or premature menopause) present an increased risk for cardiovascular disease, which might be attributed to the early onset of vascular endothelial dysfunction, associated with sex steroid deficiency. Cyclical estrogen and progestogen therapy has been shown to restore endothelial function in these young women. Further research is required to assess primarily the long-term effects of hormone replacement therapy on cardiovascular and overall prognosis in young women with premature ovarian failure, as well as the effects of different doses, duration and routes of hormone administration in these women.

Adult↗
PubMed2006

Rho family Guanine nucleotide exchange factor Brx couples extracellular signals to the glucocorticoid signaling system.

Glucocorticoids regulate many crucial biologic functions through their cytoplasmic/nuclear glucocorticoid receptors (GR). Excess, deficiency, or alteration in tissue sensitivity to glucocorticoids has been associated with major causes of human morbidity and mortality. Brx, a cytoplasmic Rho family guanine nucleotide exchange factor, binds to and influences the activity of several nuclear hormone receptors. We examined the functional and molecular interactions between GR and Brx. The glucocorticoid sensitivity of lymphocytes obtained from mice haplo-insufficient for Brx was significantly decreased. Conversely, GR-mediated transcriptional activity of a glucocorticoid response element (GRE)-mediated glucocorticoid-responsive promoter was enhanced by Brx in a guanine nucleotide exchange factor domain-dependent fashion. Brx interacted with GR, forming a ternary complex with RhoA. In a chromatin immunoprecipitation assay, Brx and RhoA were co-precipitated with GREs only in the presence of ligand-activated GR. Extracellularly administered lysophosphatidic acid, which activates its signaling cascade through a specific membrane GTP-binding protein (G-protein)-coupled receptor in a G-protein alpha(13)-, Brx-, and RhoA-dependent fashion, enhanced GR transcriptional activity, whereas depletion of endogenous Brx attenuated this effect. These findings suggest that glucocorticoid signaling and, hence, the tissue sensitivity to glucocorticoids, may be coupled to extracellular signals via Brx and small G-proteins. Nuclear Brx might act as a local GRE-GR-transcriptosome activator by mediating the effect of small G-proteins on glucocorticoid-regulated genes.

A Kinase Anchor Proteins↗
PubMed2006

Functional characterization of the natural human glucocorticoid receptor (hGR) mutants hGRalphaR477H and hGRalphaG679S associated with generalized glucocorticoid resistance.

BACKGROUND: Glucocorticoid resistance is often a result of mutations in the human glucocorticoid receptor alpha (hGRalpha) gene, which impair one or more of hGRalpha's functions. We investigated the molecular mechanisms through which two previously described mutant receptors, hGRalphaR477H and hGRalphaG679S, with amino acid substitutions in the DNA- and ligand-binding domains, respectively, affect glucocorticoid signal transduction. METHODS AND RESULTS: In transient transfection assays, hGRalphaR477H displayed no transcriptional activity, whereas hGRalphaG679S showed a 55% reduction in its ability to stimulate the transcription of the glucocorticoid-responsive mouse mammary tumor virus promoter in response to dexamethasone compared with the wild-type hGRalpha. Neither hGRalphaR477H nor hGRalphaG679S exerted a dominant negative effect upon the wild-type receptor. Dexamethasone binding assays showed that hGRalphaR477H preserved normal affinity for the ligand, whereas hGRalphaG679S displayed a 2-fold reduction compared with hGRalpha. Nuclear translocation studies confirmed predominantly cytoplasmic localization of the mutant receptors in the absence of ligand. Exposure to dexamethasone resulted in slower translocation of hGRalphaR477H (25 min) and hGRalphaG679S (30 min) into the nucleus than the wild-type hGRalpha (12 min). In chromatin immunoprecipitation assays in cells stably transfected with the mouse mammary tumor virus promoter, hGRalphaR477H did not bind to glucocorticoid-response elements, whereas hGRalphaG679S preserved its ability to bind to glucocorticoid-response elements. Finally, in glutathione-S-transferase pull-down assays, hGRalphaG679S interacted with the glucocorticoid receptor-interacting protein 1 coactivator in vitro only through its activation function (AF)-1, unlike the hGRalphaR477H and hGRalpha, which interacted with the glucocorticoid receptor-interacting protein 1 through both their AF-1 and AF-2. CONCLUSIONS: The natural mutants hGRalphaR477H and hGRalphaG679S cause generalized glucocorticoid resistance by affecting different functions of the glucocorticoid receptor, which span the cascade of the hGR signaling system.

Amino Acid Sequence↗
PubMed2006

Hypertension in Cushing's syndrome.

Cushing's syndrome can be exogenous, resulting from the administration of glucocorticoids or adrenocorticotrophic hormone (ACTH), or endogenous, secondary to increased secretion of cortisol or ACTH. Hypertension is one of the most distinguishing features of endogenous Cushing's syndrome, as it is present in about 80% of adult patients and in almost half of children and adolescents patients. Hypertension results from the interplay of several pathophysiological mechanisms regulating plasma volume, peripheral vascular resistance and cardiac output, all of which may be increased. The therapeutic goal is to find and remove the cause of excess glucocorticoids, which, in most cases of endogenous Cushing's syndrome, is achieved surgically. Treatment of Cushing's syndrome usually results in resolution or amelioration of hypertension. However, some patients may not achieve normotension or may require a prolonged period of time for the correction of hypercortisolism. Therefore, therapeutic strategies for Cushing's-specific hypertension (to normalise blood pressure and decrease the duration of hypertension) are necessary to decrease the morbidity and mortality associated with this disorder. The various pathogenetic mechanisms that have been proposed for the development of glucocorticoid-induced hypertension in Cushing's syndrome and its management are discussed.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2006

Plasma interleukin 6 levels are elevated in polycystic ovary syndrome independently of obesity or sleep apnea.

Premenopausal women with polycystic ovary syndrome (PCOS) are at a much higher risk for excessive daytime sleepiness, fatigue, and insulin resistance than control women. Elevated levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) are presumably part of the pathogenesis of these clinical manifestations. Forty-two obese women with PCOS, 17 body mass index-comparable obese controls, and 15 normal-weight controls free from apnea participated in the study that included one 8-hour nighttime polysomnography, single morning cytokine plasma concentrations, and insulin resistance indices. Women with PCOS exhibited higher plasma concentrations of IL-6 than obese controls, who had intermediate values, or normal-weight controls, who had the lowest values (4.75 +/- 0.5 vs 3.65 +/- 0.4 vs 1.84 +/- 0.3 pg/mL, P < .01). Tumor necrosis factor alpha values were higher in PCOS and obese controls compared with normal-weight controls, but the difference was not statistically significant (4.05 +/- 0.3 vs 3.79 +/- 0.2 vs 3.14 +/- 0.2 pg/mL, P = .103). Based on backward regression analysis, IL-6 levels had a stronger association with the PCOS group than with the obese group, and the sleep or hypoxia variables did not make a significant contribution to either IL-6 or TNF-alpha. Both IL-6 and TNF-alpha correlated positively with body mass index (P < .01) in obese controls but not in women with PCOS. Furthermore, within the PCOS group, IL-6 and TNF-alpha correlated more strongly with indices of insulin resistance than obesity. We conclude that IL-6 levels are elevated in obese women with PCOS independently of obesity or sleep apnea and may represent a pathophysiologic link to insulin resistance.

Adult↗
PubMed2006

Assessment of metabolic profile in a clinical setting.

PURPOSE OF REVIEW: The metabolic syndrome, a clustering of abnormalities such as hyperglycemia, insulin resistance, hypertension, dyslipidemia, and central obesity, is a principal risk factor for cardiovascular disease, the leading cause of morbidity and mortality in the Western world. There are several definitions of the metabolic syndrome, all aiming at including as many persons at risk as possible. The assessment and, hence, the identification of such persons in a clinical setting is of utmost importance. RECENT FINDINGS: Clinicians should document the presence of central obesity, assessed by waist circumference measurement or determination of body composition using dual X-ray absorptiometry or measurement of visceral fat using computed tomography or magnetic resonance imaging. The presence of dyslipidemia, insulin resistance, and arterial hypertension constitutes the full profile of the metabolic syndrome. Nevertheless, elevated uric acid levels or presence of nonalcoholic fatty liver, or the diagnosis of the polycystic ovary syndrome in women of reproductive age, all are reflected in high risk of later occurrence of the full metabolic syndrome and atherosclerotic cardiovascular disease. SUMMARY: Although no unified definition for the metabolic syndrome exists, it is important to identify persons at risk, in order to reduce the resultant high morbidity and mortality rates.

Adipose Tissue↗
PubMed2006

Corticotropin-releasing hormone modulates human trophoblast invasion through carcinoembryonic antigen-related cell adhesion molecule-1 regulation.

Abnormalities in the process of trophoblast invasion may result in abnormal placentation. Both the embryonic trophoblast and maternal decidua produce corticotropin-releasing hormone (CRH), which promotes implantation. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is expressed in extravillous trophoblasts (EVTs) of normal human placenta, may also function in tro-phoblast/endometrial interactions. We investigated whether locally produced CRH plays a role in trophoblast invasion, primarily by regulating CEACAM1 expression. We examined cultures of freshly isolated human EVTs, which express CEACAM1, and an EVT-based hybridoma cell line, which is devoid of endogenous CEACAM1. CRH inhibited EVT invasion in Matrigel invasion assays, and this effect was blocked by the CRH receptor type 1 (CRHR1)-specific antagonist antalarmin. Additionally, CRH decreased CEACAM1 expression in EVTs in a dose-dependent manner. After transfection of the hybridoma cell line with a CEACAM1 expression vector, the invasiveness of these cells was strongly enhanced. This effect was inhibited by addition of blocking monoclonal antibody against CEACAM1. Furthermore, blocking of endogenous CEACAM1 in EVTs inhibited the invasive potential of these cells. Taken together these findings suggest that CRH inhibits trophoblast invasion by decreasing the expression of CEACAM1 through CRHR1, an effect that might be involved in the pathophysiology of clinical conditions, such as preeclampsia and placenta accreta.

Antigens, CD↗
PubMed2005

The Smad6-histone deacetylase 3 complex silences the transcriptional activity of the glucocorticoid receptor: potential clinical implications.

Glucocorticoids play pivotal roles in the maintenance of homeostasis but, when dysregulated, may also have deleterious effects. Smad6, one of the transforming growth factor beta (TGFbeta) family downstream transcription factors, interacts with the N-terminal domain of the glucocorticoid receptor (GR) through its Mad homology 2 domain and suppresses GR-mediated transcriptional activity in vitro. Adenovirus-mediated Smad6 overexpression inhibits glucocorticoid action in rat liver in vivo, preventing dexamethasone-induced elevation of blood glucose levels and hepatic mRNA expression of phosphoenolpyruvate carboxykinase, a well known rate-limiting enzyme of liver gluconeogenesis. Smad6 suppresses GR-induced transactivation by attracting histone deacetylase 3 to DNA-bound GR and by antagonizing acetylation of histone H3 and H4 induced by p160 histone acetyltransferase. These results indicate that Smad6 regulates glucocorticoid actions as a corepressor of the GR. From our results and known cross-talks between glucocorticoids and TGFbeta family molecules, it appears that the anti-glucocorticoid actions of Smad6 may contribute to the neuroprotective, anticatabolic and pro-wound healing properties of the TGFbeta family of proteins.

Acetylation↗
PubMed2005

Evaluation of estrogenic/antiestrogenic activity of ellagic acid via the estrogen receptor subtypes ERalpha and ERbeta.

Ellagic acid is a plant-derived polyphenol, possessing antioxidant, antiproliferative, and antiatherogenic properties. Whether this compound has estrogenic/antiestrogenic activity, however, remains largely unknown. To answer this question, we first investigated the ability of ellagic acid to influence the activity of the estrogen receptor subtypes ERalpha and ERbeta in HeLa cells. Cells co-transfected with an estrogen response element (ERE)-driven luciferase (Luc) reporter gene and an ERalpha- or ERbeta-expression vector were exposed to graded concentrations of ellagic acid. At low concentrations (10(-7) to 10(-9) M), this compound displayed a small but significant estrogenic activity via ERalpha, whereas it was a complete estrogen antagonist via ERbeta. Further evaluation revealed that ellagic acid was a potent antiestrogen in MCF-7 breast cancer-derived cells, increasing, like the pure estrogen antagonist ICI182780, IGFBP-3 levels. Moreover, ellagic acid induced nodule mineralization in an osteoblastic cell line (KS483), an effect that was abolished by the estrogen antagonist. Endometrium-derived epithelial cells (Ishikawa) showed no response to the natural compound by using a cell viability assay (MTT). These findings suggest that ellagic acid may be a natural selective estrogen receptor modulator (SERM).

Breast Neoplasms↗
PubMed2005

Intracellular glucocorticoid signaling: a formerly simple system turns stochastic.

Glucocorticoids contribute fundamentally to the maintenance of basal and stress-related homeostasis in all higher organisms. The major roles of these steroids in physiology are amply matched by their remarkable contributions to pathology. Glucocorticoids influence about 20% of the expressed human genome, and their effects spare almost no organs or tissues. For many years we thought that the numerous actions of glucocorticoids were mediated by a single receptor molecule: the classic glucocorticoid receptor (GR) isoform alpha, a complex, multifunctional domain protein, operating as a ligand-dependent transcription factor. The GR gene, however, encodes two 3' splicing variants, GRalpha and GRbeta, from alternative use of two distinct terminal exons (9alpha and 9beta), and each variant mRNA is translated from at least eight initiation sites into multiple GRalpha and possibly GRbeta isoforms, amounting to a minimum of 16 GR monomers and 256 different homo- or heterodimers. The translational GRalpha isoforms may be produced variably in target tissues, have varying intrinsic transcriptional activities, and influence different complements of glucocorticoid-responsive genes. It is likely that expression and functional differences might also be present between the putative GRbeta translational isoforms. The presence of multiple GR monomers and dimers in different quantities with quantitatively and qualitatively different transcriptional activities suggests that the glucocorticoid signaling system is highly stochastic.

Alternative Splicing↗
PubMed2005

Acteoside and martynoside exhibit estrogenic/antiestrogenic properties.

Acteoside and martynoside are plant phenylpropanoid glycosides exhibiting anticancer, cytotoxic and antimetastatic activities. We investigated their potential to activate estrogen receptor isoforms ERalpha and ERbeta in HeLa cells transfected with an estrogen response element (ERE)-driven luciferase (Luc) reporter gene and an ERalpha or ERbeta expression vector. Their estrogenic/antiestrogenic effects were also assessed in breast cancer cells (MCF7), endometrial cancer cells (Ishikawa) and osteoblasts (KS483), by measuring IGFBP3 levels, cell viability and number of mineralized nodules, respectively, seeking for a natural selective estrogen receptor modulator (SERM). Acteoside and martynoside antagonized both ERalpha and ERbeta (p<0.001), whereas they reversed the effect of E(2) mainly via ERalpha (p<0.001). Martynoside was a potent antiestrogen in MCF-7 cells, increasing, like ICI182780, IGFBP3 levels via the ER-pathway. In osteoblasts, martynoside induced nodule mineralization, which was abolished by ICI182780, implicating an ER-mediated mechanism. Furthermore, its antiproliferative effect on endometrial cells suggests that martynoside may be an important natural SERM. Acteoside was an antiestrogen in breast cancer cells and osteoblasts, without any effect on endometrial cells. Our study suggests that the nature is rich in selective ERalpha and ERbeta ligands, the discovery of which may lead to the development of novel neutraceutical agents.

Breast Neoplasms↗
PubMed2005

Circulating peptide YY concentrations are higher in preterm than full-term infants and correlate negatively with body weight and positively with serum ghrelin concentrations.

BACKGROUND: Peptide YY (PYY) and ghrelin are gastrointestinal tract-derived hormones that play roles in the regulation of food intake and energy balance. Negative energy balance often occurs in hospitalized preterm infants. METHODS: To measure serum concentrations of PYY in preterm and full-term infants and to investigate their correlations with anthropometric characteristics, food intake, and serum ghrelin concentrations, we measured serum PYY and ghrelin concentrations by RIA in 62 healthy preterm infants [mean (SD) gestational age, 32.0 (2.1) weeks; postnatal age, 40.9 (14.8) days] and 15 healthy full-term infants of comparable postnatal age. All of the infants were formula-fed every 3 h. RESULTS: PYY concentrations were significantly higher in preterm [1126.2 (215.4) ng/L] than in full-term infants [825.3 (234.4) ng/L; P < 0.001]. In the entire study population, serum PYY concentrations correlated negatively with gestational age and anthropometric measurements (birth weight, body weight, body length, body mass index, and head circumference) and positively with serum ghrelin concentrations, whereas there was no significant correlation between PYY concentration and caloric intake or weight gain. Multiple regression analysis, after correction for prematurity, revealed that serum PYY concentrations correlated independently with serum ghrelin concentrations and infant body weight or body mass index. CONCLUSIONS: Circulating concentrations of PYY may increase in preterm infants to compensate for the negative body-weight balance. The physiologic mechanisms behind the correlation between PYY and ghrelin remain to be elucidated.

Anthropometry↗